Abstract: Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
Abstract: A reduced bone mineral density has been reported in patients with untreated celiac disease (CD) as well as in patients with poorly controlled type 1 diabetes mellitus (T1DM). The aim of this study was to evaluate the bone mineral status by phalangeal quantitative ultrasound in 52 children and adolescents with both diseases (mean age 13.3+/-4.9 years). As a control group 50 patients with T1DM and no CD (age 12.2+/-4.0 years) were studied. The following bone parameters, amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were considered and expressed as z score. Compliance to gluten free diet and long term glycemic control (mean of four determinations of HbA1c in the last year) were also assessed. The lowest mean AD-SoS z score values were found in patients with T1DM and CD, who reported transgressions to gluten free diet and exhibited positivity for serum anti-tissue transglutaminase antibodies (tTG) and/or endomysial antibodies (EmA), compared with patients with occasional transgressions but negative for anti-tTG and/or -EmA, patients strictly adherent to the diet, and patients who suffered only from diabetes (ANOVA p=0.021). No difference was found between patients with diabetes alone and patients with both diseases strictly adherent to gluten free diet. Prevalence of osteopenia (z AD-SoS values <-2 SD) was higher in patients with T1DM and CD and poor compliance to the diet (45.5%) compared with patients with T1DM (8%) or patients with both diseases strictly compliant to diet (12.9%) (p=0.015). A negative correlation between Ad-SoS z score and HbA(1c) (r -0.236, p=0.036) was found when patients with T1DM and patients with T1DM and CD, who strictly adhere to the diet, were pooled. In conclusion the quality of bone as assessed by phalangeal ultrasound in patients with T1DM and CD, who strictly adhere to gluten free diet, is similar to that found in T1DM patients. A higher prevalence of osteopenia is present in patients with both diseases who reported habitual transgressions to gluten free diet. The gluten free diet, as well as the optimization of glycemic control, plays an important role in preventing the osteopenic status caused by the clustering of these two chronic diseases.
Abstract: BACKGROUND: Pregnancy in Type 1 diabetic patients is a precarious condition, both for mother and fetus with increased the risk of prematurity and, immediately after delivery with risk of respiratory distress syndrome and hypoglycaemia in newborns. A strict control and monitoring of diabetes throughout pregnancy is important in reducing the impact of the disease on the fetus and newborn. In recent years many new technologies have been introduced to ameliorate diabetes monitoring, where the last is the Real-time Continuous Glucose Monitoring System (RT-CGMS). METHODS: In the last three years, 72 h continuous glucose monitoring system (RT-CGMS) (Medtronic, CA) was performed in 18 pregnant women with Type 1 diabetes in two moments of pregnancy: during treatment with betamethasone to prevent respiratory distress and during delivery. In both cases insulin was administered intravenous and the dose was changed on the basis of glycaemia. RESULTS: The results present the use of this new technique during two topics moments of pregnancy of type 1 diabetes patients when is very important intensively to monitor diabetes and to obtain the well being of the fetus. No infant experimented hypoglycaemia or respiratory distress syndrome at the moment and in the first hours after the birth. CONCLUSION: We wish to stress the importance reducing glycaemia during administration of betamethasone and during labor. It is conceivable that the scarce attention paid to monitoring glucose levels in diabetic mothers during labor in gynaecological world may be due to the difficulty in glucose monitoring with the devices until now available. Hopefully, our anecdotal account may prompt improvements with RT-CGMS, and may lead to a better approach to the problem, thereby changing the prognosis of infants born to diabetic mothers.
Abstract: BACKGROUND: Insulin deficiency with glucagon excess leads to the release of ketone bodies (KBs) by the liver and excretion in the urine. So far, only KB monitoring in urine has been used during assessment of children with diabetes. Currently used nitroprusside strips for urine KB detection react only with acetoacetate (AcAc) and not with the most prevalent KB moiety - 3beta-hydroxybutyrate (3HB) - that is in equilibrium with AcAc (up to 10:1 ratio). AIM: To verify the significance of 3HB in the blood compared to that of AcAc in the urine in recently diagnosed type 1 diabetic subjects independent of the presence of diabetic ketoacidosis (DKA). METHODS: A total of 118 consecutive newly diagnosed subjects with type 1 diabetes from different centers in Italy underwent intensive insulin therapy and hydration when necessary (38/118 = 32% with DKA). Hourly urine and capillary blood samples were used to monitor KBs until metabolic control was achieved. RESULTS: Although DKA was present in 32% of patients, blood 3HB was significantly increased (3.56 +/- 1.7 mmol/L) in 83% of the patients and correlated with blood glucose (r = 0.39; p < 0.01) according to a bimodal model. The strongest association was found between 3HB and venous pH (r =-0.56; p < 0.0001). Time required for blood 3HB normalization depended strongly on the starting blood KB values (r = 0.44; p < 0.0001) and was significantly lower than that required for disappearance of KB from urine (17.4 +/- 13.6 h, range 1-69 h vs. 19.7 +/- 17.8 h, range 1-120 h; p = 0.004). However, urine KBs disappeared before blood 3HB normalization in 23% of the patients. CONCLUSIONS: Blood 3HB evaluation is a better indicator of metabolic control compared to urine KB detection and is useful to predict the time required for blood KB clearing. Further studies are needed to assess its use in the early detection and management of DKA.
Abstract: Patients with type 1 diabetes require adequate amounts of macronutrients to support their training and sustain performance during regular exercise and during competitions. A frequent goal in competitive sports is to improve performance, and athletes may resort to a number of practices that can adversely affect blood glucose control and health in general in an attempt to gain a competitive advantage. These may include unsafe dietary patterns, and the use of nutritional supplements, other ergogenic aids and illegal substances. In this paper we review data on the relationship between insulin therapy and needs of single macronutrients before, during and after regular and competitive exercise in young subjects and athletes with type 1 diabetes. We also list nutrition integrators, available in the gymnasium or as over-the-counter drugs, which are increasingly being used by athletes, and describe their interactions with diabetes.
Abstract: Paediatric Diabetologists aim to personalize insulin therapy in order to attain good metabolic control and good quality of life. Nowadays this goal may be obtained through many devices: syringes, pens or injectors and by several insulin preparations. In fact besides human "traditional" (regular, NPH, Lente zinc and Ultralente zinc insulins) recently, insulin analogues have been synthesized with different pharmacokinetics: short acting (Lispro and Aspart) and long acting (Glargine, Detemir). Since children with diabetes are, often, totally c-peptide negative, insulin therapy must substitute the absence of insulin production and the successful use of short acting insulin analogues requires optimal association with basal insulin. Insulin therapy regimens are adapted to the life style of children and factors affecting the diabetologist's decision to change the regimen are not only glycaemic profiles, HbAlc and metabolic control but, also, age, school needs, prevention of hypoglycaemia, meals timing etc. and, also, culture of patients and their families, compliance to the therapy, possibility to contact frequently the diabetology team, etc. In conclusion insulin regimens must reflect the life style of the diabetic patient who is educated in the strategy of intensive insulin therapy. Italy is a "long" country and the life styles are different region by region; Italian Paediatric Diabetologists are fanciful and the personalization of insulin therapy is a recent conquest thanks to the new and old insulin preparations.
