Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus

Walli, Ravi; Michl, Gerlinde M.; Mühlbayer, Dieter; Brinkmann, Lars; Goebel, F. D.

doi:10.1007/s004330050123

Cited by 64 publications

(29 citation statements)

References 23 publications

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“…This finding correlates with clinical data suggestive of beneficial metabolic effects of TZD treatment of HAART-treated HIV patients (34,35). The fact that a beneficial effect could be observed both clinically as well as in the 3T3-L1 adipocyte cell line model suggests the potential validity of this in vitro system for studying potential therapeutic interventions for HPIinduced adipocyte abnormalities.…”

Section: Discussionsupporting

confidence: 83%

The HIV Protease Inhibitor Nelfinavir Induces Insulin Resistance and Increases Basal Lipolysis in 3T3-L1 Adipocytes

Rudich¹,

Vanounou²,

Riesenberg³

et al. 2001

Diabetes

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HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 mol/l (EC 50 ‫؍‬ 20 mol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 mol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 mol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre-and cotreatment with nelfinavir partly protected the cells from the increase in basal lipoysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.

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Section: Discussionsupporting

confidence: 83%

The HIV Protease Inhibitor Nelfinavir Induces Insulin Resistance and Increases Basal Lipolysis in 3T3-L1 Adipocytes

Rudich¹,

Vanounou²,

Riesenberg³

et al. 2001

Diabetes

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“…First, use of these regimens may cause deterioration of glycemic control in patients with preexisting diabetes. Second, because these regimens appear to induce insulin resistance predominantly in skeletal muscle and adipose tissue, antidiabetic agents that exert their major action on peripheral tissues rather than on the liver (e.g., thiazolidinediones) would appear advantageous (48). Third, because first-phase insulin release appears to be more severely impaired than second-phase insulin release, secretagogues such as the meglitinides, which primarily improve firstphase insulin release (49), may be preferable to sulfonylureas, which apparently only affect second-phase insulin release (49).…”

Section: Discussionmentioning

confidence: 99%

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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“…Pioglitazone based on its beneficial lipid effects seems a better thiazolidinedione for the treatment of diabetes in HIV-infected subjects. Another thiazolidinedione which exhibited similar effects, troglitazone, had to be withdrawn from the market due to unacceptable liver toxicity [142] . In conclusion, pioglitazone in preliminary studies appears to have a beneficial effect on insulin resistance mediated by adiponectin levels and favorably affects the lipid profile in the HIV associated metabolic syndrome.…”

Section: Therapeutic Implications Of the Adipokine Rolementioning

confidence: 99%

Leptin and Adiponectin in the HIV Associated Metabolic Syndrome: Physiologic and Therapeutic Implications

Tsiodras¹,

Mantzoros²

2006

American J. of Infectious Diseases

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Leptin and adiponectin represent two newly discovered adipose tissue derived hormones with important roles in energy homeostasis and insulin resistance. Their interrelations with the manifestations of the HIV associated metabolic syndrome and specific somatomorphic changes i.e. fat redistribution is reviewed. A synopsis of published studies is presented and the potential role of leptin and adiponectin is discussed. We have described an association of the HIV metabolic syndrome with a state of reduced insulin sensitivity due to adiponectin deficiency. The metabolic syndrome is also accompanied by leptin deficiency in lipoatrophic subjects and possibly by a leptin resistance state in lipohypertrophic patients. Adiponectin and / or leptin therapy in a manner similar to other leptin deficiency states may assist in the future management of such patients.

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Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus

Cited by 64 publications

References 23 publications

The HIV Protease Inhibitor Nelfinavir Induces Insulin Resistance and Increases Basal Lipolysis in 3T3-L1 Adipocytes

The HIV Protease Inhibitor Nelfinavir Induces Insulin Resistance and Increases Basal Lipolysis in 3T3-L1 Adipocytes

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

Leptin and Adiponectin in the HIV Associated Metabolic Syndrome: Physiologic and Therapeutic Implications

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