4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 22-25 September 2002, San Diego, CA, USA

INDINAVIR ACUTELY INHIBITS GLUCOSE INDUCED INSULIN RELEASE FROM PANCREATIC β-CELLS THROUGH BLOCK OF GLUCOSE UPTAKE

Antiviral Therapy 2002; 7:L4 (abstract 6)

JC Koster¹, M Remedi¹, H Qiu², CG Nichols¹ and PW Hruz^2
1Department of Cell Biology and Physiology, University School of Medicine, St Louis, Mo., USA; and ²Department of Pediatrics, Washington University School of Medicine, St Louis, Mo., USA

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 modelling analysis of intravenous glucose tolerance tests on PI-treated patients has revealed an impaired insulin response when faced with decreased peripheral insulin-sensitivity, suggesting β-cell dysfunction as well. To determine whether pancreatic β-cell function is acutely affected by indinavir, glucose-stimulated insulin secretion was measured in isolated mouse and rat islets and the murine insulinoma cell line, MIN6. Glucose-induced insulin release from MIN6 cells and mouse islets was significantly inhibited in a dose-dependent manner with IC₅₀ values of 5 and 4.5 μM, respectively, following 1 h treatment with indinavir. The uptake of 2-deoxyglucose in MIN6 cells was similarly inhibited with an IC₅₀ of 8.5 μM. Glucokinase activity was unaffected at drug levels as high as 1 mM. Glibenclamide (1 μM), a sulphonylurea that stimulates insulin secretion downstream of glucose uptake by inhibiting the ATP-sensitive K⁺-channel (K_ATP), reversed indinavir-mediated inhibition of insulin release in MIN6 cells. Finally, intravenous infusion of indinavir (0.5 mg/kg/min) during hyperglycaemic clamps on PI-naïve Wistar rats significantly suppressed first phase insulin response compared with water-treated controls. Taken together, these data suggest that therapeutic levels of the PI indinavir are sufficient to inhibit glucose uptake via the pancreatic glucose transporter(s), leading to decreased glucose-sensing by β-cells. Thus, together with peripheral insulin resistance, β-cell dysfunction is likely to contribute to altered glucose homeostasis, and is possibly a risk factor for developing overt diabetes.

Presenting author: JC Koster

2002-09-22
6

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