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.

Public Health Relevance

Patients with Type 2 or adult onset diabetes secrete insulin abnormally, which when coupled with their inefficient use of insulin (insulin resistance) leads to high blood sugar. Insulin is released from pancreatic islets into the blood in pulses and these pulses, which are believed to be important for effective insulin action and possibly secretion are disrupted in Type 2 patients and their relatives. Our work to understand pulsatile insulin secretion in mice will now be extended to understand human insulin secretion and how it is disrupted in Type 2 diabetes. This work will stimulate the production of novel drugs to treat Type 2 diabetes by improving the pulsatile release of insulin in diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Sato, Sheryl M
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Wedgwood, Kyle C A; Satin, Leslie S (2018) Six degrees of depolarization: Comment on ""Network science of biological systems at different scales: A review"" by Marko Gosak et al. Phys Life Rev 24:136-139
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