Physiology and Pathophysiology of Hormone Secretion from lslets of Langerhans

Abstract

Diabetes is a metabolic disorder stemming from the improper regulation of blood glucose levels by hormones secreted by pancreatic islets of Langerhans. Paper I describes the mechanism by which glucose can regulate glucagon secretion, independent of membrane potential, from pancreatic α-cells, via modulation of endoplasmic reticulum Ca2+ handling. Paper II shows that the GLP-1 metabolite GLP-1(9-36) acts directly on α-cells to inhibit glucagon secretion, via activation of Gi-coupled glucagon receptors. Paper III, shows that the islet autoantigen tetraspanin-7 regulates β-cell transmembrane Ca2+ influx and the Ca2+ sensitivity of exocytosis. Paper IV demonstrates that α-cells and their neighbouring δ-cells exhibit a novel paracrine signalling loop. δ-cells react to the activity of adjacent α-cells, secreting somatostatin, to prevent glucagon hypersecretion. This mechanism becomes sensitised following exposure to hypoglycaemia, leading to excessive intra-islet somatostatin secretion, impairing glucose counter-regulation. Together, these papers reveal novel mechanisms governing the regulation of islet hormone secretion, which may lead to improvements in therapies for diabetes.