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Incretin Regulation of Insulin Secretion in Human Neonatal Diabetes


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Monogenic diabetes is a group of disorders caused by mutations in any of one of a number of genes essential for the appropriate function of the insulin producing beta-cells in the pancreas. Estimates suggest that monogenic forms of diabetes could represent as much as 2% of all diabetes cases. Patients with diabetes occurring at an extremely young age, "neonatal diabetes", are very likely to have an underlying monogenic cause, especially when diagnosed before 6 months of age. The University of Chicago Neonatal Diabetes Registry now includes clinical and genetic information on over 200 subjects with diabetes diagnosed prior to one year of age. The most common genetic cause of diabetes in this group are activating mutations in the gene KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, which plays a critical role in insulin secretion. This group of subjects represent an unparalleled opportunity to investigate a human model of disruption of specific beta cell proteins critical for normal secretion of insulin. Patients with KCNJ11-related neonatal diabetes who were previously treated with insulin exhibit clinically excellent glucose control with minimal hypoglycemia when treated with sulfonylureas (usually glyburide). The predominant stimuli for secretion of insulin in sulfonylurea-treated patients have been suggested to be related to incretins rather than the metabolism of glucose. However, many questions remain regarding the nature of beta-cell function in such patients, as well as its long-term response to treatment. In this application, we thus propose the following Aims: 1) To fully characterize the insulin response to glucose in KCNJ11 patients compared to controls;2) To characterize the specific contribution of GLP-1 signaling on insulin secretion in KCNJ11 diabetes;3) To evaluate effect of age at genetic diagnosis of KCNJ11 diabetes and the role of incretin therapy in comparison with other forms of neonatal diabetes. During inpatient studies on subjects 18 years of age or older, we will use oral glucose tolerance testing (OGTT) followed by matched intravenous isoglycemic glucose infusion (IGI) to compare sulfonylurea-treated KCNJ11 patients with matched controls, then repeat these studies during infusions of GLP-1 and Exendin (9-39), a specific GLP-1 receptor antagonist. These tests will provide quantitative measures of insulin secretion with direct estimates of the incretin effect and evaluation of key incretin pancreatic and gut hormones. We will also monitor glucose excursion profiles with continuous glucose monitoring in response to OGTT in patients of all ages with KCNJ11 mutations as well as other forms of neonatal diabetes. These studies will test the following hypotheses: 1) Insulin secretory response to both intravenous and oral glucose is impaired in patients with KCNJ11 diabetes, 2) Oral glucose-regulated insulin secretion in KCNJ11 diabetes depends largely on GLP-1 signaling in the presence of elevated glucose, and 3) Glycemic control is dependent on age at conversion from insulin to oral sulfonylureas, that is, later age of instituting SU therapy leads to suboptimal glycemic control, with higher sulfonylurea dose and poorer neurodevelopmental outcome, and ii) glycemic control can be improved by treatment with incretin-based therapies. We anticipate that these studies will provide insight into beta cell function only possible through investigation of these rare subjects with genetic alteration of beta cell function. Furthermore, such studies have not yet been published in subjects with neonatal diabetes. We anticipate that these studies will elucidate the role of incretins in regulating insuln secretion independent of the KATP channel. Given that most of the genes causing monogenic diabetes have been associated with Type 2 diabetes through GWAS, better understanding of the pathophysiology of genetic defects causing human beta-cell dysfunction and how patients with mutations in these genes respond to different therapies could lead to improved diagnosis and treatment for those with more common polygenic forms of diabetes.

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K23DK094866


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Collapse Time 
Collapse start date
2012-05-01

Collapse end date
2015-03-31