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MICROMouse Program Application Abstract

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ß-cell gap-junctional coupling effects on plasma insulin oscillations

David Piston (Nashville, TN)

MICROMouse Program

The goal of this project is to test the effects of disrupted insulin secretion dynamics on plasma insulin oscillations and glucose tolerance. Normally, insulin is secreted from ß-cells in the islet of Langerhans in the form of discrete coordinated pulses. These coordinated insulin pulses are thought to lead to oscillating insulin output from the pancreas that are more effective in lowering blood glucose and maintaining insulin sensitivity. Previous research has shown that gap junctional coupling is necessary to coordinate [Ca2+]i oscillations and pulsatile insulin release in isolated islets. We have recently found that a loss of gap junction coupling between ß-cells through a deletion of Cx36 leads to a reduction in glucose tolerance in mice. We hypothesize that a loss of gap junctional coupling leads to a loss of plasma insulin oscillations which in turn leads to reduced insulin action. To test this hypothesis we propose one primary and one secondary specific aim. 1). Measure the plasma insulin dynamics in presence and absence of electrical coupling; 2). Measure the first and second phase insulin secretion in vivo and ex vivo in Cx36 knockout mice. Experiments will be performed on Cx36 knockout mice along with wild-type littermates and will develop and apply state-of-the-art glucose clamp measurements pioneered at Vanderbilt MMPC. These experiments will be supplemented by patch clamping, quantitative imaging and established biochemical and physiological assays. These results will improve our understanding of the impact of insulin secretion dynamics on insulin action, which is an important factor in the progression of type 2 diabetes and in the development of insulin-based and cell-based therapies for both type 1 and type 2 diabetes.

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