INSULIN-RECEPTOR DOWN-REGULATION AND IMPAIRED ANTILIPOLYTIC ACTION OF INSULIN IN DIABETIC-PATIENTS AFTER PANCREAS/KIDNEY TRANSPLANTATION

Patients with insulin-dependent diabetes who receive pancreas/ kidney transplants lose their need for insulin injections, but they become hyperinsulinemic and insulin resistant, and sometimes develop noninsulin-dependent diabetes mellitus. The reason for the insulin resistance is not well understood. Specifically, it is not known whether they become resistant to the action of insulin on lipid metabolism. Euglycemic-hyperinsulinemic clamps were performed in six pan creas/kidney (P/K) recipients, six kidney (K) recipients (to control for immunesuppressive therapy), and eight healthy controls. Measured were leg blood flow (by plethysmography), rates of lipolysis (with [H-2(5)] glycerol), fatty acid oxidation (by indirect calorimetry), fatty acid reesterification (with [H-2(5)]glycerol and [1-C-13]palmitate), monocyte membrane insulin binding (with [I-125]Tyr-A(14) insulin), and insulin receptor mass (by RIA). Fasting plasma insulin concentrations were 2 times higher in P/K and K recipients (108 pmol/L) than in controls (54 pmol/L). Insulin receptor mass in solubilized monocyte membranes from P/K and K recipients was reduced by 61% and 63%, respectively, whereas insulin binding was reduced by 73% and 70%, respectively. P/K and K recipients were resistant to the inhibitory action of insulin on lipolysis (P/K vs. controls,- P < 0.01; K vs. controls, P < 0.02) and on fatty acid reesterification (P/K vs. controls, P < 0.02; K vs. controls, P < 0.03). P/K recipients appeared to be more resistant than K recipients, but the differences between the two groups were not statistically significant. We conclude that P/K recipients were hyperinsulinemic, had downregulated the number of their monocyte insulin receptors, and were resistant to the antilipolytic action of insulin.