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

Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic β 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-K_m facultative glucose transporter expressed by β cells of normal animals. Here we report that islets of diabetic rats exhibit a marked decrease in the volume density of GLUT-2-positive β cells and a reduction at the electron-microscopic level in the number of GLUT-2-immunoreactive sites per unit of β-cell plasma membrane. The deficiency of GLUT-2 cannot be induced in normal β cells by in vivo or in vitro exposure to high levels of glucose nor can it be prevented in β 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.