Dopamine and Pancreatic Islet Function

Abstract

Pancreatic islets are spheroidal clusters of electrically and chemically connected endocrine cells, whose function plays a key role in glucose homeostasis. Islet β-cells secrete insulin in response to increased blood glucose concentration, but their response is modulated by other stimuli (such as glucagon, insulin, acetylcholine, epinephrine, etc.). The application of stimulatory glucose concentrations (>6 mM) to isolated pancreatic islets produces synchronized oscillations in intracellular [Ca2+]. During these [Ca2+] oscillations, the entire pancreatic islet secretes insulin in a pulsatile manner.We are exploring the role of endogenous production of dopamine by β-cells in the regulation of [Ca2+] oscillations and insulin secretion. Using fluorescent Ca2+ indicators, micro-fluidic devices, and confocal microscopy, we have measured the period of [Ca2+] oscillations in isolated intact islets. Treating the islets with the dopamine precursor, L-DOPA (3,4-Dihydroxy-L-phenylalanine), or a selective antagonist of D2 dopamine receptor, Raclopride, causes a decrease and an increase in the frequency of [Ca2+] oscillations. Parallel experiments were performed using islets from genetically modified mice that do not express the dopamine transporter, and it was found that their [Ca2+] oscillations are also slower than those from wild type mice. Hence, we propose that this autocrine dopaminergic system is part of the mechanism that regulates [Ca2+] oscillations.The oscillation period depends on the islet electrical and metabolic activity. To begin understanding the potential mechanisms by which dopamine is exerting its function in the β-cell, we are using computer modeling to simulate the islet activity and reproduce the data and to gather information on the main pathway involved in the observed dopaminergic effect.