The role of protease inhibitors in the pathogenesis of HIV-associated insulin resistance: cellular mechanisms and clinical implications.
HIV-associated insulin resistance frequently presents as relative lack of peripheral adipose tissue storage associated with dyslipidemia. This review discusses explanations for the links between acute and subacute abnormalities in glucose metabolism and chronic changes in adipose tissue distribution. Specifically, the molecular mechanisms by which the HIV protease inhibitor class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage are reviewed. It is proposed that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on glucose metabolism. The physiologic outcome is such that total energy storage in the adipocytes is decreased, and the remaining adipocytes resist further energy storage. The excess circulating and dietary lipid metabolites, normally "absorbed" by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue where they impair insulin action. This leads to a pathologic cycle of insulin resistance, lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome.
Noor
Mustafa A
MA
Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 4500, Princeton, NJ 08543, USA. Mustafa.noor@verizon.net
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D039682:HIV-Associated Lipodystrophy Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism
D017320:HIV Protease Inhibitors; D007328:Insulin; D005947:Glucose