A complete understanding of the molecular mechanisms leading to HIV-associated
insulin resistance remains elusive. Complex interrelationships between
genetic predisposition, disease-related body changes and multidrug
therapy all contribute to alterations in
glucose homeostasis. These abnormalities can be differentiated between acute and reversible changes directly induced by
HAART medications and more chronic and less reversible changes due to the development of
lipodystrophy and
hyperlipidemia. Implicated pathways include changes in
adipokine secretion, insulin signaling,
lipid homeostasis and disease-related increases in inflammatory mediators. The
insulin responsive facilitative
glucose transporter GLUT4 is the first molecule to have been identified as a direct target of
HIV protease inhibitors. Efforts to elucidate the mechanisms directly responsible for the evolution of
insulin resistance during
HIV infection and
therapy will be greatly assisted by the further identification and characterization of direct molecular targets amenable to pharmacologic
therapy and/or the development of newer
antiretroviral agents that do not adversely affect these target
proteins.