Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells

Abstract

The mechanism by which chronic treatment with HIV (human immunodeficiency virus)-1 protease inhibitors leads to a deterioration of glucose metabolism appears to involve insulin resistance, and may also involve impaired insulin secretion. Here we investigated the long-term effects of HIV-1 protease inhibitors on glucose-stimulated insulin secretion from beta cells and explored whether altered insulin secretion might be related to altered insulin signaling. INS-1 cells were incubated for 48 h with different concentrations of amprenavir, indinavir, nelfinavir, ritonavir or saquinavir, stimulated with 20 mM -glucose, and insulin determined in the supernatant. To evaluate insulin signaling, cells were stimulated with 100 nM insulin for 2 min, and insulin-receptor substrate (IRS)-1, -2 and Akt phosphorylation determined. Incubation for 48 h with ritonavir, nelfinavir and saquinavir resulted in impaired glucose-induced insulin secretion at 2·5, 5 and 5 µM respectively, whereas amprenavir or indinavir had no effects even at 20 and 100 µM respectively. The impaired insulin secretion by ritonavir, nelfinavir and saquinavir was associated with decreased insulin-stimulated IRS-2 phosphorylation, and, for nelfinavir and saquinavir, with decreased insulinstimulated IRS-1 and Thr 308 -Akt phosphorylation. No such effects on signaling were observed with amprenavir or indinavir. In conclusion, certain HIV-1 protease inhibitors, such as ritonavir, nelfinavir and saquinavir, not only induce peripheral insulin resistance, but also impair glucose-stimulated insulin secretion from beta cells. With respect to the long-term effect on beta-cell function there appear to be differences between the protease inhibitors that may be clinically relevant. Finally, these effects on insulin secretion after a 48 h incubation with protease inhibitor were associated with a reduction of the insulin-stimulated phosphorylation of insulin signaling parameters, particularly IRS-2, suggesting that protease inhibitor-induced alterations in the insulin signaling pathway may contribute to the impaired beta-cell function.

Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo

“…Other groups have reported that nelfinavir decreases phosphorylation of Akt at S473 in cancer cell lines, but only after 1 or 3 days of incubation (26,29). In addition, other studies have shown that HIV protease inhibitors can inhibit insulin-stimulated Akt activation (26,38,39). Our study extends these observations by showing that nelfinavir reduces Akt activation in response to EGF or IGF-I, and that decreased Akt stimulation correlates with decreased receptor tyrosine kinase activation.…”

HIV Therapy and Diabetes Risk

“…The association between protease inhibitors and diabetes was further strengthened by studies showing that switching patients to other regimens improved the hyperglycemia and hyperlipidemia observed during use of protease inhibitor-containing regimens. Focusing almost exclusively on the role of protease inhibitors, elegant studies demonstrated the rapid development of insulin resistance and concurrent impairment of insulin secretion following exposure to these agents (4). The mechanism of insulin resistance appears to involve interference with glucose transport: photo-affinity labeling has demonstrated binding of sequences within the common peptidomimetic core of HIV protease inhibitors to the major glucose transporter (GLUT4) (5).…”

Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection

“…In contrast to the acute effects of PIs on glucose-stimulated insulin release, more chronic exposure to PIs appears to alter insulin signaling with clear differences between PIs [30] . Whether this is the result of direct alterations on other protein targets or secondary changes following glucose transport inhibition remains to be determined.…”