GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system.
Adverse effects induced by HIV protease inhibitors (PIs) are a significant factor in limiting their clinical success. PIs directly contribute to peripheral insulin resistance and alterations in lipid metabolism. GS-8374 is a novel PI with potent antiretroviral activity and a favorable resistance profile. Here we report on the potential of GS-8374 to adversely affect glucose and lipid homeostasis. Acute effects of GS-8374 and control PIs on glucose uptake and lipid accumulation were assessed in vitro in mouse OP9 and primary human adipocytes, respectively. GS-8374 and atazanavir showed no effect on insulin-stimulated deoxyglucose uptake, whereas ritonavir and lopinavir caused significant reductions. Similarly, in vitro lipid accumulation was not significantly affected in adipocytes treated with either GS-8374 or atazanavir. In euglycemic-hyperinsulinemic clamp experiments performed in rats during acute infusion of therapeutic levels of PIs, sustained serum GS-8374 levels of 8 μM had no effect on peripheral glucose disposal (similar to the findings for atazanavir). Comparable serum levels of lopinavir and ritonavir produced acute 19% and 53% reductions in in vivo glucose disposal, respectively. In conclusion, similar to atazanavir, but unlike ritonavir and lopinavir, GS-8374 neither affects insulin-stimulated glucose uptake in adipocytes in culture nor acutely alters peripheral glucose disposal in a rodent model system. These results dissociate the antiretroviral activity of GS-8374 from adverse effects on insulin sensitivity observed with some of the first-generation PIs and provide further support for the use of these experimental systems in the preclinical evaluation of novel PIs.
Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8208, St. Louis, MO 63110, USA. hruz_p@kids.wustl.edu
Paul W
PW
Hruz
Qingyun
Q
Yan
Luong
L
Tsai
Joseph
J
Koster
Lianhong
L
Xu
Tomas
T
Cihlar
Christian
C
Callebaut
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D000069446:Atazanavir Sulfate; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D061466:Lopinavir; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D007328:Insulin; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D005947:Glucose; D019438:Ritonavir
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