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Insulin Resistance in HIV Protease Inhibitor-Associated Diabetes

Yarasheski Kevin E.; Tebas, Pablo; Sigmund, Catherine; Dagogo-Jack, Samuel; Bohrer, Alan; Turk, John; Halban, Philippe A.; Cryer, Philip E.; Powderly, William G.
JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1st, 1999

Background:Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy.

Objective:To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes.

Design:Cross-sectional evaluation.

Patients:8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir.

Measurements:Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 μM) on rat pancreatic β-cell function in vitro.

Results:In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum Cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat β-cells.

Conclusions:The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic β-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery.

Address correspondence and reprint requests to Kevin E. Yarasheski, Washington University Medical School, 660 South Euclid Avenue. Metabolism Division Box 8127. St. Louis. MO 63110, U.S.A.: email:

Manuscript received August 11, 1998; accepted March 10, 1999.

© 1999 Lippincott Williams & Wilkins, Inc.