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 β-cell dysfunction. To determine whether β-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 IC50 values of 1.1 and 2.1 μmol/l, respectively. The uptake of 2-deoxyglucose in MIN6 cells was similarly inhibited (IC50 of 2.0 μmol/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 β-cells. Thus, together with peripheral insulin resistance, β-cell dysfunction likely contributes to altered glucose homeostasis associated with highly active antiretroviral therapy.

Original languageEnglish
Pages (from-to)1695-1700
Number of pages6
Issue number7
StatePublished - Jul 1 2003


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