Secretagogue induced mechanisms regulating pancreatic islet electrical activity and hormone secretion
Maintaining physiological blood glucose levels is a complex process critically dependent on insulin secretion. Glucose stimulation of pancreatic beta-cells results in orchestrated electrical signaling that triggers insulin secretion. Our interest is in understanding how beta-cell ion channels are regulated during glucose stimulation and how these mechanisms become perturbed in diabetes.
Research on secretagogue modulation of beta-cell ion channels has primarily focused on the ATP sensitive potassium channel, KATP, which is an essential ion channel for normal glucose stimulated insulin secretion (GSIS). However, rodents with nonfunctional KATP channels and diabetic patients treated with blockers to KATP still exhibit glucose regulated insulin secretion. Thus KATP independent glucose responsive mechanisms play an important role during GSIS in humans. The mechanism(s) for this is unknown; however, as calcium is required for insulin secretion the mechanism must in part be coupled to calcium influx. Therefore, we are investigating the ion channels and their molecular mechanisms of regulation, independent of KATP, that help modulate secretagogue induced calcium influx and insulin secretion. The focus of this research is primarily on voltage-dependent calcium channels (CaV) and leak potassium channels. This research will test hypotheses concerning glucose and G-protein dependent regulation of islet electrical activity by CaV channel phosphorylation and modulation of islet membrane potential by leak potassium channels. These studies utilize molecular biology, genetics, fluorescent microscopy, and electrophysiology techniques on pancreatic islet-cells. Understanding how secretagogues regulate islet electrical activity distinctly from KATP may help to develop new therapies for diabetic patients that target specific elements of the beta-cell excitation-secretion pathway.