Glucose transport and NIDDM

Academic Article


  • Three major metabolic abnormalities contribute to hyperglycemia in non- insulin-dependent diabetes mellitus (NIDDM) including defective glucose- induced insulin secretion, elevated rates of hepatic glucose output, and insulin's impaired ability to stimulate glucose uptake in peripheral target tissues (insulin resistance). These functions involve cellular glucose transport in β-cells, liver, adipose tissue, and skeletal muscle; and, in some instances, abnormalities in glucose transporter isoforms (GLUT) specifically expressed in these tissues may constitute key biochemical lesions underlying defective glucose homeostasis. In animal models of NIDDM, suppression of GLUT2 in β-cells is correlated with loss of high-K(m) glucose transport and glucose-sensitive insulin secretion. Although there are no data on humans with NIDDM, GLUT2 loss would constitute an attractive mechanism for defective glucose sensing in β-cells if it can be shown that transport then becomes rate limiting for glucose metabolism. In the liver, however, hepatocyte glucose transport via GLUT2 probably plays only a permissive role in sustaining increased glucose efflux. Peripheral insulin resistance is associated with decreased glucose transport activity, the likely rate- limiting step for glucose uptake in fat and muscle. Accordingly, the insulin- responsive GLUT4 isoform expressed exclusively in insulin target tissues has been studied intensively in NIDDM. In these studies, pretranslational suppression of GLUT4 appears to be the key mechanism of insulin resistance in adipocytes. However, levels of GLUT4 protein and mRNA are normal in vastus lateralis and rectus abdominis, inferring that defects in GLUT4 functional activity or insulin-mediated translocation cause insulin resistance in muscle. Thus, the intensified study of glucose transport has provided important new insights into NIDDM pathogenesis over the past 5 yr and has presented investigators with additional intriguing hypotheses.
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    Author List

  • Garvey WT
  • Start Page

  • 396
  • End Page

  • 417
  • Volume

  • 15
  • Issue

  • 3