5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 8–11 July 2003, Le Meridien Montparnasse, Paris, France

HIV PROTEASE INHIBITORS ACUTELY INHIBIT GLUCOSE-INDUCED INSULIN RELEASE FROM HUMAN PANCREATIC β CELLS

Antiviral Therapy 2003; 8:L8 (abstract 6)

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

Homeostasis modelling assessment of HIV-infected and healthy subjects on a protease inhibitor (PI) regimen has revealed an impaired insulin response when faced with decreased peripheral insulin-sensitivity, suggesting pancreatic β-cell dysfunction. We have recently shown that HIV PIs acutely and reversibly impair glucose-stimulated insulin release from rodent pancreatic β-cells. As PIs inhibit the rodent pancreatic glucose transporter, Glut2, in a heterologous expression system and block glucose flux in a clonal β-cell line, inhibition of glucose uptake via Glut2 is likely to represent the primary mechanism by which PIs impair glucose-sensing of the β-cell. In contrast to the rodent, glucose transport in the human β-cell is mediated by Glut1 and Glut3, with significantly lower levels of the Glut2 isoform. Thus, it remains unclear whether PIs can inhibit glucose-induced insulin secretion from human islets in vitro and whether this underlies the decreased β-cell response in PI-treated subjects. To determine whether human pancreatic β-cell function is acutely affected by indinavir, glucose-stimulated insulin secretion was measured in isolated islets. Insulin release at stimulatory glucose (16.7 mM) was significantly inhibited in a dose-dependent manner with inhibitory concentration at 50% (IC₅₀) values of 0.35 µM following 1 h treatment with indinavir. Inhibition of insulin release was observed at all stimulatory concentration of glucose (7, 16.7 and 23 mM glucose) to a similar degree, although basal secretion (1 mM glucose) was unaffected by indinavir. In addition, inhibition of insulin release at stimulatory glucose (16.7 mM) was noted with all PIs tested (1 µM) with the following efficacy: indinavir > ritonavir > nelfinavir > amprenavir. Taken together, these data suggest that therapeutic levels of the PIs are sufficient to inhibit glucose-induced insulin secretion in human islets in vitro and this inhibition is likely to contribute to the decreased β-cell response observed in PI-treated subjects. It remains to be determined whether block of glucose uptake (Glut3/Glut1) in human islets underlies impaired insulin, as is predicted for the rodent β-cell.

Presenting author: JC Koster

2003-07-08
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