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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.

GS-8374, a Novel HIV Protease Inhibitor, Does Not Alter Glucose Homeostasis in Cultured Adipocytes or in a Healthy-Rodent Model System