HIV protease inhibitors acutely impair glucose-stimulated insulin release

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.