Insulin-stimulated Insulin Secretion in Single Pancreatic Beta Cells

Abstract

Functional insulin receptors are known to occur in pancreatic beta cells; however, except for a positive feedback on insulin synthesis, their physiological effects are unknown. Amperometric measurements at single, primary pancreatic beta cells reveal that application of exogenous insulin in the presence or absence of nonstimulatory concentrations of glucose evokes exocytosis mediated by the beta cell insulin receptor. Insulin also elicits increases in intracellular Ca 2؉ concentration in beta cells but has minimal effects on membrane potential. Conditions where the insulin receptor is blocked or cell surface concentration of free insulin is reduced during exocytosis diminishes secretion induced by other secretagogues, providing evidence for direct autocrine action of insulin upon secretion from the same cell. These results indicate that the beta cell insulin receptor can mediate positive feedback for insulin secretion. The presence of a positive feedback mechanism for insulin secretion mediated by the insulin receptor provides a potential link between impaired insulin secretion and insulin resistance.

Nicotinic acid-adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human beta cells

“…At some concentrations, secretion was significantly inhibited. Notably, high-resolution amperometry studies showed that the application of 100 nM insulin resulted in only modest exocytosis (Ϸ10 insulin granules) in a minority of beta cells (4,5). That insulin does not stimulate robust, prolonged hormone release agrees with the requirement for voltage-gated Ca 2ϩ channel-mediated Ca 2ϩ influx for exocytosis in human beta cells (35).…”

“…Although results from in vivo and whole islet experiments suggested a negligible or inhibitory effect of insulin on insulin release, recent experiments with dispersed rodent beta cells suggested a stimulatory effect on calcium signaling, insulin expression, and exocytosis (2-7). Unlike glucose signaling, insulin-evoked Ca 2ϩ signals in mouse beta cells required intracellular Ca 2ϩ stores sensitive to the sarcoplasmic͞endoplasmic Ca 2ϩ -ATPase (SERCA) inhibitor thapsigargin (4). Insulin action was not blocked by a phospholipase C inhibitor, suggesting indirectly that inositol 1,4,5-trisphosphate (IP 3 )-sensitive Ca 2ϩ stores were not involved (5).…”

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

“…Enhanced insulin secretion in Mck/Gcgr mice is presumably an additional mechanism that renders beta cells more competent to STZ-induced beta cell injury and apoptosis, considering that autocrine insulin action is pivotal in maintaining beta cell secretion and function [39][40][41]. Insulin prevents not only beta cell death during excessive nutritioninduced oxidative stress, but also cytokine-induced beta cell death [40,42].…”

Beneficial effects of intercellular interactions between pancreatic islet cells in blood glucose regulation

“…It has also been reported that there exist autocrine interactions via which a cell is affected by its own hormone secretion (Aspinwall et al, 1999;Cabrera et al, 2008).…”