Pancreatic β-cell signaling: toward better understanding of diabetes and its treatment

Pancreatic β-cells play a central role in the maintenance glucose homeostasis by secreting insulin, a key hormone that regulates blood glucose levels. Dysfunction of the β-cells and/or a decrease in the β-cell mass are associated closely with the pathogenesis and pathophysiology of diabetes mellitus, a major metabolic disease that is rapidly increasing worldwide. Clarification of the mechanisms of insulin secretion and β-cell fate provides a basis for the understanding of diabetes and its better treatment. In this review, we discuss cell signaling critical for the insulin secretory function based on our recent studies

GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis.

Glucagon secretion is inhibited by glucagon-like peptide-1 (GLP-1) and stimulated by adrenaline. These opposing effects on glucagon secretion are mimicked by low (1-10 nM) and high (10 muM) concentrations of forskolin, respectively. The expression of GLP-1 receptors in alpha cells is <0.2% of that in beta cells. The GLP-1-induced suppression of glucagon secretion is PKA dependent, is glucose independent, and does not involve paracrine effects mediated by insulin or somatostatin. GLP-1 is without much effect on alpha cell electrical activity but selectively inhibits N-type Ca(2+) channels and exocytosis. Adrenaline stimulates alpha cell electrical activity, increases [Ca(2+)](i), enhances L-type Ca(2+) channel activity, and accelerates exocytosis. The stimulatory effect is partially PKA independent and reduced in Epac2-deficient islets. We propose that GLP-1 inhibits glucagon secretion by PKA-dependent inhibition of the N-type Ca(2+) channels via a small increase in intracellular cAMP ([cAMP](i)). Adrenaline stimulates L-type Ca(2+) channel-dependent exocytosis by activation of the low-affinity cAMP sensor Epac2 via a large increase in [cAMP](i)