Inhibition of Id1 Augments Insulin Secretion and Protects Against High-Fat Diet–Induced Glucose Intolerance

Abstract

OBJECTIVEThe molecular mechanisms responsible for pancreatic β-cell dysfunction in type 2 diabetes remain unresolved. Increased expression of the helix-loop-helix protein Id1 has been found in islets of diabetic mice and in vitro models of β-cell dysfunction. Here, we investigated the role of Id1 in insulin secretion and glucose homeostasis.RESEARCH DESIGN AND METHODSId1 knockout (Id1−/−) and wild-type mice were fed a chow or high-fat diet. Glucose tolerance, insulin tolerance, β-cell mass, insulin secretion, and islet gene expression were assessed. Small interfering RNA (siRNA) was used to silence Id1 in MIN6 cells, and responses to chronic palmitate treatment were assessed.RESULTSId1−/− mice exhibited an improved response to glucose challenge and were almost completely protected against glucose intolerance induced by high-fat diet. This was associated with increased insulin levels and enhanced insulin release from isolated islets, whereas energy intake, body weight, fat pad weight, β-cell mass, and insulin action were unchanged. Islets from Id1−/− mice displayed reduced stress gene expression and were protected against high-fat diet–induced downregulation of β-cell gene expression (pancreatic duodenal homeobox-1, Beta2, Glut2, pyruvate carboxylase, and Gpr40). In MIN6 cells, siRNA-mediated inhibition of Id1 enhanced insulin secretion after chronic palmitate treatment and protected against palmitate-mediated loss of β-cell gene expression.CONCLUSIONSThese findings implicate Id1 as a negative regulator of insulin secretion. Id1 expression plays an essential role in the etiology of glucose intolerance, insulin secretory dysfunction, and β-cell dedifferentiation under conditions of increased lipid supply.