Inactivating mutations in KATP channels cause the most common and severe form of congenital hyperinsulinism (KATPHI). Children with KATPHI are usually unresponsive to medical therapy and require pancreatectomy to control the hypoglycemia and prevent permanent brain damage. The goal of this proposal is to elucidate the ?-cell pathophysiology in KATPHI through the examination of fuel metabolism and stimulus-secretion coupling in islets isolated from children with KATPHI. Our overall hypothesis is that disturbances in KATP channels function result not only in dysregulation of the triggering pathway of insulin release, but also have secondary consequences that drastically disturb glucose and amino acid metabolism and alter fuel-stimulated insulin secretion through both the triggering and the amplification pathway. This hypothesis will be examined in three related and overlapping specific aims:
Aim 1 characterizes fuel metabolism and fuel-mediated insulin release in human islets with inactivating mutations in KATP channels and examines the role that elevated cytosolic calcium plays in determining the fate of metabolic fuels in these islets.
Aim 2 focuses on examining the metabolic and cAMP-mediated amplification of insulin secretion within the framework of energy production in human KATPHI islets.
Aim 3 examines the differences in gene expression between KATPHI islets and normal islets and integrates the metabolic and transcriptional profile of these islets to understand the mechanisms underlying the differences in fuel metabolism and insulin secretion. KATPHI is a severe genetic disorder associated with high rates of neurodevelopmental impairment. It has been almost 20 years since the discovery of the molecular basis of this condition. However, the incomplete understanding of the pathophysiology underlying the dysregulated insulin secretion has precluded the development of effective therapies. Thus, outcomes with current treatment approaches continue to be suboptimal for children carrying the most severe mutations. Our study aims at examining the pathophysiology within the framework of the energy production/insulin secretion relationship to identify new targets for therapy. This study will improve our understanding of the mechanisms and second messengers mediating the amplifying pathway of insulin secretion, which in turn, will be helpful for understanding the mechanisms implicated in the progressive ?-cell failure that leads to type 2 diabetes. Thus, these studies may lead to the identification of novel targets for therapy not only for hyperinsulinism but also for diabetes.
KATP-hyperinsulinism is a severe genetic disorder associated with high rates of neurodevelopmental impairment due to poorly controlled hypoglycemia. Our study aims at examining the pathophysiology of KATPHI within the framework of the energy production/insulin secretion relationship to identify new targets for therapy. This study will improve our understanding of the mechanisms and second messengers mediating the amplifying pathway of insulin secretion; which in turn; will be helpful for understanding the mechanisms implicated in the progressive ?-cell failure that leads to type 2 diabetes. Thus; these studies may lead to the identification of novel targets for therapy not only for hyperinsulinism but also for diabetes.
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|Lu, Ming; Li, Changhong (2017) Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes. Ann N Y Acad Sci :|
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|Kaufman, Brett A; Li, Changhong; Soleimanpour, Scott A (2015) Mitochondrial regulation of ?-cell function: maintaining the momentum for insulin release. Mol Aspects Med 42:91-104|
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