Neonatal diabetes mellitus.
ABSTRACT An explosion of work over the last decade has produced insight into the multiple hereditary causes of a nonimmunological form of diabetes diagnosed most frequently within the first 6 months of life. These studies are providing increased understanding of genes involved in the entire chain of steps that control glucose homeostasis. Neonatal diabetes is now understood to arise from mutations in genes that play critical roles in the development of the pancreas, of beta-cell apoptosis and insulin processing, as well as the regulation of insulin release. For the basic researcher, this work is providing novel tools to explore fundamental molecular and cellular processes. For the clinician, these studies underscore the need to identify the genetic cause underlying each case. It is increasingly clear that the prognosis, therapeutic approach, and genetic counseling a physician provides must be tailored to a specific gene in order to provide the best medical care.
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ABSTRACT: AIMS/HYPOTHESIS: The main objective of this work was to discover new drugs that can activate the differentiation of multipotent pancreatic progenitors into endocrine cells. METHODS: In vitro experiments were performed using fetal pancreatic explants from rats and mice. In this assay, we examined the actions on pancreatic cell development of glibenclamide, a sulfonylurea derivative, and glycine hydrazide (GlyH-101), a small-molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR). We next tested the actions of GlyH-101 on in vivo pancreatic cell development. RESULTS: Glibenclamide (10 nmol/l-100 μmol/l) did not alter the morphology or growth of the developing pancreas and exerted no deleterious effects on exocrine cell development in the pancreas. Unexpectedly, glibenclamide at its highest concentration promoted endocrine differentiation. This glibenclamide-induced promotion of the endocrine pathway could not be reproduced when other sulfonylureas were used, suggesting that glibenclamide had an off-target action. This high concentration of glibenclamide had previously been reported to inhibit CFTR. We found that the effects of glibenclamide on the developing pancreas could be mimicked both in vitro and in vivo by GlyH-101. CONCLUSIONS/INTERPRETATION: Collectively, we demonstrate that two small-molecule inhibitors of the CFTR, glibenclamide and GlyH-101, increase the number of pancreatic endocrine cells by increasing the size of the pool of neurogenin 3-positive endocrine progenitors in the developing pancreas.Diabetologia 11/2012; · 6.49 Impact Factor
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ABSTRACT: The landmark discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka has transformed regenerative biology. Previously, insights into the pathogenesis of chronic human diseases have been hindered by the inaccessibility of patient samples. However, scientists are now able to convert patient fibroblasts into iPSCs and differentiate them into disease-relevant cell types. This ability opens new avenues for investigating disease pathogenesis and designing novel treatments. In this review, we highlight the uses of human iPSCs to uncover the underlying causes and pathological consequences of diabetes and metabolic syndromes, multifactorial diseases whose etiologies have been difficult to unravel using traditional methodologies.Cell metabolism 09/2013; · 17.35 Impact Factor
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ABSTRACT: Diabetes is highly prevalent in India and the proportion of younger patients developing diabetes is on the increase. Apart from the more universally known type 1 diabetes and obesity related type 2 diabetes, monogenic forms of diabetes are also suspected to be prevalent in many young diabetic patients. The identification of the genetic basis of the disease not only guides in therapeutic decision making, but also aids in genetic counselling and prognostication. Genetic testing may establish the occurrence and frequency of early diabetes in our population. This review attempts to explore the utilities and horizons of molecular genetics in the field of maturity onset diabetes of the young (MODY), which include the commoner forms of monogenic diabetes.Indian journal of endocrinology and metabolism. 05/2013; 17(3):430-41.