Evidence that down-regulation of beta-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia.

Abstract

Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic .beta. cells to maintain insulin secretion at a level sufficient to compensate for underlying insulin resistance. In the ZDF rat, a model of NIDDM that closely resembles the human syndrome, we have previously reported profound underexpression of GLUT-2, the high-Km facilitative glucose transporter expressed by .beta. cells of normal animals. Here we report that islets of diabetic rats exhibit a marked decrease in the volume density of GLUT-2-positive .beta. cells and a reduction at the electron-microscopic level in the number of GLUT-2-immunoreactive sites per unit of .beta.-cell plasma membrane. The deficiency of GLUT-2 cannot be induced in normal .beta. cells by in vivo or in vitro exposure to high levels of glucose nor can it be prevented in .beta. cells of prediabetic ZDF rats by elimination of hyperglycemia. We conclude that this dearth of immunodetectable GLUT-2 in NIDDM is not secondary to hyperglycemia and therefore that it may well play a causal role in the development of hyperglycemia.