Open AccessElevated Basal Insulin Secretion in Type 2 Diabetes Caused by Reduced Plasma Membrane Cholesterol
Author(s) -
Vini Nagaraj,
Abdulla S. Kazim,
Johan Helgeson,
Clemens Lewold,
Satadal Barik,
Paweł Buda,
Thomas Reinbothe,
Stefan Wennmalm,
Enming Zhang,
Erik Renström
Publication year - 2016
Publication title -
molecular endocrinology
Language(s) - English
Resource type - Journals
eISSN - 1944-9917
pISSN - 0888-8809
DOI - 10.1210/me.2016-1023
Subject(s) - medicine , endocrinology , exocytosis , insulin , biology , insulin oscillation , islet , secretion , basal (medicine) , lipid raft , pancreatic islets , cholesterol
Elevated basal insulin secretion under fasting conditions together with insufficient stimulated insulin release is an important hallmark of type 2 diabetes, but the mechanisms controlling basal insulin secretion remain unclear. Membrane rafts exist in pancreatic islet cells and spatially organize membrane ion channels and proteins controlling exocytosis, which may contribute to the regulation of insulin secretion. Membrane rafts (cholesterol and sphingolipid containing microdomains) were dramatically reduced in human type 2 diabetic and diabetic Goto-Kakizaki (GK) rat islets when compared with healthy islets. Oxidation of membrane cholesterol markedly reduced microdomain staining intensity in healthy human islets, but was without effect in type 2 diabetic islets. Intriguingly, oxidation of cholesterol affected glucose-stimulated insulin secretion only modestly, whereas basal insulin release was elevated. This was accompanied by increased intracellular Ca 2+ spike frequency and Ca 2+ influx and explained by enhanced single Ca 2+ channel activity. These results suggest that the reduced presence of membrane rafts could contribute to the elevated basal insulin secretion seen in type 2 diabetes.