Abstract: OBJECTIVE: The aim of this study was to determine whether the type 2 diabetes-associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest. RESEARCH DESIGN AND METHODS: A total of 38 healthy young Caucasian men were studied before and after bed rest using the hyperinsulinemic-euglycemic clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. The TCF7L2 rs7903146 was genotyped using allelic discrimination performed with an ABI 7900 system. The genetic analyses were done assuming a dominant model of inheritance. RESULTS: The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise of FPIR in response to insulin resistance induced by bed rest was lower in carriers of the T-allele (P < 0.001). Fasting plasma glucagon levels were significantly lower in carriers of the T-allele before and after bed rest. While carriers of the CC genotype developed increased hepatic insulin resistance, the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest. CONCLUSIONS: Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance as induced by bed rest. Reduced paracrine glucagon stimulation may contribute to the impairment of beta-cell function in the carriers TCF7L2 rs7903146 T-allele associated with increased risk of type 2 diabetes.
Abstract: Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls. The basal rate of whole body lipolysis (WBL) was elevated in LBW subjects with and without correction for abdominal obesity before and after bed rest (all P = 0.01). Skeletal muscle hormone-sensitive lipase (HSL) protein expression and phosphorylation at Ser565 were similar in the two groups. Bed rest resulted in a decrease in WBL and an increased skeletal muscle HSL Ser565 phosphorylation indicating a decreased HSL activity in both groups. All subjects developed peripheral insulin resistance in response to bed rest (all P < 0.0001) with no differences between groups. LBW subjects developed hepatic insulin resistance in response to bed rest. In conclusion, increased WBL may contribute to the development of hepatic insulin resistance when exposed to bed rest in LBW subjects. Nine days of bed rest causes severe peripheral insulin resistance and reduced WBL and skeletal muscle HSL activity, as well as a compensatory increased insulin secretion, with no differences in LBW subjects and controls.
Abstract: BACKGROUND: Low birth weight (LBW) is associated with increased risk of type 2 diabetes and cardiovascular disease. We studied endothelial function and insulin sensitivity in young men with LBW (n = 22) and controls (n = 22). METHODS: Insulin sensitivity and endothelial function was studied with venous occlusion plethysmography and intra-arterial infusions of adenosine and acetylcholine, before and during a hyperinsulinemic isoglycemic clamp. RESULTS: Forearm blood flow response to systemic hyperinsulinemia was diminished in LBW compared to controls (p < 0.05). Fractional arteriovenous glucose extraction was similar, and consequently insulin-stimulated forearm glucose clearance was diminished in LBW compared with controls (0.8 +/- 0.09 vs. 1.4 +/- 0.36 ml x 100 ml(-1) x min(-1), respectively, p < 0.05). Forearm blood flow response to adenosine and acetylcholine with or without insulin stimulation did not differ between groups. Whole-body glucose uptake was lower in LBW than controls (8.7 +/- 0.5 and 9.1 +/- 0.6 mg x min(-1) x kg(-1) lean body mass); however, this was not significant. CONCLUSIONS: Forearm blood flow response to insulin is impaired in LBW, whereas the response to adenosine and acetylcholine is preserved. The impaired insulin-mediated increase in bulk flow in LBW may be due to an impairment of insulin-mediated capillary recruitment independent of - or preceding - whole-body insulin resistance in LBW subjects.
Abstract: Background: Physical inactivity is a known risk factor for type 2 diabetes. We studied whole body and forearm insulin sensitivity in subjects at increased risk for type 2 diabetes (persons with low birth weight (LBW) (n=20) and first degree relatives to type 2 diabetic patients (FDR) (n=13)) and a control group (CON) (n=20) group wise matched for BMI, age, and physical activity level before and after ten days of bed rest. Methods: The subjects were studied by hyperinsulinemic isoglycemic clamp combined with arterial and deep-venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Results: All groups responded with a decrease in whole body insulin sensitivity in response to bed rest (CON: 6.8+/-0.5 to 4.3+/-0.3, (P<0.0001), LBW: 6.2+/-0.5 to 4.3+/-0.3 (P<0.0001) and FDR: 4.3+/-0.7 to 3.1+/-0.3 mg (.) min(-1)(.) kg (-1)(P=0.068)). Percent decrease was significantly greater in CON compared with FDR (CON: 34+/-4; LBW: 27+/-4; FDR: 10+/-13 %). Forearm insulin-stimulated glucose clearance decreased significantly in CON and LBW in response to bed rest; in FDR clearance was very low before bed rest and no change was observed. Before bed rest CON and LBW demonstrated a significant increase in FBF during hyperinsulinemia, after bed rest increase in FBF was observed only in CON. Conclusions: Bed rest induced a pronounced reduction in whole body, skeletal muscle and vascular insulin sensitivity in CON and LBW. The changes were most pronounced in CON. In FDR insulin resistance was already present before bed rest, but even this group displayed a high sensitivity to changes in daily physical activity. Key words: exercise, diabetes, metabolism.
Abstract: Context: Previous studies on leg skeletal musculature have demonstrated mitochondrial dysfunction associated with type 2 diabetes mellitus (T2DM), but it is not known whether mitochondrial dysfunction is present in the upper extremities. Objective: The aim of the study was to compare mitochondrial respiration and markers of mitochondrial content in skeletal muscle of arm and leg in patients with T2DM and obese control subjects. Patients: Ten patients with T2DM (age, 52.3 +/- 2.7 yr; body mass index, 30.1 +/- 1.2 kg/m(2)) (mean +/- se) were studied after a 2-wk washout period of oral antihyperglycemic agents. Ten control subjects (age, 54.3 +/- 2.8 yr; body mass index, 30.4 +/- 1.2 kg/m(2)) with normal fasting and 2-h oral glucose tolerance test blood glucose levels were also included. Main Outcome Measure: We measured mitochondrial respiration in saponin-treated skinned muscle fibers from biopsies of m. deltoideus and m. vastus lateralis using high-resolution respirometry. Results: In the arm, mitochondrial respiration and citrate synthase activity did not differ between groups, but mitochondrial respiration per milligram of muscle was significantly higher in the leg muscle of the control subjects compared to T2DM. Fiber type compositions in arm and leg muscles were not different between the T2DM and control group, and maximum rate of O(2) consumption did not differ between the groups. Conclusion: The results demonstrate that reduced mitochondrial function in T2DM is only present in the leg musculature. This novel finding suggests that mitochondrial dysfunction is not a primary defect affecting all skeletal muscle but could be related to a decreased response to locomotor muscle use in T2DM.
Abstract: Patients with type 2 diabetes (T2DM) have an increased risk for cardiovascular disease. We examined the effects of 8 weeks of home-based rowing training (heart rate corresponding to 65-70% of VO(2 peak)) on endothelial function and glucose clearance (local and systemic effects) in male subjects with T2DM (n=9) and matched controls (n=8). Before and after training (30 min every other day), all subjects underwent sequential graded brachial artery infusions of non-insulin vasodilators (acetylcholine; sodium nitroprusside; adenosine). Forearm blood flow was improved by training in controls (without and with insulin: P=0.003 and 0.05, respectively) but not in subjects with T2DM. Likewise, whole body glucose clearance increased in response to training in controls (P=0.05) but not in T2DM. However, in both groups, the capacity for local forearm glucose extraction (controls: P=0.001; T2DM: P=0.002) and clearance (controls: P<0.001; T2DM: P=0.01) were positively affected by exercise. While the subjects with T2DM did not respond to the same degree as controls to 8 weeks of home-based exercise, there are clear benefits as illustrated by improvements in local glucose disposal. Training of higher intensity or duration may be required in order to elicit a response similar to controls.
Abstract: Adipose tissue exerts important endocrine and metabolic functions in health and disease. Yet the bioenergetics of this tissue is not characterized in humans and possible regional differences are not elucidated. Using high resolution respirometry, mitochondrial respiration was quantified in human abdominal subcutaneous and intra-abdominal, visceral (omentum majus) adipose tissue from biopsies obtained in twenty obese patients undergoing bariatric surgery. mtDNA and gDNA were determined by PCR technique for estimation of mitochondrial density. Adipose tissue samples were permeabilized and respirometric measurements were performed in duplicate at 37 degrees C. Substrates (glutamate(G) + malate(M) + octanoyl carnitine(O) + succinate(S)) were added sequentially to provide electrons to complex I + II. ADP ((D)) for state 3 respiration was added after GM. Uncoupled respiration was measured after addition of FCCP. Visceral fat contained more mitochondria per mg tissue than subcutaneous fat, but the cells were smaller. Robust, stable oxygen fluxes were found in both tissues, and coupled state 3 (GMOS(D)) and uncoupled respiration were significantly (p<0.05) higher in visceral (0.95+/-0.05 and 1.15+/-0.06 pmol O(2) x sec(-1) x mg(-1), respectively) compared with subcutaneous (0.76+/-0.04 and 0.98+/-0.05 pmol O(2) x sec(-1) x mg(-1), respectively) adipose tissue. Expressed per mtDNA, visceral adipose tissue had significantly (p<0.05) lower mitochondrial respiration. Substrate control ratios were higher and uncoupling control ratio lower (p<0.05) in visceral compared with subcutaneous adipose tissue. Conclusions: Visceral fat is bioenergetically more active and more sensitive to mitochondrial substrate supply than subcutaneous fat. OXPHOS has a higher relative activity in visceral compared with subcutaneous adipose tissue.
Abstract: Physical training affects insulin secretion and action, but there is a paucity of data on the direct effects in skeletal muscle and adipose tissue and on the effect of training in first degree relatives (FDR) of patients with type 2 diabetes. We studied insulin action at the whole body level, and peripherally in skeletal muscle and adipose tissue as well as insulin secretory capacity in seven FDR and eight control (CON) subjects before and after 12 wk of endurance training. Training improved physical fitness. Insulin-mediated glucose uptake (GU) increased (whole body and leg; P<0.05) after training in CON but not in FDR, while glucose-mediated GU increased (P<0.05) in both groups. Adipose tissue GU was not affected by training, but it was higher (abdominal: P<0.05; femoral P=0.09) in FDR compared with CON. Training increased skeletal muscle lipolysis (P<0.05), and it was markedly higher (P<0.05) in subcutaneous, abdominal than in femoral adipose tissue and quadriceps muscle with no difference between FDR and CON. Glucose-stimulated insulin secretion was lower in FDR compared with CON, but no effect of training was seen. Glucagon-like peptide 1 stimulated insulin secretion 5-7-fold. Conclusions: Insulin secretory capacity is lower in FDR than CON, and there is dissociation between training-induced changes in insulin secretion and insulin-mediated glucose uptake. Maximal glucose uptake rates are similar between groups and increases with physical training.
Abstract: Human muscle is studied during glycogen depletion and repletion to understand the influence of exercise and muscle glycogen on total ceramide content. In addition, fiber-type-specific ceramide storage is investigated. Ten healthy males (26.4 +/- 0.9 years, BMI 24.4 +/- 0.7 kg m(-2) and VO(2max) 57 +/- 2 mL O(2) min(-1) kg(-1)) participated in the study. On the first day, one leg was glycogen-depleted (DL) by exhaustive intermittent exercise followed by low carbohydrate diet. Next day, in the overnight fasted condition, muscle biopsies were excised from vastus lateralis before and after exhaustive exercise from both DL and control leg (CL). Muscle glycogen was analyzed biochemically and total muscle ceramide content by 2D quantitative lipidomic approach. Furthermore, fiber-type ceramide content was determined by fluorescence immunohistochemistry. Basal muscle glycogen was decreased (P < 0.05) with 50 +/- 6% in DL versus CL. After exhaustive exercise, muscle glycogen was similar in CL and DL 139 +/- 38 and 110 +/- 31 mmol kg(-1), respectively. Total muscle ceramide 58 +/- 1 pmol mg(-1) was not influenced by glycogen or exercise. Ceramide content was consistently higher (P < 0.001) in type I than in type II muscle fibers. In conclusion, human skeletal muscle, ceramide content is higher in type I than in type II. Despite rather large changes in muscle glycogen induced by prior depletion, exercise to exhaustion and repletion, total muscle ceramide concentration remained unchanged.
Abstract: We compared the effects on glycaemic control of two different exercise protocols in elderly men with type 2-diabetes; one 30-minute session per day (1 x 30) and three 10-minute sessions per day (3 x 10). Cardiopulmonary fitness increased in both groups. Improvement in glycaemic control was only found in the 3 x 10 group. A likely explanation is that the total energy expenditure during training performed as multiple sessions is higher than the expenditure achieved during a single session per day.
Abstract: Glycogen synthase (GS) is considered the rate-limiting enzyme in glycogenesis but still today there is a lack of understanding on its regulation. We have previously shown phosphorylation-dependent GS intracellular redistribution at the start of glycogen re-synthesis in rabbit skeletal muscle (Prats, C., Cadefau, J. A., Cussó, R., Qvortrup, K., Nielsen, J. N., Wojtaszewki, J. F., Wojtaszewki, J. F., Hardie, D. G., Stewart, G., Hansen, B. F., and Ploug, T. (2005) J. Biol. Chem. 280, 23165-23172). In the present study we investigate the regulation of human muscle GS activity by glycogen, exercise, and insulin. Using immunocytochemistry we investigate the existence and relevance of GS intracellular compartmentalization during exercise and during glycogen re-synthesis. The results show that GS intrinsic activity is strongly dependent on glycogen levels and that such regulation involves associated dephosphorylation at sites 2+2a, 3a, and 3a + 3b. Furthermore, we report the existence of several glycogen metabolism regulatory mechanisms based on GS intracellular compartmentalization. After exhausting exercise, epinephrine-induced protein kinase A activation leads to GS site 1b phosphorylation targeting the enzyme to intramyofibrillar glycogen particles, which are preferentially used during muscle contraction. On the other hand, when phosphorylated at sites 2+2a, GS is preferentially associated with subsarcolemmal and intermyofibrillar glycogen particles. Finally, we verify the existence in human vastus lateralis muscle of the previously reported mechanism of glycogen metabolism regulation in rabbit tibialis anterior muscle. After overnight low muscle glycogen level and/or in response to exhausting exercise-induced glycogenolysis, GS is associated with spherical structures at the I-band of sarcomeres.
Abstract: AIM: Several mechanisms have been targeted as culprits of weight gain during antihyperglycaemic treatment in type 2 diabetes (T2DM). These include reductions in glucosuria, increased food intake from fear of hypoglycaemia, the anabolic effect of insulin, decreased metabolic rate and increased efficiency in fuel usage. The purpose of the study was to test the hypothesis that mitochondrial efficiency increases as a result of insulin treatment in patients with type 2 diabetes. METHODS: We included ten patients with T2DM (eight males) on oral antidiabetic treatment, median age: 51.5 years (range: 39-67) and body mass index (BMI): 30.1 +/- 1.2 kg/m2 (mean +/- s.e.). Muscle biopsies from m. vastus lateralis and m. deltoideus were obtained before and after seven weeks of intensive insulin treatment, and mitochondrial respiration was measured using high-resolution respirometry. State 3 respiration was measured with the substrates malate, pyruvate, glutamate, succinate and ADP. State 4o was measured with addition of oligomycine. An age, sex and BMI-matched control group was also included. RESULTS: HbA1c improved significantly and the patients gained on average 3.4 +/- 0.9 kg. Before treatment, respiratory control ratios (RCRs) of the T2DM were lower than the obese controls [2.6 vs. 3.2 (p < 0.05)], but RCR returned to the levels of the control subjects during treatment. Average state 4o of arm and leg declined by 14% (p < 0.05) during insulin treatment. CONCLUSIONS: Tight glycaemic control leads to reductions in inner mitochondrial membrane leak and increased efficiency of mitochondria. This change in mitochondrial physiology could contribute to the weight gain seen with antihyperglycaemic treatment.
Abstract: AIM: Skeletal muscle mitochondrial content is reduced in type 2 diabetes mellitus (T2DM). Whether hyperglycemia inhibits mitochondrial biogenesis and/or function is unknown. This study examined the effect of different levels of glycemia on skeletal muscle mitochondrial function in patients with T2DM. PATIENTS AND METHODS: Eleven patients with T2DM [9 males, 2 females; age, 52.8 +/- 2.5 yr (mean +/- se); body mass index, 30.2 +/- 1.1 kg/m(2)] in poor glycemic control were treated with insulin aspart and NPH insulin for a median period of 46 d (range, 31-59). Mitochondrial respiration and citrate synthase activity (a marker of mitochondrial content) were measured before and after treatment. Eleven healthy subjects (age, 53.3 +/- 2.7 yr; body mass index, 30.6 +/- 1.1 kg/m(2)) were included as controls. RESULTS: Hemoglobin A1c (9.1 +/- 0.5 to 7.5 +/- 0.3%; P < 0.001) and fasting plasma glucose (12.7 +/- 1.1 to 6.5 +/- 0.3 mmol/liter; P < 0.001) were reduced after treatment. Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls [substrates for complex I, 24% lower (P < 0.05); substrates for complex I+II, 17% lower (P < 0.05)]. Mitochondrial respiration and citrate synthase activity did not differ before and after improvements in glycemic control, but mitochondrial respiration correlated with fasting plasma glucose before (r(2) = 0.53; P < 0.05) but not after treatment [r(2) = 0.0024; not significant (NS)]. Mitochondrial respiration normalized to mitochondrial content did not differ between control subjects and patients with T2DM. DISCUSSION: Mitochondrial respiration and content was not improved after significant improvements in glycemic control. However, severe hyperglycemia inhibited respiration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.
Abstract: OBJECTIVES: Training improves exercise capacity in patients with heart failure (CHF) but most evidence is on selected younger patients with systolic CHF. DESIGN: All patients diagnosed with CHF over 3 years were screened for inclusion and exclusion criteria. Fifty two patients with systolic CHF (LVEF<45, NYHA II-III) received supervised exercise training twice weekly for 8 weeks. RESULTS: Mean age was 68.2 (+/-SD 11.3) years. Despite marked improvements in physical fitness (workload, 6 minute walk test, incremental shuttle walk test and sit to stand test), there were no changes in serological markers of glycemic control (glucose, insulin, glycerol, free fatty acids, HbA1c), inflammation and endothelial function (hsCRP, orosomucoid, interleukin 6, TNF-alpha, urine-orosomucoid and -albumin/creatinin), lipid metabolism, NT-proBNP or other regulatory hormones (cortisol, epinephrine and IGF-1). There were no changes in quality of life. CONCLUSIONS: The effect of exercise training in these older CHF-patients was not as impressive as reported in younger and more selected patients. More studies on the efficiency of exercise training that reflect the age- and co-morbidity of the majority of CHF-patients are needed.
Abstract: Adipokines play important regulatory roles in the pathophysiology of obesity and insulin resistance. We measured plasma and interstitial concentrations of the adipokines adiponectin, resistin, leptin, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) in subcutaneous, abdominal and femoral adipose tissue using calibrated, large-pore microdialysis technique in 8 healthy, lean men on 2 experimental days. The interstitial leptin concentration was 2.5-fold higher in subcutaneous, femoral than abdominal adipose tissue (P<0.05), but no regional differences were found for the remaining adipokines (P>0.05). Adiponectin and leptin concentrations were higher in plasma than subcutaneous adipose tissue (approximately 25-fold and approximately 2-fold, respectively, P<0.05), whereas MCP-1, IL-6 and IL-8 concentrations were higher in subcutaneous adipose tissue than plasma (approximately 100-fold, approximately 200-fold and approximately 1000-fold, respectively, P<0.05). Resistin concentrations did not differ significantly between compartments. Adipose tissue blood flow (ATBF) showed no regional difference (P>0.05). The intra- and inter-subject variations of all investigated adipokines as well as of ATBF were substantial (coefficient of variation: 4-177%). In conclusion, interstitial leptin concentrations are approximately 2.5-fold higher in subcutaneous, femoral than abdominal adipose tissue, which might be a potential mechanism behind the health-benefits of "pear-shape". Furthermore, subcutaneous adipose tissue has a marked production of pro-inflammatory adipokines.
Abstract: First-degree relatives (FDR) of patients with type 2 diabetes mellitus are at increased risk of developing type 2 diabetes mellitus. We studied if endothelial dysfunction of the resistance vessels is present and may coexist with metabolic insulin resistance in FDR. Male FDR (n = 13; 26 +/- 1 years; body mass index, 25 +/- 1 kg m(2) [mean +/- SEM]) and matched control subjects (CON) (n = 22; 25 +/- 1 years; body mass index, 24 +/- 1 kg m(2)) were studied by hyperinsulinemic (40 mU min(-1)m(-2)) isoglycemic clamp combined with brachial arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography upon stimulation with systemic hyperinsulinemia (291 +/- 11 pmol/L, pooled data from both groups) and upon intraarterial infusion of adenosine (ADN) and acetylcholine (ACH) +/- hyperinsulinemia. Forearm blood flow response to ADN and ACH was less in FDR vs CON (P < .05); systemic hyperinsulinemia added to the FBF effect of ADN in CON (P < .05) but not in FDR. In addition, FDR demonstrated impaired FBF to hyperinsulinemia (2.1 +/- 0.2 vs 4.0 +/- 0.6 mL 100 mL(-1) min(-1)) in FDR and CON, respectively (P < .05). Both M-value (5.0 +/- 0.7 vs 7.0 +/- 0.5 mg min(-1) kg(-1)) and forearm glucose clearance (0.6 +/- 0.1 vs 1.4 +/- 0.4 mL 100 mL(-1)min(-1)) were diminished in FDR compared with CON (all P < .05). FDR demonstrated endothelial dysfunction of the resistance vessels in addition to impaired insulin-stimulated increase in bulk flow. Moreover, FDR demonstrated whole-body insulin resistance as well as decreased basal and insulin-stimulated forearm glucose uptake. It remains to be established whether FDR also demonstrate impaired insulin-stimulated microvascular function.
Abstract: AIM/HYPOTHESIS: The aim of the study was to investigate mitochondrial function, fibre type distribution and substrate oxidation in arm and leg muscle during exercise in patients with type 2 diabetes and in obese and lean controls. METHODS: Indirect calorimetry was used to calculate fat and carbohydrate oxidation during both progressive arm-cranking and leg-cycling exercises. Muscle biopsies from arm and leg were obtained. Fibre type, as well as O(2) flux capacity of saponin-permeabilised muscle fibres were measured, the latter by high resolution respirometry, in patients with type 2 diabetes, age- and BMI-matched obese controls, and age-matched lean controls. RESULTS: Fat oxidation was similar in the groups during either arm or leg exercise. During leg exercise at higher intensities, but not during arm exercise, carbohydrate oxidation was lower in patients with type 2 diabetes compared with the other groups. In patients with type 2 diabetes, ADP-stimulated state 3 respiration per mg muscle with parallel electron input from complex I+II was lower in m. vastus lateralis compared with obese and lean controls, whereas no differences between groups were present in m. deltoideus. A higher percentage of type IIX fibres was seen in m. vastus lateralis in patients with type 2 diabetes compared with obese and lean controls, whereas no difference was found in the deltoid muscle. CONCLUSIONS/INTERPRETATION: This study demonstrates similar O(2) flux capacity, fibre type distribution and carbohydrate oxidation in arm muscle in the groups despite the presence of attenuated values in leg muscle in patients with type 2 diabetes compared with obese and lean controls.
Abstract: Patients with T2DM have an increased risk of CVD. Prevention of CVD represents the major goal of all treatment of T2DM, and early intervention in those patients at particularly high risk is important.We measured the insulin sensitivity and plasma biomarkers of CVD to determine whether a home-based exercise training program improves biomarker levels and insulin sensitivity. Patients with T2DM (n=12), IGT (n=4) and healthy control subjects (n=9) were studied before and after eight weeks of exercise training by rowing ergometry at 65-70% of peak oxygen uptake. Conclusions: 1) patients with T2DM have elevated plasma concentrations of CVD biomarkers compared to the matched control and IGT groups; 2) a moderate to vigorous intensity home-based training program did not reduce plasma concentrations of these CVD markers; 3) insulin sensitivity improved as a result of exercise training in the control group, but not in the T2DM group.
Abstract: OBJECTIVE: The aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects. RESEARCH DESIGN AND METHODS: A total of 13 FDR and 20 CON subjects participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics. RESULTS: Bed rest caused a significant decrease in whole-body insulin sensitivity in both groups. Hepatic insulin resistance was elevated in FDR subjects prior to bed rest and was significantly augmented by bed rest in FDR (P < 0.01) but not in CON (P = NS) subjects. The rate of whole-body lipolysis decreased during bed rest in both FDR and CON subjects, with no significant differences between the groups. Insulin resistance induced by bed rest was fully accounted for by the impairment of nonoxidative glucose metabolism in both groups (overall P < 0.001). CONCLUSIONS: Whole-body insulin action in both insulin-resistant FDR and healthy CON subjects deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen in relation to their degree of HIR but not peripheral insulin resistance.
Abstract: INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patients with low RAS activity. MATERIALS AND METHODS: Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked potentials and hypoglycaemic symptoms were recorded. RESULTS: At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness. CONCLUSION: High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.
Abstract: Reduced oxidative capacity of skeletal muscle has been proposed to lead to accumulation of intramyocellular triglyceride (IMTG) and insulin resistance. We have measured mitochondrial respiration before and after a 10% low-calorie-induced weight loss in young obese women to examine the relationship between mitochondrial function, IMTG, and insulin resistance. Nine obese women (age, 32.3 years [SD, 3.0]; body mass index, 33.4 kg/m(2) [SD, 2.6]) completed a 53-day (SE, 3.8) very low calorie diet (VLCD) of 500 to 600 kcal/d without altering physical activity. The target of the intervention was a 10% weight loss; and measurements of mitochondrial respiration, IMTG, respiratory exchange ratio, citrate synthase activity, mitochondrial DNA copy number, plasma insulin, 2-hour oral glucose tolerance test, and free fatty acids were performed before and after weight loss. Mitochondrial respiration was measured in permeabilized muscle fibers using high-resolution respirometry. Average weight loss was 11.5% (P < .05), but the levels of IMTG remained unchanged. Fasting plasma glucose, plasma insulin homeostasis model assessment of insulin resistance, and insulin sensitivity index (composite) obtained during 2-hour oral glucose tolerance test improved significantly. Mitochondrial respiration per milligram tissue decreased by approximately 25% (P < .05), but citrate synthase activity and mitochondrial DNA copy number remained unchanged. Respiratory exchange ratio decreased from 0.87 (SE, 0.01) to 0.79 (SE, 0.02) (P < .05) as a sign of increased whole-body fat oxidation. Markers of insulin sensitivity improved after the very low calorie diet; but mitochondrial function decreased, and IMTG remained unchanged. Our results do not support a direct relationship between mitochondrial function and insulin resistance in young obese women and do not support a direct relationship between IMTG and insulin sensitivity in young obese women during weight loss.
Abstract: BACKGROUND: Exercise training is known to be beneficial in chronic heart failure (CHF) patients but there is a lack of studies following patient groups for longer duration with maintenance training programs to defer deconditioning. METHODS: Study base consisted of all patients diagnosed with CHF in a 3-year period. Sixty-six patients with systolic CHF (ejection fraction <45, New York Heart Association II-III) were randomized to 12 months of either usual care orhome-based maintenance exercise with group training sessions every 2 weeks after an initial 8-week training program. The primary endpoint was maximum workload; secondary endpoints were 6-min walk test, incremental shuttle walk test, sit-to-stand test, quality of life, and serological markers. RESULTS: Six patients died and 43 completed the study. The initial 8-week training was associated with small but significant improvement in all of the functional tests. In both groups there was a significant decline in the maximum workload the next 12 months (P=0.03 and P<0.001, respectively) but after an adjustment for difference between groups in baseline characteristics, maintenance intervention reduced the decline in the maximum workload by 8.0 W (95% CI: 3.0-13.0, P=0.002). No effect of maintenance intervention was observed for 6-min walk test, incremental shuttle walk test, sit-to-stand test, or quality of life. After 14 months changes in most markers of inflammation, endothelial damage, and glycemic control were more beneficial in the intervention group. CONCLUSION: A low-cost maintenance intervention in CHF patients reduced the decline in the maximum workload compared with usual care but not in other measures of physical function. Results suggest beneficial effects of long-term maintenance training on glycemic control, inflammation, and endothelial function.
Abstract: AIMS: The objective was to re-examine endothelial function, insulin mediated vasodilation and glucose extraction in the forearm of patients with type 2 diabetes (T2DM) and matched control subjects (CON) to investigate whether blood flow impairments result from diabetes per se or from concurrent disease. METHODS: 18 subjects (10 with T2DM, 8 CON) had graded brachial artery infusions of endothelial dependent (acetylcholine: 15, 30, 60 microg/min), endothelial independent (sodium nitroprusside: 1, 3, 10 microg/min) and partially endothelial mediated (adenosine: 50, 150, 500 microg/min) vasodilators. The protocol was repeated during a hyperinsulinemic clamp. Forearm blood flow and glucose extraction were measured at each dose of vasodilator (with/without insulin). Measurements were also taken in the control arm, reflecting systemic insulin infusion only. RESULTS: Non-insulin mediated increases in bulk forearm blood flow were similar in T2DM and CON. However, insulin mediated forearm blood flow responses and glucose extraction were lower in T2DM versus CON. CONCLUSION: The vasodilatory effect of insulin is impaired in T2DM although bulk flow capacity is maintained. Insulin mediated glucose extraction is reduced during concomitant maximal stimulation of forearm blood flow with endothelial-dependent vasodilators, despite maintaining flow. This is consistent with previous work that associates T2DM with impaired insulin mediated capillary recruitment.
Abstract: OBJECTIVE: In obese subjects, chronically elevated plasma concentrations of non-esterified fatty acids (NEFAs) exert a marked risk to contract insulin resistance and subsequently type 2 diabetes. When NEFA is acutely increased due to i.v. infusion of lipid, glucose disposal during a hyperinsulinemic-euglycemic clamp is reduced. This effect has been explained by a NEFA-induced decrease in skeletal muscle insulin sensitivity caused by accumulation of the lipid intermediates such as ceramide and diacylglycerol in the myocytes. However, neither the lipid-induced reduction of glucose disposal nor the intramyocellular lipid deposition has been compared directly in obese females and males. DESIGN: We studied eight obese females and eight obese males (body mass index (BMI): 32.6+/-1.4 and 32.8+/-0.8 respectively, non significant (NS)) matched for cardiorespiratory fitness relative to lean body mass (43.7+/-1.6 and 47.6+/-1.3 ml/kg min respectively, NS). METHODS: Each subject underwent two hyperinsulinemic-euglycemic clamps with infusion of lipid or saline respectively. Furthermore, the subjects exercised during the last half an hour of each clamp. RESULTS: The lipid-induced reduction in glucose disposal during the clamp was similar in females and males (46+/-10 and 60+/-4% respectively, NS). However, whole-body insulin sensitivity as well as non-oxidative glucose disposal was higher in obese females compared with obese males both during lipid and saline infusion (P<0.001 and P=0.01 respectively). Muscle ceramide, triacylglycerol (TAG), diacylglycerol (DAG), and glycogen content were similar between sexes and remained unchanged during the clamp and when exercise was superimposed. CONCLUSIONS: The lipid-induced inhibition of glucose disposal is similar in obese females and males. However, obese females are more insulin sensitive compared with obese males (both during saline and lipid infusion), which is not due to differences in the concentration of the muscle lipid intermediates such as ceramide and DAG.
Abstract: AIMS/HYPOTHESIS: In skeletal muscle, ceramides may be involved in the pathogenesis of insulin resistance through an attenuation of insulin signalling. This study investigated total skeletal muscle ceramide fatty acid content in participants exhibiting a wide range of insulin sensitivities. METHODS: The middle-aged male participants (n=33) were matched for lean body mass and divided into four groups: type 2 diabetes (T2D, n=8), impaired glucose tolerance (IGT, n=9), healthy controls (CON, n=8) and endurance-trained (TR, n=8). A two step (28 and 80 mU m(-2) min(-1)) sequential euglycaemic-hyperinsulinaemic clamp was performed for 120 and 90 min for step 1 and step 2, respectively. Muscle biopsies were obtained from vastus lateralis at baseline, and after steps 1 and 2. RESULTS: Glucose infusion rates increased in response to insulin infusion, and significant differences were present between groups (T2D<IGT<CON<TR). At baseline, muscle ceramide content was 108+/-7, 95+/-6, 126+/-12 and 156+/-25 nmol total ceramide fatty acids/g wet weight of tissue in the T2D, IGT, CON and TR groups, respectively, and muscle ceramide content was higher (p<0.01) in the TR than the IGT group. Muscle ceramide content was not influenced by insulin infusion. Interestingly, a positive correlation (r=0.42, p<0.05) was present between muscle ceramide content at baseline and insulin sensitivity. CONCLUSIONS/INTERPRETATION: Total muscle ceramide content was similar between individuals showing marked differences in insulin sensitivity, and therefore does not seem to be a major factor in muscle insulin resistance. Furthermore, aerobic capacity does not appear to influence muscle ceramide content.
Abstract: INTRODUCTION: In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal cognitive function during hypoglycaemia. METHODS: Sixteen healthy volunteers selected by either particularly high or low serum ACE activity were subjected to hypoglycaemia (plasma glucose 2.7 mmol/L). Cognitive function was assessed by choice reaction tests. RESULTS: Despite a similar hypoglycaemic stimulus in the two groups, only the group with high ACE activity showed significant deterioration in cognitive performance during hypoglycaemia. In the high ACE group mean reaction time (MRT) in the most complex choice reaction task was prolonged and error rate (ER) was increased in contrast to the low ACE group. The total hypoglycaemic symptom response was greater in the high ACE group than in the low ACE group (p=0.031). There were no differences in responses of counterregulatory hormones or in concentrations of substrates between the groups. CONCLUSION: Healthy humans with high ACE activity are more susceptible to cognitive dysfunction and report higher symptom scores during mild hypoglycaemia than subjects with low ACE activity.
Abstract: Caffeine, an adenosine receptor antagonist, has been studied for decades as a putative ergogenic aid. In the past 2 decades, the information has overwhelmingly demonstrated that it indeed is a powerful ergogenic aid, and frequently theories have been proposed that this is due to alterations in fat and carbohydrate metabolism. While caffeine certainly mobilizes fatty acids from adipose tissue, rarely have measures of the respiratory exchange ratio indicated an increase in fat oxidation. However, this is a difficult measure to perform accurately during exercise, and small changes could be physiologically important. The few studies examining human muscle metabolism directly have also supported the fact that there is no change in fat or carbohydrate metabolism, but these usually have had a small sample size. We combined the data from muscle biopsy analyses of several similar studies to generate a sample size of 16-44, depending on the measure. We examined muscle glycogen, citrate, acetyl-CoA, glucose-6-phosphate, and cyclic adenosine monophosphate (cAMP) in resting samples and in those obtained after 10-15 min of exercise at 70%-85% maximal oxygen consumption. Exercise decreased (p < 0.05) glycogen and increased (p < 0.05) citrate, acetyl-CoA, and glucose-6-phosphate. The only effects of caffeine were to increase (p < 0.05) citrate in resting muscle and cAMP in exercise. There is very little evidence to support the hypothesis that caffeine has ergogenic effects as a result of enhanced fat oxidation. Individuals may, however, respond differently to the effects of caffeine, and there is growing evidence that this could be explained by common genetic variations.
Abstract: AIMS/HYPOTHESIS: Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content. MATERIALS AND METHODS: The O(2) flux capacity of permeabilised muscle fibres from biopsies of the quadriceps in healthy subjects (n = 8; age 58 +/- 2 years [mean+/-SEM]; BMI 28 +/- 1 kg/m(2); fasting plasma glucose 5.4 +/- 0.2 mmol/l) and patients with type 2 diabetes (n = 11; age 62 +/- 2 years; BMI 32 +/- 2 kg/m(2); fasting plasma glucose 9.0 +/- 0.8 mmol/l) was measured by high-resolution respirometry. RESULTS: O(2) flux expressed per mg of muscle (fresh weight) during ADP-stimulated state 3 respiration was lower (p < 0.05) in patients with type 2 diabetes in the presence of complex I substrate (glutamate) (31 +/- 2 vs 43 +/- 3 pmol O(2) s(-1) mg(-1)) and in response to glutamate + succinate (parallel electron input from complexes I and II) (63 +/- 3 vs 85 +/- 6 pmol s(-1) mg(-1)). Further increases in O(2) flux capacity were observed in response to uncoupling by FCCP, but were again lower (p < 0.05) in type 2 diabetic patients than in healthy control subjects (86 +/- 4 vs 109 +/- 8 pmol s(-1) mg(-1)). However, when O(2) flux was normalised for mitochondrial DNA content or citrate synthase activity, there were no differences in oxidative phosphorylation or electron transport capacity between patients with type 2 diabetes and healthy control subjects. CONCLUSIONS/INTERPRETATION: Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content.
Abstract: Exercise superimposed on insulin stimulation is shown to increase muscle glucose metabolism and these two stimuli have synergistic effects. The objective of this study was to investigate glucose infusion rates (GIR) in groups with a wide variation in terms of insulin sensitivity during insulin stimulation alone and with superimposed exercise. Patients with type 2 diabetes, subjects with impaired glucose tolerance (IGT), healthy controls, and endurance-trained subjects were studied. The groups were matched for age and lean body mass (LBM), and differed in peak oxygen uptake (VO2 peak), body fat percentage, body mass index (BMI), fasting plasma glucose concentration, and oral glucose-tolerance test (OGTT). Each subject underwent a two-step sequential hyperinsulinemic, euglycemic clamp. During the last 30 min of the 2nd clamp step, subjects exercised on a bicycle at 43% +/- 2% of VO2 peak. In agreement with the OGTT data, the presence of different GIR during insulin stimulation alone demonstrated varying levels of insulin sensitivity between groups. However, the impairment of GIR in IGT observed during insulin stimulation alone was abolished compared to controls when exercise was superimposed on insulin stimulation. Humans with IGT are resistant to insulin-stimulated but not to exercise-induced glucose uptake.
Abstract: Aerobic exercise increases whole body adipose tissue lipolysis, but is lipolysis higher in subcutaneous adipose tissue (SCAT) adjacent to contracting muscles than in SCAT adjacent to resting muscles? Ten healthy, overnight-fasted males performed one-legged knee extension exercise at 25% of maximal workload (W(max)) for 30 min followed by exercise at 55% W(max) for 120 min with the other leg and finally exercised at 85% W(max) for 30 min with the first leg. Subjects rested for 30 min between exercise periods. Femoral SCAT blood flow was estimated from washout of (133)Xe, and lipolysis was calculated from femoral SCAT interstitial and arterial glycerol concentrations and blood flow. In general, blood flow and lipolysis were higher in femoral SCAT adjacent to contracting than adjacent to resting muscle (time 15-30 min; blood flow: 25% W(max) 6.6 +/- 1.0 vs. 3.9 +/- 0.8 ml x 100 g(-1) x min(-1), P < 0.05; 55% W(max) 7.3 +/- 0.6 vs. 5.0 +/- 0.6 ml x 100 g(-1) x min(-1), P < 0.05; 85% W(max) 6.6 +/- 1.3 vs. 5.9 +/- 0.7 ml x 100 g(-1) x min(-1), P > 0.05; lipolysis: 25% W(max) 102 +/- 19 vs. 55 +/- 14 nmol x 100 g(-1) x min(-1), P = 0.06; 55% W(max) 86 +/- 11 vs. 50 +/- 20 nmol x 100 g(-1) x min(-1), P > 0.05; 85% W(max) 88 +/- 31 vs. -9 +/- 25 nmol x 100 g(-1) x min(-1), P < 0.05). In conclusion, blood flow and lipolysis are generally higher in SCAT adjacent to contracting than adjacent to resting muscle irrespective of exercise intensity. Thus specific exercises can induce "spot lipolysis" in adipose tissue.
Abstract: According to the free radical theory of aging, reactive oxygen species (ROS) act as a driving force of the aging process, and it is generally believed that mitochondrial dysfunction is a major source of increased oxidative stress in tissues with high content of mitochondria, such as muscle or brain. However, recent experiments in mouse models of premature aging have questioned the role of mitochondrial ROS production in premature aging. To address the role of mitochondrial impairment and ROS production for aging in human muscles, we have analyzed mitochondrial properties in muscle fibres isolated from the vastus lateralis of young and elderly donors. Mitochondrial respiratory functions were addressed by high-resolution respirometry, and ROS production was analyzed by in situ staining with the redox-sensitive dye dihydroethidium. We found that aged human skeletal muscles contain fully functional mitochondria and that the level of ROS production is higher in young compared to aged muscle. Accordingly, we could not find any increase in oxidative modification of proteins in muscle from elderly donors. However, the accumulation of lipofuscin was identified as a robust marker of human muscle aging. The data support a model, where ROS-induced molecular damage is continuously removed, preventing the accumulation of dysfunctional mitochondria despite ongoing ROS production.
Abstract: OBJECTIVES: Hyperlactatemia is prevalent in HIV-infected patients on highly active antiretroviral therapy (HAART) and may be associated with depletion of mitochondrial DNA. However, the correlation between fasting lactate and mitochondrial DNA may be weak or absent, implicating that other factors e.g. glucose turnover may contribute to hyperlactatemia. METHODS: HIV-infected patients receiving HAART who had lipodystrophy (LIPO, n=18) or were without lipodystrophy (NONLIPO, n=18) were investigated. Insulin sensitivity (M-value), glucose oxidation rate (GOX) and fasting endogenous glucose production (EGP) were determined by hyperinsulinemic euglycemic clamp, indirect calorimetry and glucose tracer technique, respectively. RESULTS: Fasting p-lactate (median 1.2 mmol/L; range 0.6-4.3, n=36) tended to be increased in LIPO (P=0.12); 6 patients (4 LIPO) had lactate > or =2.0 mmol/L. Fasting lactate correlated inversely with M-value (P<0.001) and positively with fasting EGP (P<0.05) and fasting GOX (P<0.05), together explaining 51% (R2, n=36) of the variation in fasting lactate. Lactate increased in NONLIPO (P<0.05) but not in LIPO (P>0.5) during clamp. Incremental (clamp minus fasting value) GOX (P<0.01) was decreased and incremental insulin (P<0.01) was increased in LIPO. CONCLUSIONS: Fasting EGP, GOX and insulin resistance may be major determinants of fasting lactate levels in HIV-infected patients on HAART. Insulin levels per se may not determine plasma lactate in such patients.
Abstract: Caffeine (CAF) impedes insulin-mediated glucose disposal (IMGD) and increases plasma adrenaline concentrations ([ADR]; 0.6 nm). While the antagonism of ADR abolishes the CAF effect, infusion of ADR (0.75 nm) has no effect on IMGD. We have now examined CAF and ADR in concert to determine whether or not they elicit an additive response on IMGD. We hypothesized that CAF + ADR would elicit a greater effect than either CAF or ADR alone (i.e. that CAF effects would not be solely attributed to ADR). Subjects (n = 8) completed four trials in a randomized manner. An isoglycaemic-hyperinsulinaemic clamp was performed 30 min after the following treatments were administered: (1) placebo capsules and saline infusion ([ADR] = 0.29 nm) (PL trial), (2) CAF capsules (dose = 5 mg kg(-1)) and saline infusion ([ADR] = 0.62 nm) (CAF trial), (3) PL capsules and ADR infusion ([ADR] = 1.19 nm) (ADR trial), and (4) CAF capsules (dose = 5 mg kg(-1)) and ADR infusion ([ADR] = 0.93 nm) (CAF + ADR trial). As expected, CAF, ADR and CAF + ADR decreased (P <or= 0.05) IMGD compared to PL. CAF + ADR resulted in a more pronounced decrease in IMGD versus PL (42%) compared to CAF (26%) or ADR (24%) alone; however, the effect was not fully additive (P = 0.08). Furthermore, CAF decreased IMGD to a similar magnitude as ADR despite a 50% lower [ADR]. In summary, while ADR contributes to the CAF-induced impairment in IMGD, it is not solely responsible for caffeine's effects.
Abstract: The term "endothelial dysfunction" refers to the inability or attenuated effect of the endothelial cells in participating in the relaxation of the adjacent smooth muscle, thus causing less vasodilation. Although endothelial dysfunction is often seen in patients with type 2 diabetes, it does not necessarily follow that insulin resistance and (or) hyperglycemia is causing the inability to respond properly to vasodilatory stimuli. Rather, this could be related to the impact of concomitant cardiovascular risk factors that are almost invariably present in patients with type 2 diabetes. The impact of physical training - or the opposite, inactivity - on endothelial function is not fully elucidated. Some studies have shown positive effects of physical training, whereas others have not. In general, physical training can improve endothelial function when this is impaired. However, physical training does not seem to have any effect on endothelial function when this is normal.
Abstract: Physical training is recommended for the prevention and treatment of cardiovascular disease in the general population. In patients with type 2 diabetes this is even more important, because the risk of clinical atherosclerotic disease is 2- to 3-fold that of nondiabetics and the survival rate is poorer. However, increased daily physical activity (e.g., walking for exercise) has been shown to reduce the risk of premature death from all causes and from cardiovascular disease in particular. The mechanism for the positive effect of physical training may be a reduction of known risk factors for atherosclerosis, but a direct effect on the atherosclerotic process per se cannot be excluded.
Abstract: OBJECTIVE: We studied how an acute bout of exercise influences expression and concentration of adiponectin and regulators of adiponectin in adipose tissue and plasma. DESIGN AND METHODS: Eight overweight and eight lean males were examined by large-pore microdialysis in s.c. abdominal adipose tissue (SCAAT) and had arterialized blood sampled. On one day subjects rested for 3 h, exercised for 1 h at 55% of maximal oxygen uptake and rested again for 2.5 h, and on another day subjects rested for 6.5 h. On the day including exercise SCAAT was biopsied before and after exercise. RESULTS: Exercise increased the SCAAT interstitial adiponectin concentration in both overweight and lean subjects and concentrations did not differ between groups. Plasma adiponectin did not increase during exercise and was similar in overweight and lean subjects. Adiponectin mRNA in SCAAT decreased during exercise and was similar in overweight and lean subjects. Surprisingly, the interstitial adiponectin concentration in SCAAT was only 20% of the plasma concentration. SCAAT interleukin-6 (IL-6) microdialyzate and plasma concentrations and SCAAT IL-6 mRNA increased during exercise in both groups. Tumor necrosis factor- (TNF-) plasma concentration did not change during exercise in any of the groups, but SCAAT TNF- mRNA increased after exercise in both groups. Furthermore, exercise decreased SCAAT leptin mRNA with no change in resistin mRNA. CONCLUSIONS: Acute exercise increases adipose tissue interstitial adiponectin concentration in both overweight and lean subjects with no major changes in plasma adiponectin concentration. The interstitial concentration of adiponectin in SCAAT is only 20% of that in plasma.
Abstract: AIMS/HYPOTHESIS: We evaluated and compared the effects on glycaemic control of two different exercise protocols in elderly men with type 2 diabetes mellitus. METHODS: Eighteen patients with type 2 diabetes mellitus carried out home-based bicycle training for 5 weeks. Patients were randomly assigned to one of two training programmes at 60% of maximal oxygen uptake: three 10 min sessions per day (3 x 10) or one 30 min session per day (1 x 30). Plasma insulin, C-peptide and glucose concentrations were measured during a 3 h oral glucose tolerance test (OGTT). Insulin sensitivity index (ISI(composite)), pre-hepatic insulin secretion rates (ISR) and change in insulin secretion per unit change in glucose concentrations (B(total)) were calculated. RESULTS: Cardiorespiratory fitness increased in response to training in both groups. In group 3 x 10 (n = 9) fasting plasma glucose (p = 0.01), 120 min glucose OGTT (p = 0.04) and plasma glucose concentration areas under the curve at 120 min (p < 0.04) and 180 min (p = 0.07) decreased. These parameters remained unchanged in group 1 x 30 (n = 9). No significant changes were found in ISI(composite), ISR and B(total) in either of the exercise groups. In a matched time-control group (n = 10), glycaemic control did not change. CONCLUSIONS/INTERPRETATION: Moderate to high-intensity training performed at 3 x 10 min/day is preferable to 1 x 30 min/day with regard to effects on glycaemic control. This is in spite of the fact that cardiorespiratory fitness increased similarly in both exercise groups. A possible explanation is that the energy expenditure associated with multiple short daily sessions may be greater than that in a single daily session.
Abstract: The Danish Fitness and Nutrition Council has evaluated the basis for recommending strategies to prevent obesity among children and adolescents. There is limited evidence of a preventive effect from large population based interventions. It is possible, though, to change to a healthier lifestyle. Currently, many different Administrations conduct interventions against obesity, and it is suggested that an independent authority should be established whose primary aim is to reduce the prevalence of obesity and which will be responsible for the effort against obesity.
Abstract: Ageing is associated with a loss in both muscle mass and in the metabolic quality of skeletal muscle. This leads to sarcopenia and reduced daily function, as well as to an increased risk for development of insulin resistance and type 2 diabetes. A major part, but not all, of these changes are associated with an age-related decrease in the physical activity level and can be counteracted by increased physical activity of a resistive nature. Strength training has been shown to improve insulin-stimulated glucose uptake in both healthy elderly individuals and patients with manifest diabetes, and likewise to improve muscle strength in both elderly healthy individuals and in elderly individuals with chronic disease. The increased strength is coupled to improved function and a decreased risk for fall injuries and fractures. Elderly individuals have preserved the capacity to improve muscle strength and mass with training, but seem to display a reduced sensitivity towards stimulating protein synthesis from nutritional intake, rather than by any reduced response in protein turnover to exercise.
Abstract: Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients with lipodystrophy (LIPO) and those without (controls). LIPOX was estimated by indirect calorimetry during fasting and steady state of a hyperinsulinemic euglycemic clamp in 36 (18 LIPO and 18 controls) normoglycemic HIV-infected men on highly active antiretroviral therapy. In LIPO, TNF-alpha correlated with clamp FFA (r = 0.67, P < .01), clamp LIPOX (r = 0.47, P < .05), incremental FFA (r = 0.69, P < .01), and incremental LIPOX (r = 0.64, P < .01), all of which, but not the clamp LIPOX correlation (r = 0.29, P > .05), remained significant after correction for insulin sensitivity. None of these correlations were significant in controls. In all patients, TNF-alpha correlated with clamp FFA (r = 0.61, P < .001), clamp LIPOX (r = 0.43, P < .01), and incremental FFA (r = 0.43, P < .01), with the 2 former correlations remaining significant after correction for insulin sensitivity. LIPOX and FFA (fasting and clamp values combined) correlated strongly and positively in both LIPO (R2 = 0.43, P < .001) and controls (R2 = 0.60, P < .0001). Fasting FFA and LIPOX did not differ between study groups; however, the insulin-mediated suppression of FFA and LIPOX was attenuated in LIPO (P's < .05). Our data indicate that higher TNF-alpha, independently of insulin sensitivity, is associated with attenuated insulin-mediated suppression of FFA and LIPOX in HIV-LIPO, suggesting in turn that TNF-alpha stimulates lipolysis in this syndrome. Furthermore, FFA may be a major determinant of LIPOX in HIV-infected patients on highly active antiretroviral therapy.
Abstract: OBJECTIVES: We examined whether insulin-resistant lipodystrophic HIV-infected patients with known high fasting prehepatic insulin secretion rates (FISRs) displayed alterations in first-phase prehepatic insulin response to intravenous glucose (ISREG0-10 min). METHODS: Eighteen normoglycaemic lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp technique. The disposition index (Di=ISREG0-10 min x SIRd) was calculated to estimate the beta-cell response relative to insulin sensitivity. RESULTS: FISR was increased by 69% (P<0.001), whereas median Di was decreased by 75% (P<0.01), primarily as a result of a reduction of SI(Rd) by 60% (P<0.001) in LIPO patients compared with controls. Three LIPO groups were identified arbitrarily according to their FISR and ISREG0-10 min values relative to those of controls. Four LIPO patients displayed high FISR [+3 standard deviations (SD), P<0.001], high ISREG0-10 min (+3 SD, P<0.001) and low SIRd (P<0.01), suggesting an intact B-cell capacity to compensate insulin resistance; six LIPO patients exhibited high FISR (+3SD, P<0.001), low ISREG0-10min (-1 SD, P=0.01), and low SIRd (P<0.01), suggesting depletion of readily releasable insulin stores; the remaining eight LIPO patients and controls displayed identical FISR and ISREG0-10 min. Increased concentrations of the nonglucose insulin secretagogues triglyceride (+124%), alanine (+35%) and glucagon (+88%), and also lactate (+96%) and tumour necrosis factor (TNF)-alpha (+62%) were observed in the 10 LIPO patients with aberrations in FISR and ISREG0-10 min compared with the remaining HIV-infected patients (all P<0.05). CONCLUSION: Plasma triglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients.
Abstract: The cause of insulin resistance and type 2 diabetes is unknown. The major part of insulin-mediated glucose disposal takes place in the skeletal muscle, and increased amounts of intramyocellular lipid has been associated with insulin resistance and linked to decreased activity of mitochondrial oxidative phosphorylation. This review will cover the present knowledge and literature on the topics of the activity of oxidative enzymes and the electron transport chain (ETC) in skeletal muscle of patients with type 2 diabetes. Different methods of studying mitochondrial function are described, including biochemical measurements of oxidative enzyme and electron transport activity, isolation of mitochondria for measurements of respiration, and ATP production and indirect measurements of ATP production using nuclear magnetic resonance (NMR) - spectroscopy. Biochemical markers of mitochondrial content are also discussed. Several studies show reduced activity of oxidative enzymes in skeletal muscle of type 2 diabetics. The reductions are independent of muscle fiber type, and are accompanied by visual evidence of damaged mitochondria. In most studies, the reduced oxidative enzyme activity is explained by decreases in mitochondrial content; thus, evidence of a functional impairment in mitochondria in type 2 diabetes is not convincing. These impairments in oxidative function and mitochondrial morphology could reflect the sedentary lifestyle of the diabetic subjects, and the influence of physical activity on oxidative activity and mitochondrial function is discussed. The studies on insulin-resistant offspring of type 2 diabetic parents have provided important insights in the earliest metabolic defects in type 2 diabetes. These defects include reductions in basal ATP production and an attenuated response to insulin stimulation. The decreased basal ATP production does not affect overall lipid or glucose oxidation, and no studies linking changes in oxidative activity and insulin sensitivity in type 2 diabetes have been published. It is concluded that evidence of a functional impairment in mitochondria in type 2 diabetes is not convincing, and that intervention studies describing the correlation between changes in insulin resistance and mitochondrial function in type 2 diabetes are lacking. Specific effects of regular physical training and muscular work on mitochondrial function and plasticity in type 2 diabetes remain an important area of research.
Abstract: This study was performed to investigate the effects of intermittent hypoxic exposure on blood and exercise parameters. Eight sea level residents were exposed to 2 h daily stimulus to 4100 m altitude in a hypobaric chamber for a total of 14 days. Exercise performance was evaluated at sea level before and after the hypoxic stimulation. Blood samples were obtained before, during, and at time points up to 14 days after the hypoxic exposure. No changes were observed in haemoglobin, haematocrit, reticulocytes, serum transferrin receptors, or EPO levels in the blood. Submaximal cycle (150 W) ergometer exercise corresponded to a oxygen uptake of 1.9+/-0.1 and 1.9+/-0.1 L min(-1) before and after the intermittent altitude exposure, respectively. At maximal exercise the workloads attained were 343+/-17 and 354+/-27 W before and after the exposure, with corresponding oxygen uptakes of 4.0+/-0.2 and 4.2+/-0.2 L min(-1). It is concluded that intermittent hypoxic exposure to 4100 m altitude for 2 h daily and a total of 14 days does not affect exercise capacity.
Abstract: Insulin-mediated glucose clearance (GC) is diminished in type 2 diabetes. Skeletal muscle has been estimated to account for essentially all of the impairment. Such estimations were based on leg muscle and extrapolated to whole body muscle mass. However, skeletal muscle is not a uniform tissue and insulin resistance may not be evenly distributed. We measured basal and insulin-mediated (1 pmol min-1 kg-1) GC simultaneously in the arm and leg in type 2 diabetes patients (TYPE 2) and controls (CON) (n=6 for both). During the clamp arterio-venous glucose extraction was higher in CON versus TYPE 2 in the arm (6.9+/-1.0 versus 4.7+/-0.8%; mean+/-s.e.m.; P=0.029), but not in the leg (4.2+/-0.8 versus 3.1+/-0.6%). Blood flow was not different between CON and TYPE 2 but was higher (P<0.05) in arm versus leg (CON: 74+/-8 versus 56+/-5; TYPE 2: 87+/-9 versus 43+/-6 ml min-1 kg-1 muscle, respectively). At basal, CON had 84% higher arm GC (P=0.012) and 87% higher leg GC (P=0.016) compared with TYPE 2. During clamp, the difference between CON and TYPE 2 in arm GC was diminished to 54% but maintained at 80% in the leg. In conclusion, this study shows that glucose clearance is higher in arm than leg muscles, regardless of insulin resistance, which may indicate better preserved insulin sensitivity in arm than leg muscle in type 2 diabetes.
Abstract: The incidence of osteoporosis is increasing and the general practitioner is integral to identifying these patients. It is, therefore, of interest to characterize the referral pattern of patients scheduled for determination of bone density by means of dual-energy X-ray absorptiometry scanning. Altogether, 1551 scans from first-time referred women were analyzed with respect to normal bone mineral density (BMD), osteopenia, and osteoporosis as the outcome, and the results were compared with age and body mass index (BMI). Using multiple regression analysis, risk estimates for osteoporosis were calculated with respect to patient characteristics. Only 21% of the referred patients had osteoporosis and 34% had osteopenia. Of these, 24% had osteopenia and a Z-score below -1. Half of the referred patients were women less than 60 yr with a markedly low risk of osteoporosis. A BMI less than 20 kg/m(2) increased the predictive value considerably. A low BMI is a good indicator for referral of women less than 60 yr for measurements of bone density. Forty-five percent of the referred women from general practitioners had a normal BMD.
Abstract: OBJECTIVES: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and beta-cell function in lipodystrophic HIV-infected patients. METHODS: [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. RESULTS: Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; > 34%, P < 0.001), hepatic insulin sensitivity (> 40%, P < 0.03), incremental glucose disposal (>50%, P < 0.001) and incremental exogenous glucose storage (>50%, P < 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P < 0.01), increased clamp free fatty acids (P < 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P < 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r = 0.69), incremental glucose disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all P < 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P = 0.05) in LIPO compared with the combined groups of NONLIPO and NAIVE, indicating an impaired adaptation of beta-cell function to insulin resistance in LIPO. CONCLUSION: Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and beta-cell function.
Abstract: Strength training enhances insulin sensitivity and represents an alternative to endurance training for patients with type 2 diabetes (T2DM). The 5'AMP-activated protein kinase (AMPK) may mediate adaptations in skeletal muscle in response to exercise training; however, little is known about adaptations within the AMPK system itself. We investigated the effect of strength training and T2DM on the isoform expression and the heterotrimeric composition of the AMPK in human skeletal muscle. Ten patients with T2DM and seven healthy subjects strength trained (T) one leg for 6 weeks, while the other leg remained untrained (UT). Muscle biopsies were obtained before and after the training period. Basal AMPK activity and protein/mRNA expression of both catalytic (alpha1 and alpha2) and regulatory (beta1, beta2, gamma1, gamma2a, gamma2b and gamma3) AMPK isoforms were independent of T2DM, whereas the protein content of alpha1 (+16%), beta2 (+14%) and gamma1 (+29%) was higher and the gamma3 content was lower (-48%) in trained compared with untrained muscle (all P < 0.01). The majority of alpha protein co-immunoprecipitated with beta2 and alpha2/beta2 accounted for the majority of these complexes. gamma3 was only associated with alpha2 and beta2 subunits, and accounted for approximately 20% of all alpha2/beta2 complexes. The remaining alpha2/beta2 and the alpha1/beta2 complexes were associated with gamma1. The trimer composition was unaffected by T2DM, whereas training induced a shift from gamma3- to gamma1-containing trimers. The data question muscular AMPK as a primary cause of T2DM whereas the maintained function in patients with T2DM makes muscular AMPK an obvious therapeutic target. In human skeletal muscle only three of 12 possible AMPK trimer combinations exist, and the expression of the subunit isoforms is susceptible to moderate strength training, which may influence metabolism and improve energy homeostasis in trained muscle.
Abstract: The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.
Abstract: Low birth weight (LBW) is associated with increased risk of developing type 2 diabetes later in life. Progression from normal to impaired glucose tolerance and overt diabetes may depend, to some extent, on elevation of plasma free fatty acids (FFAs). We undertook this study to elucidate whether a prolonged physiological lipid load could unmask or augment existing metabolic defects in otherwise healthy young LBW subjects. Forty 19-year-old men (LBW [n = 20], controls [normal birth weight, NBW] [n = 20]) without a family history of diabetes underwent an intravenous glucose tolerance test (0.3 g kg(-1)), followed by 2-step hyperinsulinemic-euglycemic clamps (2 x 120 minutes: 10 and 40 mU m(-2) min(-1)) in combination with [3-3H]-glucose and indirect calorimetry. The tests were preceded, in randomized order, by a 24-hour continuous intralipid (20%, 0.4 mg mL(-1) h(-1)) or saline infusion. Estimates of cellular glucose metabolism were obtained and a disposition index calculated. Clamp FFA concentrations were 4- to ten-fold higher during lipid infusion. Both groups experienced a similar decrease in insulin-stimulated glucose disposal in response to lipid infusion (approximately 15%; P < .05), which was mainly accounted for by reduced glucose oxidation (approximately 30%; P < .001). Glycolysis, glucose storage, and glucose production were not significantly altered by lipid infusion. Nevertheless, the LBW group had significantly lower insulin-stimulated glycolysis during lipid infusion (approximately 27%; P < .05) than the NBW group. An appropriate increase in insulin secretion matched the decline in insulin sensitivity in both groups. A 24-hour low-grade intralipid infusion has similar effects on whole-body glucose metabolism and first-phase insulin secretion in 19-year-old, healthy, lean, LBW men with normal glucose tolerance and in NBW controls. We reproduced our previous finding of lower insulin-stimulated glycolysis in this population.
Abstract: Oxidative stress is implicated in diabetes complications, during which endogenous antioxidant defenses have important pathophysiological consequences. To date, the significance of endogenous antioxidants such as metallothioneins I and II (MT-I+II) in type 2 diabetes remains unclear. To examine the MT-I+II-mediated antioxidant capacity and its response to exercise training in the skeletal muscle of patients with type 2 diabetes, biopsies and blood samples were taken from 13 matched subjects (type 2 diabetes n = 8, control subjects n = 5) both before and after 8 weeks of exercise training. Immunohistochemical analysis revealed reduced MT-I+II levels in the skeletal muscle of type 2 diabetic subjects compared with control subjects. Control subjects produced a robust increase of MT-I+II in response to training; however, in type 2 diabetes, MT-I+II levels remained essentially unchanged. Significantly lower levels of MT-I+II were also detected in the plasma of type 2 diabetic subjects compared with control subjects. These results suggest that, in control subjects, the MT-I+II defense system is active and inducible within skeletal muscle tissue and plasma. In type 2 diabetes, reduced levels of MT-I+II in muscle and plasma, as well as the deficient MT-I+II response to exercise, indicate that this antioxidant defense is impaired. This study presents a novel candidate in the pathogenesis of complications related to oxidative stress in type 2 diabetes.
Abstract: While caffeine impedes insulin-mediated glucose disposal in humans, its effect on endo-genous glucose production (EGP) remains unknown. In addition, the mechanism involved in these effects is unclear, but may be due to the accompanying increase in adrenaline concentration. We studied the effect of caffeine on EGP and glucose infusion rates (GIR), and whether or not adrenaline can account for all of caffeine's effects. Subjects completed three isoglycaemic-hyperinsulinaemic clamps (with 3-[(3)H]glucose infusion) 30 min after ingesting: (1) placebo capsules (n= 12); (2) caffeine capsules (5 mg kg(-1)) (n= 12); and either (3) placebo plus a high-dose adrenaline infusion (HAdr; adrenaline concentration, 1.2 nM; n= 8) or (4) placebo plus a low-dose adrenaline infusion (LAdr; adrenaline concentration, 0.75 nM; n= 6). With caffeine, adrenaline increased to 0.6 nM but no effect on EGP was observed. While caffeine and HAdr decreased GIR by 13 (P < 0.05) and 34% (P < 0.05) versus the placebo, respectively, LAdr did not result in a significant reduction (5%) in GIR versus the placebo. Due to the fact that both caffeine and LAdr resulted in similar adrenaline concentrations, but resulted in different decreases in GIR, it is concluded that adrenaline alone does not account for the effects of caffeine and additional mechanisms must be involved.
Abstract: Insulin resistance is currently a major health problem. This may be because of a marked decrease in daily physical activity during recent decades combined with constant food abundance. This lifestyle collides with our genome, which was most likely selected in the late Paleolithic era (50,000-10,000 BC) by criteria that favored survival in an environment characterized by fluctuations between periods of feast and famine. The theory of thrifty genes states that these fluctuations are required for optimal metabolic function. We mimicked the fluctuations in eight healthy young men [25.0 +/- 0.1 yr (mean +/- SE); body mass index: 25.7 +/- 0.4 kg/m(2)] by subjecting them to intermittent fasting every second day for 20 h for 15 days. Euglycemic hyperinsulinemic (40 mU.min(-1).m(-2)) clamps were performed before and after the intervention period. Subjects maintained body weight (86.4 +/- 2.3 kg; coefficient of variation: 0.8 +/- 0.1%). Plasma free fatty acid and beta-hydroxybutyrate concentrations were 347 +/- 18 and 0.06 +/- 0.02 mM, respectively, after overnight fast but increased (P < 0.05) to 423 +/- 86 and 0.10 +/- 0.04 mM after 20-h fasting, confirming that the subjects were fasting. Insulin-mediated whole body glucose uptake rates increased from 6.3 +/- 0.6 to 7.3 +/- 0.3 mg.kg(-1).min(-1) (P = 0.03), and insulin-induced inhibition of adipose tissue lipolysis was more prominent after than before the intervention (P = 0.05). After the 20-h fasting periods, plasma adiponectin was increased compared with the basal levels before and after the intervention (5,922 +/- 991 vs. 3,860 +/- 784 ng/ml, P = 0.02). This experiment is the first in humans to show that intermittent fasting increases insulin-mediated glucose uptake rates, and the findings are compatible with the thrifty gene concept.
Abstract: Strength training represents an alternative to endurance training for patients with type 2 diabetes. Little is known about the effect on insulin action and key proteins in skeletal muscle, and the necessary volume of strength training is unknown. A total of 10 type 2 diabetic subjects and 7 healthy men (control subjects) strength-trained one leg three times per week for 6 weeks while the other leg remained untrained. Each session lasted no more than 30 min. After strength training, muscle biopsies were obtained, and an isoglycemic-hyperinsulinemic clamp combined with arterio-femoral venous catheterization of both legs was carried out. In general, qualitatively similar responses were obtained in both groups. During the clamp, leg blood flow was higher (P < 0.05) in trained versus untrained legs, but despite this, arterio-venous extraction glucose did not decrease in trained legs. Thus, leg glucose clearance was increased in trained legs (P < 0.05) and more than explained by increases in muscle mass. Strength training increased protein content of GLUT4, insulin receptor, protein kinase B-alpha/beta, glycogen synthase (GS), and GS total activity. In conclusion, we found that strength training for 30 min three times per week increases insulin action in skeletal muscle in both groups. The adaptation is attributable to local contraction-mediated mechanisms involving key proteins in the insulin signaling cascade.
Abstract: Lactate is released from skeletal muscle in proportion to glucose uptake rates, and it leaves the cells via simple diffusion and two monocarboxylate transporter proteins, MCT1 and MCT4. In response to endurance training MCT1 - and possibly MCT4 - content in muscle increases. The MCTs have not previously been measured in patients with type 2 diabetes (Type 2), and the response to strength training is unknown. Ten Type 2 and seven healthy men (Control) strength-trained one leg (T) 3 times a week for 6 weeks while the other leg remained untrained (UT). Each session lasted no more than 30 min. After strength training, muscle biopsies were obtained and an isoglycaemic, hyperinsulinaemic clamp, combined with arterial and femoral venous catheterization of both legs, was carried out. During hyperinsulinaemia lactate release was always increased in T versus UT legs. MCT1 was lower (P<0.05) and MCT4 similar in Type 2 versus Control. With training, MCT1 content always increased, while MCT4 only increased in Control. Conclusions: MCT1 content in skeletal muscle in Type 2 is lower compared with healthy men. Strength training increases MCT1 content in healthy men and in Type 2, thus normalizing the content in Type 2.
Abstract: Insulin therapy to maintain euglycemia increases survival in critically ill patients. To explore possible mechanisms of action, we investigated the effect of endotoxin on circulating cytokines, free fatty acids (FFA), and leukocytes during manipulated plasma glucose and insulin concentrations. Ten volunteers underwent three trials each, receiving an intravenous bolus of endotoxin (0.2 ng/kg) during normoglycemia (trial A, control), during a hyperglycemic clamp at 15 mM (trial B), and during a hyperinsulinemic euglycemic clamp (trial C). Endotoxin induced an increase in neutrophil count, a decrease in lymphocyte count, and an increase in serum levels of TNF-alpha, IL-6, and FFA. There was no difference in the TNF response between the three trials; the IL-6 levels were increased during the late phase of trials B and C compared with trial A. The endotoxin-induced elevation in FFA in trial A was suppressed during trials B and C. Clamping (trials B and C) caused a reduction in lymphocyte count that persisted after endotoxin injection. We conclude that low-dose endotoxemia triggers a subclinical inflammatory response and an elevation in FFA. The finding that high insulin serum concentrations induce a more prolonged increase in the anti-inflammatory cytokine IL-6 and suppress the levels of FFA suggests that insulin treatment of patients with sepsis may exert beneficial effects by inducing anti-inflammation and protection against FFA toxicity, and thereby inhibit FFA-induced insulin resistance.
Abstract: Strenuous exercise increases the cerebral uptake of carbohydrate out of proportion to that of oxygen, but it is unknown whether such enhanced carbohydrate uptake is influenced by the marked endocrine response to exercise. During exhaustive exercise this study evaluated the a-v differences across the brain (a-v diff) of hormones that could influence its carbohydrate uptake (n= 9). In addition, neuroendocrine activity and a potential uptake of hormones via the cerebrospinal fluid (CSF) were assessed by lumbar puncture postexercise and at rest (n= 6). Exercise increased the arterial concentration of noradrenaline and adrenaline, but there was no cerebral uptake. However, following exercise CSF noradrenaline was 1.4 (0.73-5.5) nmol l(-1), and higher than at rest, 0.3 (0.19-1.84) nmol l(-1) (P < 0.05), whereas adrenaline could not be detected. Exercise increased both the arterial concentration of NH(4)(+) and its a-v diff, which increased from 1 (-12 to 5) to 17 (5-41) micromol l(-1) (P < 0.05), while the CSF NH(4)(+) was reduced to 7 (0-10) versus 11 (7-16) micromol l(-1) (P < 0.05). There was no release from, or accumulation in the brain of interleukin (IL)-6, tumour necrosis factor (TNF-alpha), heatshock protein (HSP72), insulin, or insulin-like growth factor (IGF)-I. The findings indicate that for maximal exercise, the concentration of noradrenaline is increased within the brain, whereas blood borne hormones and cytokines are seemingly unimportant. The results support the notion that the exercise-induced changes in brain metabolism are controlled by factors intrinsic to the brain.
Abstract: Ten patients with type 2 diabetes and seven controls were strength-trained with one leg for 30 min three times per week for 6 weeks. The training-induced changes in the protein densities of the Na,K-pump subunits and the Na+/H+ exchanger protein NHE1 were quantified with Western blotting of needle biopsy material obtained from trained and untrained legs of both groups. Training increased the bench press and knee-extensor force by 77+/-15 and 28+/-1%, respectively, in the control subjects, and by 75+/-7 and 42+/-8%, respectively, in the diabetics. In the control subjects the Na,K-pump isoform alpha1 was increased by 37% (P<0.05) in trained compared to untrained leg, and in the diabetics the alpha1 content was 45% higher (P=0.052) in trained compared to untrained leg. For the alpha2 isoform the corresponding values were 21% and 41% (P<0.05), respectively. The content of the beta1 subunit in the control subjects was 33% higher (P<0.05) in trained compared to untrained leg, and 47% higher (P=0.06) in trained compared to untrained leg in the diabetics. Thus, a limited amount of strength-training is able to increase the Na,K-pump subunit and isoform content both in controls and in patients with type 2 diabetes.
Abstract: In healthy young subjects, training increases insulin sensitivity but decreases the capacity to secrete insulin. We studied whether training changes beta-cell function in type 2 diabetic patients. Patients, stratified into "moderate" and "low" secretors according to individual C-peptide responses to an intravenous glucagon test, were randomly assigned to a training program [ergometer cycling 30-40 min/day, including at least 20 min at 75% maximum oxygen consumption (Vo(2 max)), 5 days/wk for 3 mo] or a sedentary schedule. Before and after the intervention (16 h after last training bout), a sequential hyperglycemic (90 min at 11, 18, and 25 mM) clamp was performed. An intravenous bolus of 5 g of arginine was given at the end. Training increased Vo(2 max) 17 +/- 13% and decreased heart rate during submaximal exercise (P < 0.05). During the 3 mo of sedentary lifestyle, insulin and C-peptide responses to the clamp procedures were unchanged in both moderate and low secretors. Likewise, no change in beta-cell response was seen after training in the low secretors (n = 5). In contrast, moderate secretors (n = 9) showed significant increases in beta-cell responses to 18 and 25 mM hyperglycemia and to arginine stimulation. Glucagon responses to arginine as well as measures of insulin sensitivity and Hb A(1c) levels were not altered by training. In conclusion, in type 2 diabetic patients, training may enhance beta-cell function if the remaining secretory capacity is moderate but not if it is low. The improved beta-cell function does not require changes in insulin sensitivity and Hb A(1c) concentration.
Abstract: We examined whether plasma concentrations of nonglucose insulin secretagogues are associated with prehepatic insulin secretion rates (ISR) in nondiabetic, insulin-resistant, human immunodeficiency virus (HIV)-infected, lipodystrophic patients (LIPO). Additionally, the negative feedback of insulin on ISR was evaluated. ISR were estimated by deconvolution of plasma C-peptide concentrations during fasting (basal) and during the last 30 min of a 120-min euglycemic insulin clamp (40 mU.m(-2).min(-1)). Eighteen normoglycemic LIPO were compared with 25 normoglycemic HIV-infected patients without lipodystrophy (controls). Thirty minutes before start of the clamp, a bolus of glucose was injected intravenously to stimulate endogenous insulin secretion. Insulin sensitivity index (SiRd) was estimated from glucose tracer analysis. LIPO displayed increased basal ISR (69%), clamp ISR (114%), basal insulin (130%), and clamp insulin (32%), all P < or = 0.001, whereas SiRd was decreased (57%, P < 0.001). In LIPO, ISRbasal correlated significantly with basal insulin, alanine, and glucagon (all r > 0.65, P < 0.01), but not with glucose. In control subjects, ISR(basal) correlated significantly with insulin, glucagon, and glucose (all r > 0.41, P < 0.05), but not with alanine. In LIPO, ISRclamp correlated significantly with clamp free fatty acids (FFA), alanine, triglyceride, and glucagon (all r > 0.51, P < 0.05). In control subjects, ISRclamp correlated with clamp triglyceride (r = 0.45, P < 0.05). Paradoxically, in LIPO, ISRclamp correlated positively with clamp insulin (r = 0.68, P < 0.01), which suggests an absent negative feedback of insulin on ISR. Our data support evidence that lipodystrophic, nondiabetic, HIV-infected patients exhibit increased ISR, which can be partially explained by an impaired negative feedback of insulin on beta-cells and an increased stimulation of ISR by FFA, alanine, triglyceride, and glucagon.
Abstract: BACKGROUND: We studied the role of the central nervous system, neural feedback from contracting skeletal muscles, and sympathetic activity to the heart in the control of heart rate and blood pressure during 2 levels of dynamic exercise. METHODS AND RESULTS: Spinal cord-injured individuals (SCI) with (paraplegia, n=4) or without (tetraplegia, n=6) sympathetic innervation to the heart performed electrically induced exercise. Responses were compared with those established by able-bodied individuals (control, n=6) performing voluntary exercise at a similar pulmonary oxygen uptake. In all subjects, cardiac output and leg blood flow increased, but in SCI they reached a maximal value. The increase in cardiac output was mainly elicited by an increase in stroke volume in individuals with tetraplegia, whereas in individuals with paraplegia it was by heart rate. The increase in SCI was slow compared with that in controls. During exercise, blood pressure was stable in controls, whereas it decreased over time in SCI and especially in individuals with tetraplegia. CONCLUSIONS: The autonomic nervous system provides for acceleration of the heart at the onset of exercise, but a slow increase in heart rate is established even without central command, neural feedback from working muscles, or autonomic influence on the heart. Yet an intact autonomic nervous system is a prerequisite for a large rise in cardiac output and in turn leg blood flow during exercise. Thus, when the sympathetic nervous system is injured at a level where it influences the heart, vasodilatation in working muscles challenges blood pressure.
Abstract: Insulin resistance in skeletal muscle is a hallmark feature of type 2 diabetes. An increasing number of enzymes and metabolic pathways have been implicated in the development of insulin resistance. However, the primary cellular cause of insulin resistance remains uncertain. Proteome analysis can quantitate a large number of proteins and their post-translational modifications simultaneously and is a powerful tool to study polygenic diseases like type 2 diabetes. Using this approach on human skeletal muscle biopsies, we have identified eight potential protein markers for type 2 diabetes in the fasting state. The observed changes in protein expression indicate increased cellular stress, e.g. up-regulation of two heat shock proteins, and perturbations in ATP (re)synthesis and mitochondrial metabolism, e.g. down-regulation of ATP synthase beta-subunit and creatine kinase B, in skeletal muscle of patients with type 2 diabetes. Phosphorylation appears to play a key, potentially coordinating role for most of the proteins identified in this study. In particular, we demonstrated that the catalytic beta-subunit of ATP synthase is phosphorylated in vivo and that the levels of a down-regulated ATP synthase beta-subunit phosphoisoform in diabetic muscle correlated inversely with fasting plasma glucose levels. These data suggest a role for phosphorylation of ATP synthase beta-subunit in the regulation of ATP synthesis and that alterations in the regulation of ATP synthesis and cellular stress proteins may contribute to the pathogenesis of type 2 diabetes.
Abstract: BACKGROUND: Surgery is succeeded by long-lasting state of relative peripheral insulin resistance, which is reduced by giving glucose infusion or oral carbohydrate-rich drinks immediate before operating instead of fasting. The aim of the present study was to investigate whether oral carbohydrate or carbohydrate with peptide drinks preoperatively instead of fasting would improve postoperative voluntary muscle strength, nutritional intake and ambulation, decrease postoperative fatigue, anxiety and discomfort, and reduce the endocrine response to surgery. METHODS: Forty-eight patients were included and randomized into three groups to receive 2 x 400 ml of carbohydrate-rich drinks or to fast overnight and allowed only water. Voluntary grip and quadriceps strength, body composition, pulmonary function, VAS-score of eight parameters of wellbeing, muscle biopsies and insulin, glucagon, IGF-1 and free fatty acids were measured before and after the operation. The basic postoperative regimen for all groups were immediate oral nutrition and early enforced mobilization. RESULTS: Significant postoperative decrease in glycogen synthase activity in the muscle biopsies was reduced in the intervention groups, and in combination, the intervention groups had a less reduced quadriceps strength after one week (-10% vs. -16%, NS) and one month (-5% vs. -13%, P < 0.05). Minor changes in the endocrine response to surgery were found without differences between the groups, and there were no differences between the groups in ambulation time, nutritional intake or subjective measures of wellbeing.
Abstract: The purpose of the current study was to test the hypothesis that an altered fat distribution in elderly healthy subjects and in patients with type-2 diabetes contributes to high circulating levels of interleukin (IL)-6 and tumor necrotic factor (TNF)-alpha, which secondly is related to lower muscle mass. Twenty young controls, (20-35 yr), 20 healthy elderly subjects (65-80 yr) and 16 elderly patients with type 2 diabetes (65-80 yr) were included in a cross sectional study. Plasma levels of TNF-alpha and IL-6 were measured after an overnight fast. Dual-energy X-ray absorptiometry and total body potassium counting measured truncal fat, appendicular skeletal muscle mass (ASM) and body cell mass (BCM), respectively. TNF-alpha, IL-6 and the relative truncal fat mass were higher in elderly compared with young controls. ASM was lower in diabetic men than in young controls and BCM was lower in elderly men compared with young men. TNF-alpha and IL-6 were correlated with the absolute as well as the relative truncal fat mass in univariate regression analyses. Similar results were found in multivariate linear regression analyses after adjusting for the effect of age and gender. TNF-alpha was related to lower ASM and BCM in elderly men both in a univariate regression analysis and a multivariate regression analysis. In conclusion, high plasma levels of TNF-alpha and IL-6 in elderly healthy people and in patients with type 2 diabetes are associated with increased truncal fat mass, suggesting that cytokines are partly derived from this adipose tissue bed. Furthermore, TNF-alpha was related to lower ASM and BCM, suggesting that TNF-alpha contributes to sarcopenia in ageing.
Abstract: Endurance training elicits profound adaptations of skeletal muscle, including increased expression of several proteins. The 5'-AMP activated protein kinase (AMPK) may be one of these, considering the fact that acute exercise increases AMPK activity. Eight young (26 +/- 1 year) lean, healthy males endurance trained one leg (while the other leg remained resting) on an ergometer bicycle for 30 min/day for four weeks (workload corresponding to approximately 70% of maximal oxygen uptake). Muscle biopsies were obtained approximately 18 h after the previous training session. On day eight GLUT4 protein expression was 36% higher in trained (T) compared with untrained (UT) (P < 0.05), but no further increase was seen at day 14 and 30 despite continuously increasing absolute workloads. Expression of AMPKalpha2 and actin did not change with training. In contrast, expression of AMPKalpha1 was 27% higher in T vs. UT muscle (P < 0.05) (measured only on day 30). Conclusions: GLUT4 protein expression increases substantially after seven days of endurance training with no further increase with prolonged training at progressively increasing workloads. AMPKalpha1 and alpha2 behave differently in their expression in response to endurance training. AMPKalpha1 protein content is increased after one month of training, while no change in AMPKalpha2 and actin expression was detected over the time course of the training period.
Abstract: Aerobic endurance training increases insulin action in skeletal muscle, but the effect of resistance training has not been well described. Controversy exists about whether the effect of resistance training is merely due to an increase in muscle mass. We studied the effect of cessation of resistance training in young, healthy subjects by taking muscle biopsies and measuring insulin-mediated whole body and leg glucose uptake rates after 90 days of heavy resistance training (T) and again after 90 days of de-training (dT). Data on leg glucose uptake were expressed relative to accurate measures of leg muscle mass by MRI scanning. Muscle strength (239 +/- 43 vs. 208 +/- 33 N m), quadriceps area (8463 +/- 453 vs. 7763 +/- 329 mm2) and glycogen content (458 +/- 22 vs. 400 +/- 26 mmol (kg dry weight muscle)(-1)) decreased, while myosin heavy chain isoform IIX increased 4-fold in dT vs. T, respectively (all P < 0.05). GLUT4 mRNA levels and enzyme activities and mRNA levels of glycolytic, lipolytic and glyconeogenic enzymes did not change with de-training. Likewise, capillary density did not change. Whole body glucose uptake decreased 11 % and leg glucose uptake decreased from 75 +/- 11 (T) to 50 +/- 6 (dT) nmol min(-1) (mm muscle)(-2) (P < 0.05) at maximal insulin, the latter decrease being due to decreased arterio-femoral venous glucose extraction. The decrease was mainly due to reduced non-oxidative glucose disposal. We have thus shown that 90 days after the termination of heavy resistance training, insulin-mediated glucose uptake rates per unit of skeletal muscle have decreased significantly.
Abstract: We studied whether endurance training impacts insulin sensitivity by affecting the structural and storage lipids in humans. Eight male subjects participated (age 25 +/- 1 years, height 178 +/- 3 cm, weight 76 +/- 4 kg [mean +/- SE]). Single-leg training was performed for 30 min/day for 4 weeks at approximately 70% of single-leg maximal oxygen uptake. After 8, 14, and 30 days, a two-step hyperinsulinemic-euglycemic glucose clamp, combined with catheterization of an artery and both femoral veins, was performed. In addition, a muscle biopsy was obtained from vastus lateralis of both legs. Maximal oxygen uptake increased by 7% in the trained leg (T), and training workload increased (P < 0.05) from 79 +/- 12 to 160 +/- 15 W. At day 8, glucose uptake was higher (P < 0.01) in the trained (0.8 +/- 0.2, 6.0 +/- 0.8, 13.4 +/- 1.2 mg x min(-1) x kg(-1) leg wt) than the untrained leg (0.5 +/- 0.2, 3.7 +/- 0.6, 10.5 +/- 1.5 mg x min(-1) x kg(-1) leg wt) at basal and the two succeeding clamp steps, respectively. After day 8, training did not further increase leg glucose uptake. Individual muscle triacylglycerol fatty acid composition and total triacylglycerol content were not significantly affected by training and thus showed no relation to leg glucose uptake. Individual muscle phospholipid fatty acids were not affected by training, but the content of phospholipid polyunsaturated fatty acids was higher (P < 0.06) after 30 than 8 days in T. Furthermore, after 30 days of training, the sum of phospholipid long-chain polyunsaturates was correlated to leg glucose uptake (r = 0.574, P < 0.04). Endurance training did not influence muscle triacylglycerol content or total triacylglycerol fatty acid composition. In contrast, training induced a minor increase in the content of phospholipid fatty acid membrane polyunsaturates, which may indicate that membrane lipids may have a role in the training-induced increase in insulin sensitivity.
Abstract: We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp (HI), 40 mU/m(2) x min], 3-(3)H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.
Abstract: Several studies have linked low birth weight (LBW) and type 2 diabetes. We investigated hepatic and peripheral insulin action including intracellular glucose metabolism in 40 19-year-old men (20 LBW, 20 matched control subjects), using the hyperinsulinemic-euglycemic clamp technique at two physiological insulin levels (10 and 40 mU/m(2) per min), indirect calorimetry, and [3-(3)H]glucose. Insulin secretion was examined during an oral and intravenous glucose tolerance test. Fasting p-glucose was higher in the LBW group (5.6 +/- 0.1 vs. 5.4 +/- 0.1; P < 0.05). Basal plasma glycerol concentrations were significantly lower in the LBW group. Insulin-stimulated glycolytic flux was significantly reduced, and suppression of endogenous glucose production was enhanced in the LBW group. Nevertheless, basal and insulin-stimulated rates of whole-body peripheral glucose disposal, glucose oxidation, lipid oxidation, exogenous glucose storage, and nonoxidative glucose metabolism were similar in the two groups. Insulin secretion was reduced by 30% in the LBW group, when expressed relative to insulin sensitivity (disposition index = insulin secretion x insulin action). We propose that reduced insulin-stimulated glycolysis precedes overt insulin resistance in LBW men. A lower insulin secretion may contribute to impaired glucose tolerance and ultimately lead to diabetes.
Abstract: Increased daily physical activity is effective in the prevention of type 2 diabetes and several of the components in the metabolic syndrome. However, dedicated efforts in exercise training will also be effective in the treatment of the metabolic syndrome. The effect on glycaemic control is of the same order of magnitude as can be achieved by oral antidiabetic drugs. In addition, exercise (endurance and/or strength training) will also improve insulin resistance and body composition. The results are more doubtful for the dyslipidaemia and hypertension, but if the training is combined with an appropriate diet, these abnormalities are also correctable.
Abstract: PURPOSE: Individuals with spinal cord injuries (SCI) have an increased prevalence of insulin resistance and type 2 diabetes mellitus. In able-bodied individuals, training with large muscle groups increases insulin sensitivity and may prevent type 2 diabetes mellitus. However, individuals with SCI cannot voluntarily recruit major muscle groups, but by functional electrical stimulation (FES) they can now perform ergometer bicycle training. METHODS: Ten subjects with SCI (35 +/- 2 yr (mean +/- SE), 73 +/- 5 kg, level of lesion C6--Th4, time since injury: 12 +/- 2 yr) performed 1 yr of FES cycling (30 min x d(-1), 3 d x wk(-1) (intensive training)). Seven subjects continued 6 months with reduced training (1 d x wk(-1) (reduced training)). A sequential, hyperinsulinemic (50 mU x min(-1) x m(-2) (step 1) and 480 mU x min(-1) x m(-2) (step 2)), euglycemic clamp, an oral glucose tolerance test (OGTT), and determination of GLUT 4 transporter protein in muscle biopsies were performed before and after training. RESULTS: Insulin-stimulated glucose uptake rates increased after intensive training (from 4.9 +/- 0.5 mg x min(-1) x kg(-1) to 6.2 +/- 0.6 mg x min(-1) x kg(-1) (P < 0.008) (step 1) and from 9.0 +/- 0.8 mg x min(-1) x kg(-1) to 10.6 +/- 0.8 mg x min(-1) x kg(-1) (P = 0.103) (step 2)). With the reduction in training, insulin sensitivity decreased to a similar level as before training (P > 0.05). GLUT 4 increased by 105% after intense training and decreased again with the training reduction. The subjects had impaired glucose tolerance before and after training, and neither glucose tolerance nor insulin responses to OGTT were significantly altered by training. CONCLUSIONS: Electrically induced bicycle training, performed three times per week increases insulin sensitivity and GLUT 4 content in skeletal muscle in subjects with SCI. A reduction in training to once per week is not sufficient to maintain these effects. FES training may have a role in the prevention of the insulin resistance syndrome in persons with SCI.
Abstract: Exercise-induced increases in cardiac output (CO) and oxygen uptake (VO2) are tightly coupled, as also in absence of central motor activity and neural feedback from skeletal muscle. Neuromodulators of vascular tone and cardiac function - such as calcitonin gene related peptide (CGRP) - may be of importance. Spinal cord injured individuals (six tetraplegic and four paraplegic) performed electrically induced cycling (FES) with their paralyzed lower limbs for 29 +/- 2 min to fatigue. Voluntary cycling performed both at VO2 similar to FES and at maximal exercise in six healthy subjects served as control. In healthy subjects, CGRP in plasma increased only during maximal exercise (33.8 +/- 3.1 pmol l(-1) (rest) to 39.5 +/- 4.3 (14%, P<0.05)) with a mean extraction over the working leg of 10% (P<0.05). Spinal cord injured individuals had more pronounced increase in plasma CGRP (33.2 +/- 3.8 to 46.9 +/- 3.6 pmol l-1, P<0.05), and paraplegic and tetraplegic individuals increased in average by 23% and 52%, respectively, with a 10% leg extraction in both groups (P<0.05). The exercise induced increase in leg blood flow was 10-12 fold in both spinal cord injured and controls at similar VO2 (P<0.05), whereas CO increased more in the controls than in spinal man. Heart rate (HR) increased more in paraplegic subjects (67 +/- 7 to 132 +/- 15 bpm) compared with controls and tetraplegics (P<0.05). Mean arterial pressure (MAP) was unchanged during submaximal exercise and increased during maximal exercise in healthy subjects, but decreased during the last 15 min of exercise in the tetraplegics. It is concluded that plasma CGRP increases during exercise, and that it is taken up by contracting skeletal muscle. The study did not allow for a demonstration of the origin of the CGRP, but its release does not require activation of motor centres. Finally, the more marked increase in plasma CGRP and the decrease in blood pressure during exercise in tetraplegic humans may indicate a role of CGRP in regulation of vascular tone during exercise.
Abstract: The mechanism behind exercise-induced decreases in plasma insulin concentrations was examined in eight healthy young men. In addition, the influence of specific alpha(1)- and alpha(2)-adrenoceptor blockade on glucose kinetics during exercise was studied. To test the hypothesis that exercise-induced decreases in insulin secretion are mediated via alpha(2)-adrenoceptors, all subjects exercised for 60 min on separate occasions under four conditions: with and without alpha(1)-receptor blockade (1 mg prazosin) and with and without or alpha(2)-receptor blockade (15 mg yohimbine). Glucose kinetics were measured using [3-(3)H]glucose. During exercise with alpha(2)-receptor blockade, the insulin concentration initially increased (first 20 min) then decreased, whereas it continually decreased in the corresponding control experiment. The C-peptide concentration did not change during exercise with alpha(2)-receptor blockade but decreased in the control experiment. During exercise with alpha(1)-receptor blockade and corresponding control experiments, insulin and C-peptide levels always decreased. With alpha(1)-receptor blockade, the glucose concentration increased (first 30 min) and then decreased, whereas it slightly decreased in all other experiments. In addition, with alpha(1)-receptor blockade, the glucose rate of appearance (Ra) increased rapidly (because of higher catecholamine concentrations in alpha(1)-receptor blockade versus control) and the glucose rate of disappearance (Rd) was higher compared with control. During exercise with alpha(2)-receptor blockade, the Ra and Rd were always lower compared with control. Therefore, we conclude that exercise-induced decreases in insulin secretion are mediated via alpha(2)-adrenoceptors and that blockade of alpha(1)- and alpha(2)-adrenoceptors during exercise elicits opposite responses in glucose Ra and Rd.
Abstract: Motor center activity and reflexes from contracting muscle have been shown to be important for mobilization of free fatty acids (FFA) during exercise. We studied FFA metabolism in the absence of these mechanisms: during involuntary, electrically induced leg cycling in individuals with complete spinal cord injury (SCI). Healthy subjects performing voluntary cycling served as controls (C). Ten SCI (level of injury: C5-T7) and six C exercised for 30 min at comparable oxygen uptake rates (approximately 1 l/min), and [1-14C]palmitate was infused continuously to estimate FFA turnover. From femoral arteriovenous differences, blood flow, muscle biopsies, and indirect calorimetry, leg substrate balances as well as concentrations of intramuscular substrates were determined. Leg oxygen uptake was similar in the two groups during exercise. In SCI, but not in C, plasma FFA and FFA appearance rate fell during exercise, and plasma glycerol increased less than in C (P < 0.05). Fractional uptake of FFA across the working legs decreased from rest to exercise in all individuals (P < 0.05) but was always lower in SCI than in C (P < 0.05). From rest to exercise, leg FFA uptake increased less in SCI than in C subjects (14 +/- 3 to 57 +/- 20 vs. 41 +/- 13 to 170 +/- 57 micromol x min(-1) x leg(-1); P < 0.05). Muscle glycogen breakdown, leg glucose uptake, carbohydrate oxidation, and lactate release were higher (P < 0.05) in SCI than in C during exercise. Counterregulatory hormonal changes were more pronounced in SCI vs. C, whereas insulin decreased only in C. In conclusion, FFA mobilization, delivery, and fractional uptake are lower and muscle glycogen breakdown and glucose uptake are higher in SCI patients during electrically induced leg exercise compared with healthy subjects performing voluntary exercise. Apparently, blood-borne mechanisms are not sufficient to elicit a normal increase in fatty acid mobilization during exercise. Furthermore, in exercising muscle, FFA delivery enhances FFA uptake and inhibits carbohydrate metabolism, while carbohydrate metabolism inhibits FFA uptake.
Abstract: Insulin mediates an increase in blood flow in the skeletal muscle. This may be brought about through recruitment of sympathetic vasodilatory nervous activity in the central nervous system (CNS). Insulin may also mediate the vasodilatation by locally acting mechanisms in the skeletal muscle, which in turn could be modulated by vasoconstrictive sympathetic nervous activity. Five men with complete motoric lesions of their cervical spinal cord (SCI) and nine healthy (H) men underwent a hyperinsulinemic (480 mU x min(-1) x m(-2)), euglycemic clamp combined with arterio-venous catheterization of one leg and microdialysis of the thigh muscle. In response to hyperinsulinemia leg blood flow increased similarly in the two groups. Leg glucose extraction and uptake were significantly lower in SCI compared with H. Two hours post clamp, leg glucose uptake rates had not yet returned to basal values. Norepinephrine concentrations in arterial plasma and in the dialysate (reflecting extracellular fluid) did not change in response to insulin in either group, but increased in response to suprapubic bladder tapping in the SCI. Potassium balance measured by microdialysis shifted from a net release to a net uptake in response to insulin, with no difference between SCI and H. In conclusion, the mechanism by which insulin mediates an increase in skeletal muscle blood flow is not due to a CNS recruitment of sympathetic vasodilatory nervous activity. Nor is the insulin-mediated vasodilatation modulated by vasoconstrictive sympathetic nervous activity. The vasodilatation seen in response to hyperinsulinemia is a locally acting mechanism. People with SCI are markedly insulin resistant compared with able-bodied individuals.
Abstract: The mechanisms behind the vasodilatory effect of insulin are not fully understood, but nitric oxide plays an important role. We have investigated the possibility that insulin mediates vasodilatation in the human skeletal muscle via an increase in extracellular adenosine concentrations. In eight healthy subjects (H) and in four subjects with a complete, high (C5-C6/7) spinal cord injury (SCI) a hyperinsulinaemic (480 mU min-1 kg-1), isoglycaemic clamp was performed. SCI subjects were included as it has been proposed that adenosine and adenine nucleotides may be released from nerve endings in the skeletal muscle. Adenosine concentrations in the extracellular fluid (ECF) of skeletal muscle in the thigh were measured by means of the microdialysis technique. Leg blood flow (LBF) was measured by termodilution. In response to insulin infusion, LBF always increased (P < 0.05) (from 228 +/- 25 and 318 +/- 18 mL min-1 to 451 +/- 41 and 530 +/- 29 mL min-1, SCI and H, respectively [mean +/- SEM]). Concentrations of adenosine in the muscle ECF did not change with infusion of insulin and did not differ between groups (before: 147 +/- 55 [SCI] and 207 +/- 108 [H] nmol L-1; during: 160 +/- 36 [SCI] and 165 +/- 74 [H] nmol L-1). No significant correlation between concentrations of adenosine and corresponding LBF rates was achieved (LBF=[-0.0936. Adenosine] + 475. R=-0.092, P=0.22, number of samples=181, number of subjects=12). Conclusion: the mechanism by which insulin mediates an increase in skeletal muscle blood flow is not associated with adenosine in the ECF.
Abstract: OBJECTIVE: To determine whether the plasma glucose-lowering effects of sulfonylureas and acute submaximal exercise are additive and, accordingly, to determine whether they may increase the risk of hypoglycemia when combined in fasting patients. RESEARCH DESIGN AND METHODS: Eight postabsorptive type 2 diabetic patients were examined at three occasions: after oral sulfonylurea (7 mg glibenclamide), during 60 min of ergometer cycle exercise at 57 +/- 3% of VO2max, and during exercise after glibenclamide. RESULTS: Heart rate, VO2, and lactate responses to exercise were comparable (P > 0.05) on days with and without glibenclamide. Plasma insulin concentrations were always increased by glibenclamide, and they were lowered identically by exercise with and without glibenclamide. However, throughout exercise, absolute concentrations of insulin were lower on days without glibenclamide compared with days with glibenclamide (34.5 +/- 4.7 vs. 47.4 +/- 5.5 pmol/l; P < 0.05). At the start of exercise, glucose concentrations were similar between experiments (P > 0.05). The rate of decrease in glucose during exercise was higher (P < 0.05) on days with both glibenclamide and exercise, compared with days with glibenclamide alone and days with exercise alone (-0.035 +/- 0.009 vs. -0.016 +/- 0.002 and -0.022 +/- 0.005 mmol.l-1.min-1, respectively). Consequently, the glucose nadir was lower on days with glibenclamide and exercise than on days with glibenclamide or exercise alone (6.7 +/- 1.1 vs. 8.1 +/- 0.9 and 7.6 +/- 1.0 mmol/l, respectively; P < 0.05). During exercise, the rate of appearance of plasma glucose determined by 3-[3H]glucose infusion was lower on days with glibenclamide than on days without glibenclamide (2.3 +/- 0.1 vs. 2.9 +/- 0.1 mg.min-1.kg-1; P < 0.05). In contrast, glucose clearance was identical (P > 0.05). CONCLUSIONS: In postabsorptive type 2 diabetic patients, the hypoglycemic action of glibenclamide and exercise is enhanced when the treatments are combined. The interaction reflects an increased inhibition by glibenclamide-enhanced insulin levels of hepatic glucose production when hepatic glucose production is accelerated by exercise.
Abstract: Insulin and muscle contractions are major stimuli for glucose uptake in skeletal muscle and have in young healthy people been shown to be additive. We studied the effect of superimposed exercise during a maximal insulin stimulus on glucose uptake and clearance in trained (T) (1-legged bicycle training, 30 min/day, 6 days/wk for 10 wk at approximately 70% of maximal O(2) uptake) and untrained (UT) legs of healthy men (H) [n = 6, age 60 +/- 2 (SE) yr] and patients with Type 2 diabetes mellitus (DM) (n = 4, age 56 +/- 3 yr) during a hyperinsulinemic ( approximately 16,000 pmol/l), isoglycemic clamp with a final 30 min of superimposed two-legged exercise at 70% of individual maximal heart rate. With superimposed exercise, leg glucose extraction decreased (P < 0.05), and leg blood flow and leg glucose clearance increased (P < 0.05), compared with hyperinsulinemia alone. During exercise, leg blood flow was similar in both groups of subjects and between T and UT legs, whereas glucose extraction was always higher (P < 0.05) in T compared with UT legs (15.8 +/- 1.2 vs. 14.6 +/- 1.8 and 11.9 +/- 0.8 vs. 8.8 +/- 1.8% for H and DM, respectively) and leg glucose clearance was higher in T (H: 73 +/- 8, DM: 70 +/- 10 ml. min(-1). kg leg(-1)) compared with UT (H: 63 +/- 8, DM: 45 +/- 7 ml. min(-1). kg leg(-1)) but not different between groups (P > 0.05). From these results it can be concluded that, in both diabetic and healthy aged muscle, exercise adds to a maximally insulin-stimulated glucose clearance and that glucose extraction and clearance are both enhanced by training.
Abstract: AIMS/HYPOTHESIS: The influence of postprandial high intensity exercise on glycaemia was studied in patients with Type II diabetes mellitus. METHODS: Patients who were treated by diet only (n = 8) ate a standardised breakfast and 4 h later a standardised lunch. They were studied in the resting state (control day) and on another day (exercise day) when they did intermittent exercised at high intensity after breakfast) (4 bouts including 3 min at 56.5 +/- 3.9 % V.(O2) (max) (means +/- SEM), 4 min at 98.3 +/- 5.1 % V.(O2) (max) and 6 min of rest). Responses were calculated as areas under the plasma concentration curve (AUC) during 4 h after either breakfast or lunch. RESULTS: Breakfast-AUCs for glucose, insulin and C peptide were lower (p < 0.05) on the exercise day compared with the control day (glucose: 538 +/- 94 vs 733 +/- 64 mmol. l(-1). 240 min; insulin: 16 +/- 4 vs 22 +/- 3 pmol. ml(-1). 240 min; C peptide: 143 +/- 22 vs 203 +/- 29 pmol. ml(-1). 240 min). After breakfast glucose appearance was unaffected by exercise, whereas disappearance and clearance increased (p < 0.05). Muscle glycogen was diminished by exercise (p < 0.05). After lunch no differences were observed between experiments. Exercise-induced reductions in glucose, insulin and C peptide responses were similar (p > 0.05) in this study of intermittent, high intensity exercise and in a previous study of isocaloric but prolonged moderate (45 min at 53 +/- 2 % V.(O2) (max)) postprandial exercise. CONCLUSION/INTERPRETATION: Postprandial high intensity exercise does not deteriorate glucose homeostasis but reduces both glucose concentrations and insulin secretion. The effect of exercise is related to energy expenditure rather than to peak exercise intensity. Finally, postprandial exercise does not influence glucose homeostasis during a subsequent main meal. [Diabetologia (1999) 42: 1282-1292]
Abstract: The purpose of this study was to determine the in-vivo and in-vitro effects of insulin, at physiological and supraphysiological concentrations, on the human immune system. Ten healthy young men went through a sequential two-step hyperinsulinaemic euglycaemic clamp. Plasma insulin concentrations were increased from baseline (9.0 microU/ml) to 49.1 microU/ml after 1 h of insulin infusion (step I) and to 1281 microU/ml (step II) after 2 h of infusion. As control experiments infusions of isotonic saline were performed. The unstimulated natural killer (NK) cell activity among blood mononuclear cells (BMNC) increased in response to supraphysiological plasma insulin levels (baseline versus step II: 20.6 +/- 11.3 versus 27.8 +/- 14.4%). The percentages of the D16+ NK cells did not change, indicating an enhanced cytotoxic capability per individual NK cell. Insulin also slightly increased the activity of NK cells in vitro. A decline at step II in the concentrations of monocytes (0.29 +/- 0.09 versus 0.12 +/- 0.03 x 10(9)/L), lymphocytes (1.57 +/- 0.46 versus 1.22 +/- 0.25 x 10(9)/L), and CD16+(24.2 +/- 17.5 versus 16.7 +/- 11.2 x 10(7)/L), CD14+ (20.9 +/- 10.8 versus 8.6 +/- 3.9 x 10(7)/L), HLA-DR+ (37.2 +/- 22.1 versus 19.2 +/- 10.7 x 10(7)/L) and CD45RO+ (91.6 +/- 33.4 versus 61.7 +/- 6.4 x 10(7)/L) cells as well as in the percentages of CD14+ cells (11.2 +/- 4.7 versus 6.4 +/- 2.3%) and CD14+/HLA-DR+ monocytes (9.7 +/- 3.9 versus 4.8 +/- 2.8%) were observed. No changes were found at step I. Hyperinsulinaemia did not change the percentages of the CD3+, CD4+, CD8+, CD19+, CD56+, CD11a+, CD45RO+ and CD45RA+ cells, the numbers of circulating immunoglobulin (Ig)G-, IgA- and IgM- secreting cells, or the proliferative responses of BMNC to phytohaemagglutinin, purified derivative of tuberculin or interleukin (IL)-2. Hyperinsulinaemia did not change the in-vitro sensibility to insulin. In conclusion, supraphysiological insulin levels increased the activity of the individual NK cells, but decreased the numbers of NK cells, lymphocytes and activated monocytes. The findings are presumably of minor clinical relevance but may indicate an insulin-induced immune activation.
Abstract: The influence of exercise on glycaemia in the post-prandial state was studied for the first time in non-insulin-dependent diabetic (NIDDM) patients. Meal-induced glucose responses were followed for 8 h in 9 diet-treated patients with NIDDM. Subjects consumed a standardized breakfast and 4 h later a standardized lunch. They were studied in the resting state (control day (CD)) and on another day 45 min of bicycle exercise (53 +/- 2% VO2max (mean +/- SEM)) was performed 45 min after breakfast (exercise day (ED)). On day 3 (diet day (DD)), the breakfast meal was reduced corresponding to the extra energy expenditure during the exercise period on ED. Responses were calculated as areas under the plasma concentration curve (AUC) during 4 h after either breakfast (B-AUC) or lunch (L-AUC). B-AUC for glucose was identical on ED (215 +/- 63 mmol/l.240 min) and DD (219 +/- 60 mmol/l.240 min) and on these days lower (p < 0.05) than on CD (453 +/- 78 mmol/l.240 min). L-AUC for glucose on CD, ED and DD did not differ significantly. B-AUCs for both insulin and C-peptide were also significantly lower on ED and DD as compared to CD (Insulin: 31337 +/- 8682, 26092 +/- 6457 and 47649 +/- 15046 mmol/l.240 min, respectively. C-peptide: 99 +/- 19, 104 +/- 26 and 195 +/- 31 pmol/ml.240 min, respectively). Rate of appearance (Ra) for glucose was unaffected by exercise whereas rate of disappearance (Rd) increased significantly. No differences in Ra or Rd were observed after lunch. In conclusion, post-prandial exercise of moderate intensity decreases glycaemia and plasma insulin levels after breakfast in NIDDM patients, but this effect does not persist during and after the following lunch meal. Reduction of breakfast caloric intake has the same effect on post-prandial glycaemia and insulin secretion as an equivalent exercise-induced increase in caloric expenditure.
Abstract: 1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia. Insulin action on glucose uptake has never been investigated during altitude hypoxia. 2. In eight healthy, sea level resident men (27 +/- 1 years (mean +/- S.E.M); weight, 72 +/- 2 kg; height, 182 +/- 2 cm) hyperinsulinaemic (50 mU min-1 m-2), euglycaemic clamps were carried out at sea level, and subsequently on days 2 and 7 after a rapid passive ascent to an altitude of 4559 m. 3. Acute mountain sickness scores increased in the first days of altitude exposure, with a peak on day 2. Basal HGP did not change with the transition from sea level (2.2 +/- 0.2 mg min-1 kg-1) to altitude (2.0 +/- 0.1 and 2.1 +/- 0.2 mg min-1 kg-1, days 2 and 7, respectively). Insulin-stimulated glucose uptake rate was halved on day two compared with sea level (4.5 +/- 0.6 and 9.8 +/- 1.1 mg min-1 kg-1, respectively; P < 0.05), and was partly restored on day 7 (7.4 +/- 1.4 mg min-1 kg-1; P < 0.05 vs. day two and sea level). Concentrations of glucagon and growth hormone remained unchanged, whereas glucose, C-peptide and cortisol increased on day 2. Noradrenaline concentrations increased during the stay at altitude, while adrenaline concentrations remained unchanged. In response to insulin infusion, catecholamines increased on day 2 (noradrenaline and adrenaline) and day 7 (adrenaline), but not at sea level. 4. In conclusion, insulin action decreases markedly in response to two days of altitude hypoxia, but improves with more prolonged exposure. HGP is always unchanged. The changes in insulin action may in part be explained by the changes in counter-regulatory hormones.
Abstract: Age-induced reduction of whole body insulin action has been attributed to decreased insulin action in skeletal muscle. Physical training improves insulin action, but the effect has never been investigated specifically in aged human skeletal muscle. Seven young men [age: 23 +/- 1 yr (mean +/- SE; range, 21-24 yr); weight: 70 +/- 1 kg; body fat: 8 +/- 1%] and eight aged men [59 +/- 1 yr (range, 58-64 yr); 83 +/- 2 kg; 20 +/- 2%] performed one-legged bicycle training on a modified ergometer cycle for 10 weeks, 6 days/week, at 70% of VO2 peak. Glucose clearance rates in whole body and leg were measured 16 hr after training by a hyperinsulinemic (28, 88, and 480 mU.min-1.min-2), isoglycemic clamp combined with leg balance technique. Peak oxygen uptake during the bicycle test was always lower (p < .05) in aged vs. young subjects. Furthermore, VO2 peak was higher after training in trained (T) vs. untrained (UT) (p < .05) legs. Whole body glucose clearance rate was lower in aged vs. young subjects (p < .05) when expressed per kg body weight, but similar when expressed relative to fat free mass. Leg blood flow was always lower in aged vs. young men (p < .05). At basal and during insulin infusion, leg blood flow in young men did not differ significantly in T vs. UT legs (maximum insulin: 81 +/- 7 vs. 71 +/- 5 ml.min-1.kg leg-1), while in aged subjects it increased (p < .05) with training (maximum insulin: 57 +/- 5 vs. 48 +/- 5 ml.min-1.kg leg-1). Leg glucose extraction was always higher in aged vs. young men during the two last clamp steps (p < .05). Furthermore, leg glucose extraction was increased by training in young (p < .05) but not significantly in aged subjects. Leg glucose clearance rates increased (p < .05) with training and was similar in aged men (T: 1 +/- 1, 8 +/- 1, 21 +/- 2, and 24 +/- 2; UT: 1 +/- 1, 6 +/- 1, 14 +/- 2, and 20 +/- 2 ml.min-1.kg leg-1) and young men (T: 1 +/- 1, 12 +/- 3, 23 +/- 3, and 26 +/- 3; UT: 1 +/- 1, 8 +/- 2, 17 +/- 2, and 21 +/- 2 ml.min-1.kg leg-1). Therefore, insulin action in muscle is not reduced by aging. At high insulin concentrations, the leg blood flow is lower, whereas glucose extraction is higher in aged compared with young men. Training increases overall insulin action on glucose clearance in skeletal muscle identically in aged and young subjects.
Abstract: In patients with non-insulin-dependent diabetes mellitus (NIDDM), a decreased effect of insulin in stimulating leg blood flow (LBF) has been reported. We reinvestigated the effect of insulin on LBF and validated our data by use of other measures. Eight healthy men (control group) and seven men with NIDDM were studied (age 59 +/- 1 and 58 +/- 3 years, weight 83 +/- 3 and 86 +/- 6 kg, fat-free mass 66 +/- 1 and 64 +/- 3 kg, respectively [mean +/- SE, all P > 0.05]; body mass index 26 +/- 1 and 29 +/- 1 kg/m2, fasting plasma insulin 72 +/- 7 and 187 +/- 22 pmol/l, fasting plasma glucose 5.8 +/- 0.2 and 10.2 +/- 1.7 mmol/l [all P < 0.05]). A three-step hyperinsulinemic glucose clamp (ambient glucose level) was performed, combined with catheterization of an artery and both femoral veins. Expiratory air was collected, LBF was measured by thermodilution, and blood was sampled and analyzed for oxygen content. Insulin concentration was increased to 416 +/- 22 and 509 +/- 43 (step I), 1,170 +/- 79 and 1,299 +/- 122 (step II), and 15,936 +/- 1,126 and 16,524 +/- 1,916 (step III) pmol/l in control and NIDDM subjects, respectively (P > 0.05). LBF increased similarly (P > 0.05) in the two groups (from 287 +/- 23 and 302 +/- 12 [basal] to 308 +/- 31 and 362 +/- 9 [I], 371 +/- 29 and 409 +/- 17 [II], and 434 +/- 32 and 472 +/- 29 [III] ml.min-1.leg-1 in control and NIDDM subjects, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Physical training increases insulin action in skeletal muscle in healthy men. In non-insulin-dependent diabetes mellitus (NIDDM), only minor improvements in whole-body insulin action are seen. We studied the effect of training on insulin-mediated glucose clearance rates (GCRs) in the whole body and in leg muscle in seven patients with NIDDM and in eight healthy control subjects. One-legged training was performed for 10 weeks. GCR in whole body and in both legs were measured before, the day after, and 6 days after training by hyperinsulinemic (28, 88, and 480 mU x min(-1) x m(-2)), isoglycemic clamps combined with the leg balance technique. On the 5th day of detraining, one bout of exercise was performed with the nontraining leg. Muscle biopsies were obtained before and after training. Whole-body GCRs were always lower (P < 0.05) in NIDDM patients compared with control subjects and increased (P < 0.05) in response to training. In untrained muscle, GCR was lower (P < 0.05) in NIDDM patients (13 +/- 4, 91 +/- 9, and 148 +/- 12 ml/min) compared with control subjects (56 +/- 12, 126 +/- 14, and 180 +/- 14 ml/min). It Increased (P < 0.05) in both groups in response to training (43 +/- 10, 144 +/- 17, and 205 +/- 24 [NIDDM patients] and 84 +/- 10, 212 +/- 20, and 249 +/- 16 ml/min [control subjects]). Acute exercise did not increase leg GCR. In NIDDM patients, the effect of training was lost after 6 days, while the effect lasted longer in control subjects. Training increased (P < 0.05) muscle lactate production and glucose storage as well as glycogen synthase (GS) mRNA in both groups. We conclude that training increases insulin action in skeletal muscle in control subjects and NIDDM patients, and in NIDDM patients normal values may be obtained. The increase in trained muscle cannot fully account for the increase in whole-body GCR. Improvements in GCR involve enhancement of insulin-mediated increase in muscle blood flow and the ability to extract glucose. They are accompanied by enhanced nonoxidative glucose disposal and increases in GS mRNA. The improvements in insulin action are short-lived.
Abstract: In young healthy individuals, an i.v. glucose bolus leads to an immediate increase in plasma insulin, whereas in non-insulin-dependent diabetic patients this early response is diminished, lacking or even negative. In the present study, we sought to determine whether negative responses were also present during square-wave glucose stimulation (transition from 18 to 25 mM), whether they represented a decrease in beta-cell secretion, whether they were accompanied by an altered response to arginine (5 g L-arginine bolus), and whether they were a consequence of ageing rather than of diabetes. A group of 12 patients (aged 53 +/- 2 years, mean +/- SE) with non-insulin-dependent diabetes (D) and 12 matched healthy controls (C; aged 47 +/- 1 years) were evaluated twice at an interval of 3 months. Other baseline values were body mass index (BMI) 28 +/- 1 (D) and 26 +/- 1 (C) kg/m2, fasting C-peptide 0.85 +/- 0.12 (D) and 0.92 +/- 0.10 (C) nmol/l, and fasting P-glucose 12.3 +/- 0.9 (D) and 5.8 +/- 0.1 (C) mM, P < 0.05. Paradoxical responses (a decrease of two or more times the SD of the analysis within 15 min of increasing the glucose concentration) were seen in five diabetic patients for insulin (22 +/- 8%) and in nine diabetic patients for C-peptide (13 +/- 3%), but never in the healthy controls. Plasma glucose increased and protein decreased similarly, whether the responses were paradoxical or not. Paradoxial responses were reproduced after three months. Responses to arginine did not correlate with responses to glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Exercise adds to the effect of maximal insulin on whole body glucose uptake. Training increases contraction-induced glucose transport measured in vitro but not glucose utilization in human muscle exercising during normoinsulinemia. We studied whether exercise adds to the effect of maximal insulin in human muscle and whether trained (T) and untrained (UT) muscle differ. Six healthy men [23 +/- 0.4 (SE) yr] trained one leg for 10 wk, 6 days/wk, 30 min/day at 70% of one-legged maximal O2 uptake while keeping the other leg sedentary. At 16 h after the last training bout, both femoral veins and a radial artery were catheterized and 150-min hyperinsulinemic (480 mU.min-1.m-2) euglycemic clamp was performed. During the final 30 min, subjects performed two-legged bicycling at 76 +/- 0.3% of maximal heart rate. During exercise, blood flow (597 +/- 45 vs. 572 +/- 37 ml.min-1.kg-1), O2 uptake (74 +/- 6 vs. 68 +/- 6 ml O2.min-1.kg-1), and carbohydrate oxidation (88 +/- 10 vs. 81 +/- 7 mg.min-1.kg-1) increased similarly (P > 0.05) in T and UT legs, respectively. Arteriovenous glucose difference decreased (P < 0.05) during exercise but tended to remain higher in T (0.47 +/- 0.04) than in UT (0.41 +/- 0.05 mol/l) (P < 0.1). Glucose uptake increased with exercise, the increase being higher in T than in UT (change: 28 +/- 5 vs. 23 +/- 5 mg.min-1.kg-1; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit insulin resistance and decreased glucose transport in skeletal muscle. Total content of muscle GLUT4 protein is not affected by NIDDM, whereas GLUT4 mRNA content is reported, variously, to be unaffected or increased. Physical training is recommended in the treatment of NIDDM, but the effect of training on muscle GLUT4 protein and mRNA content is unknown. To clarify the effect of training in NIDDM, seven men with NIDDM (58 +/- 2 years of age [mean +/- SE]) and eight healthy men (59 +/- 1 years of age) (control group) performed one-legged ergometer bicycle training for 9 weeks, 6 days/week, 30 min/day. Biopsies were obtained from the vastus lateralis leg muscle before and after training. GLUT4 protein analyses was performed along with analyses of muscle biopsies from five young (23 +/- 1 years of age) (young group), healthy subjects who participated in a previously published identical study. In response to training, maximal oxygen uptake increased (delta 3.3 +/- 1.8 in NIDDM subjects and 4.5 +/- 1.2 ml.min-1.kg-1 in control subjects [both P < 0.05]). Before training, GLUT4 protein content was similar in NIDDM, control, and young subjects (0.35 +/- 0.02, 0.34 +/- 0.03, and 0.41 +/- 0.03 arbitrary units, respectively), and it increased (P < 0.05) in all groups during training (to 0.43 +/- 0.03, 0.40 +/- 0.03, and 0.57 +/- 0.08 arbitrary units, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The diurnal variations of serum-erythropoietin concentration ([s-EPO]) were investigated in six physically trained (T) and eight untrained (UT) men. The T subjects had a higher mean maximal oxygen uptake than UT subjects [75.7 (SEM 1.6) ml.min-1.kg-1 versus 48.3 (SEM 1.4) ml.min-1.kg-1, P < 0.0001] and a lower mean body mass index [BMI, 21.7 (SEM 0.7) kg.m-2 versus 24.4 (SEM 0.6) kg.m-2, P = 0.02]. Each subject was followed individually for 24 h as they performed their normal daily activities. Venous blood samples were collected from awakening (0 min) until the end of the 24-h period (1440 min). Both T and UT had a nadir of [s-EPO] 120 min after awakening [10.0 (SEM 0.3) U.l-1 versus 11.5 (SEM 2.1) U.l-1, P > 0.05]. The UT and T increased their [s-EPO] to peak values at 960 min and 960-1200 min, respectively (ANOVA P = 0.03) after awakening [UT: 18.4 (SEM 2.8) U.l-1; T: 16.2 (SEM 2.5) U.l-1, P > 0.05]. The mean 24-h [s-EPO] were 14.5 (SEM 1.0) U.l-1 and 14.9 (SEM 0.9) U.l-1 in T and UT, respectively (P > 0.05). The individual mean 24-h [s-EPO] were not correlated to body mass, BMI or maximal oxygen uptaken. Significant diurnal variations in [s-EPO] occurred in these healthy subjects irrespective of their levels of physical activity.
Abstract: 1. Physical training enhances sensitivity and responsiveness of insulin-mediated glucose uptake in human muscle. This study examines if this effect of physical training is due to increased insulin receptor function or increased total concentration of insulin-recruitable glucose transporter protein (GLUT 4). 2. Seven healthy young subjects carried out single leg bicycle training for 10 weeks at 70% of one leg maximal oxygen uptake (VO2,max). Subsequently biopsies were taken from the vastus lateralis muscle of both legs. 3. Single leg VO2,max increased for the trained leg (46 +/- 3 to 52 +/- 2 ml min-1 kg-1 (means +/- S.E.M., P < 0.05), and cytochrome c oxidase activity was higher in this compared to the untrained leg (2.0 +/- 0.1 vs. 1.4 +/- 0.1 nmol s-1 (mg muscle)-1, P < 0.05). Insulin binding as well as basal- and insulin-stimulated receptor kinase activity did not differ between trained and untrained muscle. The concentration of GLUT 4 protein was higher in the former (14.9 +/- 1.9 vs. 11.6 +/- 1.0 arbitrary units (micrograms protein)-1 in crude membranes, P < 0.05). The training-induced increase in GLUT 4 (26 +/- 11%) matched a previously reported increase in maximum insulin-stimulated leg glucose uptake (25 +/- 7%) in the same subjects, and individual values of the two variables correlated (correlation coefficient (r) = 0.84, P < 0.05). 4. In conclusion, in human muscle training induces a local contraction-dependent increase in GLUT 4 protein, which enhances the effect of insulin on glucose uptake. On the other hand, insulin receptor function in muscle is unlikely to be affected by training.
Abstract: Compared with untrained subjects, in trained subjects the increased insulin sensitivity and decreased glucose induced insulin secretion will tend to promote health by decreasing glucose levels and insulin secretion, whereas the increased food intake will tend to increase these variables. To evaluate the net effect of training, we administered oral glucose loads making up identical fractions of daily carbohydrate intake (i.e., same relative glucose loads) to 8 athletes and 7 sedentary subjects (age: 25 +/- 1 vs. 24 +/- 1 yr [mean +/- SE] [NS]; body weight: 76.0 +/- 1.3 vs. 79.3 +/- 2.3 kg [NS]; maximal oxygen uptake: 76 +/- 2 vs. 48 +/- 1 ml O2.kg-1.min-1 [2P < 0.05], respectively). Furthermore, 24 h plasma concentration profiles of glucose, C-peptide, and insulin were determined during ordinary living conditions. Daily carbohydrate intake was higher (2P < 0.05) in athletes compared with sedentary subjects (678 +/- 34 vs. 294 +/- 18 g.day-1, respectively). In response to same relative oral glucose loads, glucose and C-peptide responses were similar in athletes compared to sedentary subjects. Twenty-four hour integrated glucose and C-peptide concentrations did not differ between athletes and sedentary subjects (7.4 +/- 0.2 vs. 7.3 +/- 0.6 mol.L-1.1440 min [2P > 0.05] and 923 +/- 99 vs. 1047 +/- 175 pM.ml-1.1440 min [2P > 0.05], respectively), and insulin concentrations tended to be lower in athletes compared with sedentary subjects (124 +/- 13 vs. 175 +/- 38 pM.ml-1.1440 min [2P > 0.05]).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: During insulin stimulation whole body glucose uptake is increased in trained compared with untrained humans. However, it is not known which tissue is responsible. Seven young male subjects bicycle trained one leg for 10 wk at 70% of maximal O2 consumption (VO2max). Sixteen hours after last exercise bout, a three-step euglycemic hyperinsulinemic clamp (clamp 1) was performed (insulin levels, means +/- SE: 9 +/- 1, 53 +/- 3, 174 +/- 5, and 2,323 +/- 80 was microU/ml), with measurement of arteriovenous differences and blood flow in both legs. After 6 days of detraining subjects were restudied, having exercised the untrained leg 16 h before. VO2max for trained (T) and untrained (UT) legs was 52 +/- 2 vs. 44 +/- 2 ml.min-1.kg-1 (P < 0.05). In clamp 1 glucose uptake in T and UT legs was 1.0 +/- 0.2 vs. 0.5 +/- 0.1 mg.min-1.kg-1 (basal), 9.7 +/- 2.3 vs. 6.7 +/- 1.7 (P < 0.05) (step I), 19.2 +/- 2.8 vs. 14.3 +/- 2.0 (P < 0.05) (step II), and 22.8 +/- 2.3 vs. 18.6 +/- 2.2 (P < 0.05) (step III). During insulin infusion lactate release (P < 0.05) [8.9 +/- 1.8 vs. 2.9 +/- 0.9 mumol.min-1.kg-1 (step I), 24.6 +/- 3.1 vs. 12.5 +/- 2.6 (step III)] and glycogen storage (P < 0.1) calculated by indirect calorimetry [6.7 +/- 2.3 vs. 5.0 +/- 1.7 mg.min-1.kg-1 (step I), 16.8 +/- 2.1 vs. 14.1 +/- 1.8 (step III)] were always higher in T than in UT legs. Release of glycerol, free fatty acids, and tyrosine and clearance of insulin were not influenced by training. Insulin-mediated glucose uptake was not increased after detraining or a single bout of exercise. In conclusion, training increases sensitivity and responsiveness of insulin-mediated glucose uptake in human muscle by local mechanisms. Glycolysis and glycogen storage are equally enhanced. The training effect represents a genuine adaptation to repeated exercise but is short lived. Insulin clearance in muscle is not influenced by training.
Abstract: Physical training decreases resting heart rate as well as heart rate and catecholamine responses to ordinary physical activity and mental stress. These effects have been speculated to diminish cardiac morbidity. However, the sparing of heartbeats and catecholamine production might be outweighed by exaggerated responses during training sessions. To elucidate this issue, heart rate was measured continuously and plasma catecholamine concentrations were measured frequently during 24 h of ordinary living conditions in seven endurance-trained athletes (T) and eight sedentary or untrained (UT) young males. T subjects had lower heart rates than UT subjects during sleep and during nontraining awake periods. However, because of the increase during training, the total 24-h heartbeat number did not differ between groups (107,737 +/- 3,819 for T vs. 113,249 +/- 6,879 for UT, P = 0.731). Neither during sleep nor during awake nontraining periods were catecholamine levels lower in T than in UT subjects. Peak catecholamine levels during exercise in T were much higher than peak levels in UT subjects, and 24-h average epinephrine and norepinephrine concentrations were twice as high. We concluded that in highly trained athletes the total number of heartbeats per day is not decreased and the catecholamine production is, in fact, increased.
Abstract: From responses to identical absolute glucose loads in trained (T) and untrained (UT) subjects, it has been inferred that training promotes health by reducing glucose levels and insulin secretion. To mimic daily living conditions, we studied responses to oral glucose loads making up identical fractions of daily carbohydrate intake (i.e., same relative glucose load) in seven T and eight UT males [maximal O2 uptake (VO2max) 76 +/- 2 vs. 48 +/- 1 (SE) ml.min-1.kg-1; age 24 +/- 1 vs. 25 +/- 1 yr]. Daily energy intake was higher in T than in UT subjects (18,607 +/- 835 vs. 12,493 +/- 720 kJ/day, P less than 0.05), reflecting a 2.3 times higher carbohydrate intake (678 +/- 34 vs. 294 +/- 18 g/day, P less than 0.05). After 1 g/kg body wt glucose, C-peptide and insulin responses were lower in T than in UT subjects (P less than 0.05). However, after identical relative glucose loads [high: 2.3 +/- 0.2 (T) vs. 1 (UT) g/kg; low: 1 (T) vs. 0.4 +/- 0.03 (UT) g/kg], glucose [incremental areas 300 +/- 56 (T) vs. 304 +/- 35 (UT) mM.180 min and 148 +/- 30 (T) vs. 124 +/- 22 (UT)] and C-peptide [181 +/- 18 (T) vs. 171 +/- 27 (UT) nM.180 min, and 100 +/- 13 (T) vs. 71 +/- 12 (UT)] responses did not differ between groups, while insulin responses were lower in T [at low relative load 15 +/- 4 (T) vs. 20 +/- 2 (UT) nM.180 min, P less than 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Impaired glucose tolerance develops in normal humans after short-term bed rest. To elucidate the mechanism, insulin action on whole body glucose uptake rate (WBGUR) and leg glucose uptake rate (LGUR) was measured by sequential euglycemic clamp technique combined with femoral arterial and venous cannulation at insulin concentrations of 10 +/- 1, 18 +/- 1, 37 +/- 2, and 360 +/- 15 microU/ml. Studies were performed before (C) and after (BR) 7 days of strict bed rest. WBGUR was significantly lower after bed rest than before (5.5 +/- 0.4 and 7.2 +/- 0.8 mg.min-1.kg-1, respectively) when insulin was 37 microU/ml. LGUR was even more markedly depressed by bed rest, being 0.6 +/- 0.1, 0.9 +/- 0.2, and 2.8 +/- 0.4 mg.min-1.kg leg-1 (BR) compared with 0.9 +/- 0.1, 1.7 +/- 0.4, and 5.9 +/- 0.5 mg.min-1.kg leg-1 (C) (P less than 0.05) at the three lower insulin concentrations. At these insulin concentrations also, lactate release and glucose oxidation and glycogen storage estimated by indirect calorimetry were lower in the leg after bed rest. At the highest insulin dose WBGUR was similar on BR and C days, while LGUR was lower after bed rest. In conclusion, 7 days of bed rest decrease whole body insulin action, a fact that is explained by decreased insulin action in inactive muscle.
Abstract: Compared with untrained (UT) subjects, in trained (T) subjects the increased insulin sensitivity and decreased glucose induced insulin secretion would tend to promote health by decreasing glucose levels and insulin secretion whereas the increased food intake would tend to increase these variables. To study the net effect of training, blood was sampled from seven T and eight UT young men [VO2max: 76 +/- 2 (T) vs. 48 +/- 1 (UT) mL.kg-1.min-1] for 24 h during ordinary living conditions. Athletes exercised 204 +/- 20 min and ate 50% more calories and 130% more carbohydrate than UT subjects (P less than 0.05). However, 24-h integrated plasma concentrations of glucose, C-peptide, glucagon, free fatty acids, and glycerol as well as glycosylated hemoglobin levels were identical in T and UT subjects. Mean insulin concentration was 41% lower in T than in UT but levels differed significantly (P less than 0.05) only late during the night. Urinary excretion of pancreatic peptides paralleled plasma concentrations. In conclusion, during training adaptations in pancreas- and insulin-sensitive tissues allow the necessary increase in food intake without harmful hyperglycemia and overloading of beta-cells, but sparing of insulin secretion and reductions in glucose levels are only relative to food intake. However, training may be wholesome by increasing hepatic insulin extraction and thereby decreasing arterial insulin levels. Training-induced beta-cell adaptation is not caused by diminished average glucose levels. Finally, renal handling of insulin, C-peptide, and glucagon is not influenced by training.
Abstract: Glucose-stimulated insulin secretion is depressed by training. To further elucidate the beta-cell adaptation to training, a nonglucose secretagogue was applied. Arginine was infused for 90 min to seven trained and seven untrained young men. Arginine and glucose concentrations increased identically in the groups. The insulin response was biphasic and waned despite increasing arginine concentrations. Both these phases as well as C-peptide responses were reduced in trained subjects, whereas proinsulin responses were similar in the groups. Identical increases were found in glucagon, growth hormone, catecholamines, and production and disappearance of glucose; identical decreases were found in free fatty acids, glycerol, and beta-hydroxybutyrate. In conclusion, in men training diminishes both arginine- and glucose-stimulated insulin secretion, indicating a profound beta-cell adaptation. Being enhanced, the effects of insulin on both production and disposal of glucose are changed in the opposite direction to beta-cell secretion by training. The responses of glucagon- and growth hormone-secreting cells to arginine do not change with training.
Abstract: Physical training decreases glucose-stimulated insulin secretion. To further explore the influence of the level of daily physical activity on beta-cell secretion, the effect of 7 days of bed rest was studied in six young, healthy men by sequential hyperglycemic clamp technique (7, 11, and 20 mM glucose, each step lasting 90 min). At 11 and 20 mM glucose, insulin concentrations in plasma were higher after (87 +/- 11 and 303 +/- 63 microU/ml) than before (63 +/- 5 and 251 +/- 50 microU/ml, P less than 0.05) bed rest. Also C-peptide levels were higher after bed rest than before during glucose stimulation. The responses of other hormones, metabolites, or electrolytes influencing beta-cell secretion were not influenced by bed rest. In spite of increased insulin levels after bed rest, glucose disposal at 20 mM of glucose was significantly lower after bed rest than before. It is concluded that bed rest for 7 days increases the glucose-stimulated insulin response, at least partly due to a beta-cell adaptation increasing glucose-stimulated insulin secretion. However, the insulin secretion does not increase adequately compared with the peripheral insulin resistance induced by bed rest.
