METABOLICALLY COUPLED ION CHANNEL INTERACTIONS IN ISLETS

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Glucose-stimulated insulin secretion (GSIS) from pancreatic islets is defective in Type 2 diabetes (T2DM). In healthy islets, GSIS is triggered by a complex network of intracellular signals (including [Ca2+]i) following glucose uptake and metabolism. Oscillatory insulin secretion is important for insulin action, and is disrupted in T2DM. We hypothesize that normal islet oscillations are critical for robust glucose sensing and insulin secretion. Individual islets exhibit diverse oscillatory patterns which may be fast (10-60s) or slow (2-5 min.). Despite intensive study, the mechanisms underlying these oscillations are unclear. The slow oscillations are less understood despite their potentially greater significance, as evidence by our recent data showing islet [Ca2+]i oscillations account for slow pulsatile insulin in vivo. We hypothesize that slow oscillations reflect glycolytic oscillations driven by phosphofructokinase. We recently developed a 'Combined Oscillation Model' (COM) where oscillatory glycolysis quantitatively interacts with faster electrical/[Ca2+]i oscillations. COM accounts for a wide spectrum of islet behavior including diverse [Ca2+]i patterns. Islets, however, also exhibit slow oscillations in O2 usage, mitochondrial potential and NAD(P)H. The objectives of this proposal are to: 1) determine whether metabolic oscillations are important for [Ca2+]i oscillations and secretion, and whether they are mitochondrial or glycolytic; 2) determine how [Ca2+]i and metabolism interact; 3) determine how ion channel(s) couple metabolism to electrical activity in beta cells; and 4) understand how diverse ionic/metabolic interactions control insulin secretion. Experimental results will be used to test the COM and other current hypotheses of islet function. Patch clamp electrophysiology, amperometry, and [Ca2+]i and [Na+]i imaging will be combined with measurements of NAD(P)H, mitochondrial potential, and O2 usage in islets from wild type and SUR1 knockout mice to carry out these objectives. Performing these studies test a new comprehensive theory of islet function which may have translational impact to help improve islet transplantation and help diabetes researcher more rationally design drugs to improve insulin secretion and islet viability in T2DM.