Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in β-cell function

Andersen, Ove; Haugaard, Steen B.; Andersen, Ulrik B.; Friis-Møller, Nina; Storgaard, Heidi; Vølund, Aage; Nielsen, Jens; Iversen, Johan; Madsbad, Sten

doi:10.1016/s0026-0495(03)00201-4

Cited by 45 publications

(51 citation statements)

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“…We recently reported that HIV-infected patients who had lipodystrophy compared with HIV-infected patients without fat redistribution, exhibited deterioration in insulin sensitivity (14). In the present study, we have investigated in more detail several aspects of the glucose…”

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confidence: 84%

Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic β-cells

et al. 2005

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Objectives: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and b-cell function in lipodystrophic HIV-infected patients. Methods: [3-3 H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naïve to antiretroviral therapy (NAÏVE) respectively). b-cell function was evaluated by an intravenous glucose tolerance test. Results: Compared with NONLIPO and NAÏVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; . 34%, P , 0.001), hepatic insulin sensitivity (. 40%, P , 0.03), incremental glucose disposal (. 50%, P , 0.001) and incremental exogenous glucose storage (. 50%, P , 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P , 0.01), increased clamp free fatty acids (P , 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P , 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r ¼ 0.69), incremental glucose disposal (r ¼ 0.71) and incremental exogenous glucose storage (r ¼ 0.40), all P , 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P ¼ 0.05) in LIPO compared with the combined groups of NONLIPO and NAÏVE, indicating an impaired adaptation of b-cell function to insulin resistance in LIPO. Conclusion: Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and b-cell function.

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confidence: 84%

Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic β-cells

et al. 2005

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“…All patients were on HAART and of male sex. A description of selection, anthropometry, immunology, components of HAART, and glucose metabolism of all subjects has been presented (11,21). In brief, for case subjects, a questionnaire and a physical examination had to be positive for signs of lipodystrophy, whereas for control subjects, both the questionnaire and physical examination had to be negative.…”

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confidence: 99%

“…A euglycemic-hyperinsulinemic clamp preceded by an intravenous glucose tolerance test was undertaken as described previously (11). In brief, a primed continuous infusion of [3-3 H]tritiated glucose (bolus, 2.05 Ci ⅐ mmol Ϫ1 ⅐ l Ϫ1 fasting plasma glucose; continuous, 0.11 Ci/min; New England Nuclear, Boston, MA) was initiated at 0900, at the start of a 150-min basal period (Ϫ150 to 0 min) and continued throughout the study, which included an intravenous glucose tolerance test (0 -30 min, 300 mg glucose/kg body wt, performed to characterize the first-phase insulin response [22]; data from the intravenous glucose tolerance test and a 120-min euglucemichyperinsulinemic clamp (30 -150 min) have been presented previously [11,21]). Two steady-state periods were predefined, i.e., at Ϫ60 to Ϫ30 min as basal and 120 -150 min as clamp.…”

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confidence: 99%

“…The muscle samples were freeze-dried and were carefully dissected free of eventually remaining blood, fat, and connective tissue before analysis of muscle enzyme activity and phosphorylation, which were measured in muscle homogenates (25). Body composition was estimated by dual-energy X-ray absorptiometry scanning (XR-36; Norland Medical System, Fort Atkinson, WI) as previously described (21). Glycogen synthase activity.…”

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Skeletal Muscle Insulin Signaling Defects Downstream of Phosphatidylinositol 3-Kinase at the Level of Akt Are Associated With Impaired Nonoxidative Glucose Disposal in HIV Lipodystrophy

et al. 2005

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More than 40% of HIV-infected patients on highly active antiretroviral therapy (HAART) experience fat redistribution (lipodystrophy), a syndrome associated with insulin resistance primarily affecting insulin-stimulated nonoxidative glucose metabolism (NOGM ins ). Skeletal muscle biopsies, obtained from 18 lipodystrophic nondiabetic patients (LIPO) and 18 nondiabetic patients without lipodystrophy (NONLIPO) before and during hyperinsulinemic (40 mU ⅐ m ؊2 ⅐ min ؊1 )-euglycemic clamps, were analyzed for insulin signaling effectors. All patients were on HAART. Both LIPO and NONLIPO patients were normoglycemic (4.9 ؎ 0.1 and 4.8 ؎ 0.1 mmol/l, respectively); however, NOGM ins was reduced by 49% in LIPO patients (P < 0.001). NOGM ins correlated positively with insulin-stimulated glycogen synthase activity (I-form, P < 0.001, n ‫؍‬ 36). Glycogen synthase activity (I-form) correlated inversely with phosphorylation of glycogen synthase sites 2؉2a (P < 0.001, n ‫؍‬ 36) and sites 3a؉b (P < 0.001, n ‫؍‬ 36) during clamp. Incremental glycogen synthase-kinase-3␣ and -3␤ phosphorylation was attenuated in LIPO patients (Ps < 0.05). Insulin-stimulated Akt Ser473 and Akt Thr308 phosphorylation was decreased in LIPO patients (P < 0.05), whereas insulin receptor substrate-1-associated phosphatidylinositol (PI) 3-kinase activity increased significantly (P < 0.001) and similarly (NS) in both groups during clamp. Thus, low glycogen synthase activity explained impaired NOGM ins in HIV lipodystrophy, and insulin signaling defects were downstream of PI 3-kinase at the level of Akt. These results suggest mechanisms for the insulin resistance greatly enhancing the risk of type 2 diabetes in HIV lipodystrophy. Diabetes 54:3474 -3483, 2005

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“…HIV-infected patients on highly active antiretroviral therapy (HAART) are at high risk of developing impaired glucose tolerance (IGT) and insulin resistance [10][11][12][13][14][15], which, in these patients, is associated with fat redistribution [10][11][12][13][14][15]. One possible explanation for b-cell dysfunction in HIV-infected patients on HAART is therefore reduced incretin secretion.…”

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Enhanced glucagon‐like peptide‐1 (GLP‐1) response to oral glucose in glucose‐intolerant HIV‐infected patients on antiretroviral therapy

et al. 2005

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ObjectivesWe investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV-infected patients on highly active antiretroviral therapy (HAART). MethodsEighteen HIV-infected male patients (six lipodystrophic and 12 nonlipodystrophic) with normal glucose tolerance (NGT) were compared with 10 HIV-infected male patients (eight lipodystrophic and two nonlipodystrophic) with IGT. Plasma concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations. ResultsThe incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared with NGT patients (1455 AE 422 vs. 409 AE 254 pmol/L/180 min, respectively; Po0.05), whereas the incrAUC for GIP did not differ between the study groups (7689 AE 1097 vs. 8041 AE 998 pmol/L/180 min, respectively; not significant). In pooled study groups, the GIP incrAUC correlated positively with the ISR incrAUC without adjustment (r 5 0.38, Po0.05) and following adjustment for glucose incrAUC (r 5 0.49, Po0.01). ConclusionsOur data suggest: (1) that glucose-intolerant, HIV-infected male patients may display enhanced GLP-1 responses to oral glucose compared with normal glucose-tolerant HIV-infected male patients, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART.Keywords: GLP-1, GIP, glucose tolerance, HIV, incretins IntroductionGlucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) account for the major part of the so-called incretin effect [1], i.e. the enhancement of the insulin response following oral ingestion compared with intravenous administration of glucose, given that the different routes of administration induce similar plasma glucose concentrations [2]. In healthy subjects, the incretins GLP-1 and GIP are responsible for as much as half of the substrate-dependent insulin release after food ingestion [3]. In type 2 diabetic patients, the secretion of GLP-1 after food ingestion is impaired [4]. Recently, in subjects with obesity-related insulin resistance and normal fasting glucose levels, the GLP-1 response after a meal was found to be progressively blunted in relation to increasing insulin resistance [5] 91to be linked mechanistically to glucose intolerance via its impact on gastric emptying and pancreatic beta cell action and proliferation [6][7][8][9]. HIV-infected patients on highly active antiretroviral therapy (HAART) are at high risk of developing impaired glucose tolerance (IGT) and insulin resistance [10][11][12][13][14][15], which, in these patients, is associated with fat redistribution [10][11][12][13][14][15]. One p...

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Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in β-cell function

Cited by 45 publications

References 47 publications

Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic β-cells

Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic β-cells

Skeletal Muscle Insulin Signaling Defects Downstream of Phosphatidylinositol 3-Kinase at the Level of Akt Are Associated With Impaired Nonoxidative Glucose Disposal in HIV Lipodystrophy

Enhanced glucagon‐like peptide‐1 (GLP‐1) response to oral glucose in glucose‐intolerant HIV‐infected patients on antiretroviral therapy

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