HIV Protease Inhibitors Acutely Impair Glucose-Stimulated Insulin Release

Abstract

HIV protease inhibitors (PIs) acutely and reversibly inhibit the insulin-responsive glucose transporter Glut 4, leading to peripheral insulin resistance and impaired glucose tolerance. Minimal modeling analysis of glucose tolerance tests on PI-treated patients has revealed an impaired insulin secretory response, suggesting additional pancreatic ␤-cell dysfunction. To determine whether ␤-cell function is acutely affected by PIs, we assayed glucose-stimulated insulin secretion in rodent islets and the insulinoma cell line MIN6. Insulin release from MIN6 cells and rodent islets was significantly inhibited by the PI indinavir with IC 50 values of 1.1 and 2.1 mol/l, respectively. The uptake of 2-deoxyglucose in MIN6 cells was similarly inhibited (IC 50 of 2.0 mol/ l), whereas glucokinase activity was unaffected at drug levels as high as 1 mmol/l. Glucose utilization was also impaired at comparable drug levels. Insulin secretogogues acting downstream of glucose transport mostly reversed the indinavir-mediated inhibition of insulin release in MIN6 cells. Intravenous infusion of indinavir during hyperglycemic clamps on rats significantly suppressed the first-phase insulin response. These data suggest that therapeutic levels of PIs are sufficient to impair glucose sensing by ␤-cells. Thus, together with peripheral insulin resistance, ␤-cell dysfunction likely contributes to altered glucose homeostasis associated with highly active antiretroviral therapy. Diabetes 52: 1695-1700, 2003

Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection

“…Again, in vitro studies have provided insights into the molecular mechanism(s) for impaired glucose stimulated insulin release from these cells. While the direct molecular targets for PIs in these cells has not yet been established, defective glucose transport and/or metabolism has been implicated [28] . Thus, it is possible that the effects on β-cell function are due in part to acute changes in the function of the related glucose transporter(s) present in this tissue, namely GLUT2.…”

Effect of Maternal Use of Antiretroviral Agents on Serum Insulin Levels of the Newborn Infant

“…Therefore, it is reasonable to assume that these findings eventually detected in humans may indicate a still early diabetogenic effect secondary to the use of antiretroviral drugs during the limited period of pregnancy. However, few conclusive studies are available about the physiopathology of the changes induced by these drugs from the viewpoint of glucose intolerance (5,11,13,14).…”

Human Immunodeficiency Virus infection and cardiovascular disease

“…Mechanisms of insulin resistance in the HIV-positive population are not known, but may relate to altered nutrient metabolism, changes in body composition, and/or direct effects of antiviral agents. Preliminary data include the demonstration of altered lipolysis and increased serum free fatty acids in HIV-positive individuals (Koster et al, 2003). Excess free fatty acids in the circulation may reduce insulin sensitivity through inappropriate lipid storage in muscle and liver, resulting in impaired glucose utilization and insulin-mediated inhibition of glycogenolysis and gluconeogenesis (Grunfeld et al, 2010).…”