With the widespread use of HAART, HIV-infected populations have experienced high rates of metabolic complications, including insulin resistance, body fat redistribution, and dyslipidemia. Insulin resistance, in particular, has received much attention because of its potential progression to diabetes mellitus and association with cardiovascular disease. Insulin resistance in HIV -infected persons is likely a result of multiple factors relating to the host, the virus, and antiretrovirals. A better understanding of the mechanism of insulin resistance is critical to limit the risk of ultimate progression to diabetes mellitus and cardiovascular disease.
The Department of Health and Human Services currently recommends one of two antiretroviral agents as part of 151 line HAART regimens in the US, efavirenz or lopinavir/ritonavir. Few studies have compared the prevalence of metabolic complications in HIV-infected persons receiving efavirenz vs. lopinavir/ritonavir-based HAART, both of which have been associated with insulin resistance and dyslipidemia. Insulin resistance is characterized by decreased responsiveness of the liver and peripheral muscle to the effects of insulin. The mechanism of insulin resistance in HIV infected persons may be different from that of the general population, given that insulin resistance in HIV is often seen in the setting of lipodystrophy. Increased rates of lipolysis and delivery of fatty acid metabolites to the liver may further perturb hepatic glucose metabolism. Previous studies have demonstrated that indinavir impairs peripheral glucose transport by inhibiting GLUT-4 protein. The effect of antiretrovirals on hepatic insulin resistance has not been well examined. The effects of efavirenz and lopinavir/ritonavir on peripheral muscle and hepatic insulin sensitivity are unclear; studies after long-term use are needed to assess the effect of chronic HAART administration. A better understanding of the mechanism of insulin resistance in HIV will guide treatment and prevention efforts, as well as the development of alternative HAART regimens to minimize the risk of insulin resistance. Specific aims of this proposal are:
1. To examine whole body insulin sensitivity in HIV-infected persons receiving efavirenz vs. lopinavir/ritonavir based HAART for > l year using a euglycemic hyperinsulinemic clamp.
2. To examine hepatic and peripheral muscle insulin sensitivity in mY-infected persons on efavirenz vs. lopinavir/ritonavir-based HAART for::::l year using stable isotope infusion and nuclear magnetic resonance spectroscopy.
HIV -infected participants receiving efavirenz or lopinavir/ritonavir for > l year will be recruited from the NFHL study and the Infectious Diseases Clinics at New England Medical Center and Boston Medical Center. Participants with glucose intolerance, but without overt diabetes, measured by 2 hr 75 g oral glucose tolerance test, will subsequently undergo euglycemic hyperinsulinemic clamp testing and [6,6-2H2]-glucose infusion to measure whole body and hepatic insulin sensitivity, respectively. NMR spectroscopy will be used to measure peripheral insulin sensitivity.
This proposal represents a new collaboration between established investigators working in HIV and nutrition (Dr. Wanke) and glucose metabolism (Dr. Bhasin), both of whom will mentor Dr. Kohli. This proposal will provide preliminary data for a K23 submission by Dr. Kohli focusing on the mechanism of insulin resistance in mv -infected persons.
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