Studies into the role of glucose transporter function in insulin resistance

Peripheral tissue insulin resistance is a key factor in the pathogenesis of type II diabetes mellitus and a risk factor for hypertension and cardiovascular disease. The mechanisms underlying this resistance remain unclear. Studies have shown defects in many biochemical pathways, indicating that an early step in insulin action is involved. Glucose transport in muscle and adipose tissue is the earliest and rate limiting step in glucose metabolism, and is decreased in several insulin resistant states. The aim of this project was to investigate the role of glucose transporter expression and function in insulin resistance. I raised and purified antibodies specific to different transporter isoforms in order to assess tissue glucose transporter levels. Neonatal streptozotocin-injected rats showed marked glucose intolerance, but were not insulin resistant, indicating that hypoinsulinaemia per se does not lead to insulin resistance. High-fat fed rats became mildly glucose intolerant, and showed a 37% decrease in insulin sensitivity. Adipocyte glucose transport was decreased, although not significantly, by 20%. Adipocytes showed a 30% reduction in GLUT4 levels and 34% decrease in insulin induced translocation. GLUT1 levels were unchanged. In skeletal muscle, diaphragm and heart, GLUT4 and GLUT1 levels were unchanged. Therefore, although glucose transporter depletion may explain insulin insensitivity in fat, it cannot explain it in the tissues which are the major site for whole body disposal. The proportion of saturated and mono-unsaturated fatty acids were increased in membrane phospholipids of skeletal muscle, heart and diaphragm in fat fed rats, with a concomitant decrease in linoleic acid. There was also a reduction in cholesterol: phospholipid ratio. Membrane lipid fluidity was unchanged, suggesting that the reduction in cholesterol: phospholipid ratio compensates for the increase in saturated fatty acids, thus maintaining normal fluidity. Preliminary studies on cirrhotic subjects indicated no changes in glucose uptake, GLUT4 levels or translocation in adipocytes, or in skeletal muscle GLUT4. Thus, these studies indicate that in insulin resistant states changes in glucose transporter levels are not found in the major tissues for insulin stimulated glucose disposal, although they are sometimes found in adipose tissue. Changes in membrane lipid composition may be involved