Metabolically Coupled Ion Channel Interactions in Islets

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 DESCRIPTION (provided by applicant): Patients with type 2 diabetes (T2DM) have reduced first phase insulin secretion and disrupted insulin pulsatility. We have studied oscillations in iset electrophysiology, calcium, and glucose metabolism that mediate pulsatile insulin secretion in mouse and developed the Dual Oscillator Model (DOM), which successfully predicts many features of normal mouse islets based on slow glycolytic oscillations due to phosphofructokinase-M (PFKM). However, controversies and anomalies remain concerning the origin, regulation and functional significance of slow oscillations. The significance of understanding pulsatile insulin secretion is that even if therapies are developed to increase beta cell mass in people with diabetes, restoring physiological pulsatility will optimize the efficacy o secreted insulin on its targets without overworking beta cells. Our long-term objective is to understand defective beta cell function in T2DM in order to restore pulsatile secretion. During the last period of support we developed new tools for studying the dynamics of islet metabolism and function and obtained new evidence for DOM. Building on this progress, we will determine the phase relationships between electrical and metabolic oscillations, test whether metabolic oscillations are glycolytic or mitochondrial, and clarify the relationship between metabolic, Ca and secretory oscillations in beta cells. We will determine how closely the oscillatory mechanisms of mouse islets pertain to human, whether islets from T2DM patients have altered oscillations and, if so, what aspects are affected. We will test our new hypothesis that altered ATP-sensitive potassium channel (KATP) trafficking in beta cells sets the glucose sensitivity of islet oscillations. Electrophysiology, [Ca2+] imaging, modeling, and novel optical probes to measure glycolytic activity, mitochondrial redox potential (MRP), ATP/ADP, cellular lactate and insulin secretion will be used to study the islets of wild type mice, mice lacking KATP channels, and islets from normal and T2DM humans.