Metabolic basis of HIV-lipodystrophy syndrome

Sekhar, Rajagopal V.; Jahoor, Farook; White, A. Clinton; Pownall, Henry J.; Visnegarwala, Fehmida; Rodriguez‐Barradas, Maria C.; Sharma, Morali D.; Reeds, Peter J.; Balasubramanyam, Ashok

doi:10.1152/ajpendo.00058.2002

Cited by 110 publications

(104 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, we did find an increase in FFA turnover and clearance after treatment. Recently, Sekhar et al (42) provided strong evidence that the HLS is associated with increased FFA turnover and suggested that this reflected ongoing fat redistribution. Thus, the increased FFA turnover that we found in the absence of obvious lipodystrophy may be an early indicator for changes in lipid metabolism, which might eventually lead to the development of lipodystrophy.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Increased plasma FFA concentration is due to increased lipolysis (5,6), with increased net release of FFAs from adipose tissue (5,7). In other insulin-resistant states (e.g., obesity and type 2 diabetes), increased rates of lipolysis and plasma FFA concentration are related to the degree of insulin resistance (8 -10).…”

mentioning

confidence: 99%

Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but Has No Effect on Endogenous Glucose Production in HIV Lipodystrophy

et al. 2007

View full text Add to dashboard Cite

HIV-infected patients with lipodystrophy (HIV lipodystrophy) are insulin resistant and have elevated plasma free fatty acid (FFA) concentrations. We aimed to explore the mechanisms underlying FFA-induced insulin resistance in patients with HIV lipodystrophy. Using a randomized, placebo-controlled, cross-over design, we studied the effects of an overnight acipimox-induced suppression of FFAs on glucose and FFA metabolism by using stable isotopelabeled tracer techniques during basal conditions and a two-stage euglycemic-hyperinsulinemic clamp (20 and 50 mU insulin/m 2 per min, respectively) in nine patients with nondiabetic HIV lipodystrophy. All patients received antiretroviral therapy. Biopsies from the vastus lateralis muscle were obtained during each stage of the clamp. Acipimox treatment reduced basal FFA rate of appearance by 68.9% (95% CI 52.6 -79.5) and decreased plasma FFA concentration by 51.6% (42.0 -58.9) (both, P < 0.0001). Endogenous glucose production was not influenced by acipimox. During the clamp, the increase in glucose uptake was significantly greater after acipimox treatment compared with placebo (acipimox: 26. 85 , decreased phosphorylation of glycogen synthase (GS) site 3a ؉ b, and increased GS activity (percent I-form) in skeletal muscle (P < 0.01). Acipimox decreased phosphorylation of GS (site 3a ؉ b) (P < 0.02) and increased GS activity (P < 0.01) in muscle. The present study provides direct evidence that suppression of lipolysis in patients with HIV lipodystrophy improves insulin-stimulated peripheral glucose uptake. The increased glucose uptake may in part be explained by increased dephosphorylation of GS (site 3a ؉ b), resulting in increased GS activity.

show abstract

“…Recent evidence (12,36,44) indicates that basal whole body lipolytic rate, intramyocellular lipid (IMCL), and hepatic lipid content are elevated in people with HIV-lipodystrophy who take protease inhibitor (PI)-including HAART. Although controversial (36), resting whole body fatty acid (FA) oxidation appears to be decreased in HIV-infected individuals with metabolic complications (22) and may be the result of HIVand/or nucleoside analog reverse transcriptase inhibitor-associated mitochondrial toxicity (21).…”

mentioning

confidence: 99%

Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART

Cade¹,

Reeds²,

Mittendorfer³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

Metabolic basis of HIV-lipodystrophy syndrome

Cited by 110 publications

References 36 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

Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but Has No Effect on Endogenous Glucose Production in HIV Lipodystrophy

Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART

Contact Info

Product

Resources

About