The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes

Ranganathan, Subramania; Kern, PA

doi:10.1677/joe.0.1720155

Cited by 56 publications

(44 citation statements)

References 34 publications

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“…Because this occurred in the face of increased plasma insulin levels, these observations provide evidence for impaired suppression of lipolysis by insulin. The latter is consistent with recent reports that nelfinavir, saquinavir, and ritonavir increase lipolysis (11,35,37). We found no alteration of plasma lipids except for an increase in LDL cholesterol.…”

Section: Discussionsupporting

confidence: 93%

Mechanisms for the Deterioration in Glucose Tolerance Associated With HIV Protease Inhibitor Regimens

et al. 2003

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The mechanisms responsible for the deterioration in glucose tolerance associated with protease inhibitorcontaining regimens in HIV infection are unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, ␤-cell function has not been evaluated in detail. The present study was therefore undertaken to assess the effects of protease inhibitor-containing regimens on hepatic, muscle, and adipose tissue insulin sensitivity as well as pancreatic ␤-cell function. We evaluated ␤-cell function in addition to glucose production, glucose disposal, and free fatty acid (FFA) turnover using the hyperglycemic clamp technique in combination with isotopic measurements in 13 HIV-infected patients before and after 12 weeks of treatment and in 14 normal healthy volunteers. ␤-Cell function and insulin sensitivity were also assessed by homeostasis model assessment (HOMA). Treatment increased fasting plasma glucose concentrations in all subjects (P < 0.001). Insulin sensitivity as assessed by HOMA and clamp experiments decreased by ϳ50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). ␤-Cell function decreased by ϳ50% (P ‫؍‬ 0.002), as assessed by HOMA, and firstphase insulin release decreased by ϳ25%, as assessed by clamp data (P ‫؍‬ 0.002). Plasma FFA turnover and clearance both increased significantly (P < 0.001). No differences at baseline or in responses after treatment were observed between drug naïve patients who were started on a nucleoside reverse transcriptase inhibitor (NRTI) plus a protease inhibitor and patients who had been on long-term NRTI treatment and had a protease inhibitor added. The present study indicates that protease inhibitor-containing regimens impair glucose tolerance in HIV-infected patients by two mechanisms: 1) inducement of peripheral insulin resistance in skeletal muscle and adipose tissue and 2) impairment of the ability of the ␤-cell to compensate. Diabetes 52: 918 -925, 2003 U se of protease inhibitors has remarkably improved long-term survival after HIV infection (1,2). However, up to 60% of HIV-infected patients treated with these agents develop either impaired glucose tolerance (IGT) or type 2 diabetes (3-6), and it now appears to be well established that regimens including protease inhibitors are associated with insulin resistance (2,5,7,8). Noor et al. (9,10) have shown that acute and 4-week protease inhibitor exposure of normal volunteers reduces glucose disposal during euglycemichyperinsulinemic clamp experiments. Moreover, in vitro studies have demonstrated that protease inhibitors reduce insulin-stimulated glucose uptake in adipocytes and skeletal muscle (11,12).Knowledge of the mechanisms responsible for deterioration in glucose tolerance during protease inhibitorcontaining regimens is still incomplete. It is unclear whether protease inhibitors adversely affect pancreatic ␤-cell function (4,8) and what effec...

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Section: Discussionsupporting

confidence: 93%

Mechanisms for the Deterioration in Glucose Tolerance Associated With HIV Protease Inhibitor Regimens

et al. 2003

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“…These results on lipolysis did not agree with those reported by others (8,19,20). The differences, however, could have been due to the use of a different PI (i.e., Nelfinavir) in the studies cited (8,19,20) and the PI concentrations employed (maximum concentrations used in other studies (8,(22)(23)(24) (Ͼ20.0 M). Also, our protocol had PI present during fat cell differentiation while others did not expose the adipocytes until differentiation was complete, upon which the PI was added for 18 h-48 h before measuring lipolysis (8).…”

Section: Discussioncontrasting

confidence: 55%

“…These included the 3T3 L1 pre-adipocytes (this study), 3T3 F442A pre-adipocytes (19), and C3H10T1/2 cells (8) Further, the concentrations of PI used in this study are in the physiological range (3)(4)(5). The clinical evidence on insulin resistance and adiposity indicated that multiple sites are affected in fat tissue (23,24). Our data indicate that the effects of PI while elevating basal TG synthesis are not manifested by increased insulin-stimulated TG synthesis.…”

Section: Discussionmentioning

confidence: 95%

The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

Cammalleri

Germinario

2003

Journal of Lipid Research

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“…The 3T3-L1 adipocyte, however, did not exhibit increased insulin-stimulated 2-DG transport after short-term exposure to PI and showed decreased basal 2-DG transport (Murata et al 2000). Controversy does exist as others (Ranganathan & Kern 2002) have shown increased basal 2-DG transport in 3T3-L1 adipocytes in the presence of indinavir and saquinavir. Also, they showed little or no effect of PI on insulin-stimulated 2-DG transport.…”

Section: Discussionmentioning

confidence: 91%

The long-term effects of anti-retroviral protease inhibitors on sugar transport in L6 cells

Germinario

Colby-Germinario²,

Cammalleri³

et al. 2003

Journal of Endocrinology

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The objective of this study was to investigate the longterm effects of anti-retroviral protease inhibitors (PIs) on 2-deoxy--glucose (2-DG) transport in L6 cells in vitro. Exposure of L6 cells to saquinavir, ritonavir, indinavir and amprenavir resulted in significant increases in 2-DG transport using PI concentrations of 1-10 µM with continual exposure to PI. After removal of the PI for up to 48 h, 2-DG transport increases did not change and remained at pre-reversal levels. These changes in 2-DG transport were not related to stress-induced sugar transport or to apoptosis. The examination of glucose transporter (GLUT) 1, 3 or 4 translocation with subcellular fractionation indicated that insulin (i.e. 67 nM) could induce the translocation of all the GLUTs to the plasma membrane. Also, ritonavir (10 µM), which leads to a 2-fold increase in 2-DG transport, demonstrated increased GLUT (i.e. 1, 3 or 4) presence in the plasma membrane fraction, in the presence or absence of insulin. This increased 2-DG transport involved transporter presence in plasma membrane preparations and did not affect the ability of insulin to stimulate 2-DG transport with continual PI exposure. The mechanism(s) involved indicates ready reversibility of PI effects on transporters. The mechanism(s) why reversibility of PI-induced 2-DG transport was similar plus or minus PI was not apparent.

show abstract

The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes

Cited by 56 publications

References 34 publications

Mechanisms for the Deterioration in Glucose Tolerance Associated With HIV Protease Inhibitor Regimens

Mechanisms for the Deterioration in Glucose Tolerance Associated With HIV Protease Inhibitor Regimens

The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

The long-term effects of anti-retroviral protease inhibitors on sugar transport in L6 cells

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