10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

ACUTE EFFECTS OF RITONAVIR IN GLUT4 AND GLUT2 KNOCKOUT MICE

Antiviral Therapy 2008; 13(Suppl. 4):A4 (abstract no. O-03)

J Koster¹ and PW Hruz^1,2
1Department of Cellular Biology and Physiology; and ²Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA

OBJECTIVES: The ability of HIV protease inhibitors (PIs) to acutely block facilitative glucose transporter (GLUT) activity has been established in vitro and is believed to contribute to altered glucose homeostasis in vivo. However, several GLUT-independent mechanisms have been postulated to mediate both inhibition of peripheral glucose disposal and impairment of glucose-stimulated insulin secretion. To determine the specific contribution of GLUT blockade on PI-mediated insulin resistance, the acute effect of ritonavir on glucose homeostasis was investigated in previously established genetically modified mice lacking either the insulin-responsive transporter GLUT4 (G4KO) or the pancreatic transporter GLUT2 (G2KO).

METHODS: G4KO and non-transgenic C57BL/6J control mice (n=11 per group) were given a single 10 mg/kg intra-peritoneal injection of ritonavir or vehicle 15 min prior to the start of a standard 2 g/kg intraperitoneal glucose tolerance test. Pancreatic islets were isolated from G2KO mice, which have GLUT1 expressed under the control of the rat insulin promoter in order to circumvent the neonatal lethality associated with GLUT2 ablation. Islets were then exposed to 20 µM ritonavir or vehicle for 60 min in the presence of 1 and 16.7 mM glucose and total insulin secretion was assessed.

RESULTS: Under control conditions, G4KO mice exhibited increased fasting blood glucose values when compared with wild-type C57BL/6J mice (340 ±47 and 116 ±10 mg/dl, respectively, P<0.001). Importantly, ritonavir produced a significant impairment in glucose disposal in wild-type mice (blood glucose at 30 min=322 ±32 mg/dl with PI versus 237 ±21 mg/dl without PI, P<0.001) but did not exacerbate glucose intolerance in G4KO mice (blood glucose at 30 min=427 ±40 mg/dl with PI versus 452 ±27 mg/dl without PI). In contrast to the differential effects of ritonavir on glucose tolerance in G4KO versus wild-type mice, relative glucose-stimulated insulin secretion (GSIS) was sensitive to inhibition by ritonavir in both wild-type and G2KO islets (51 ±13% and 69 ±13% reduction in GSIS, respectively).

CONCLUSIONS: These data confirm that the acute effect of ritonavir on peripheral glucose disposal is mediated through direct inhibition of GLUT4 activity in vivo. In contrast, the effect of ritonavir on insulin secretion does not appear to be mediated by GLUT2 blockade. The ability of GLUT4 blockade to contribute to derangements in the other molecular pathways that influence insulin sensitivity remains to be determined.

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2008-11-06
O-03

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