Insulin resistance among HIV-infected patients: unraveling the mechanism.
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HIV Infections↗
Biomedical subjects
Colleen Hadigan
Publications and source records attributed to Colleen Hadigan.
Increased cardiovascular disease risk indices in HIV-infected women.
Little is known regarding cardiovascular disease risk indices in HIV-infected women. This study investigated cardiovascular disease risk indices in 100 consecutively recruited HIV-infected women and 75 healthy female control subjects. Subjects were recruited from hospital- and community-based health care providers. C-reactive protein (CRP), interleukin-6 (IL-6), adiponectin, lipid, and glucose levels were the main outcome measures. CT scan, dual-energy x-ray absorptiometry (DXA), and anthropometry were used to assess body composition. Although similar in age, weight, and racial composition, HIV-infected women demonstrated higher CRP (4.6 +/- 0.7 vs. 2.3 +/- 0.4 mg/L, P = 0.007), IL-6 (2.7 +/- 0.2 vs. 1.8 +/- 0.1 pg/mL, P = 0.02), triglyceride (1.84 +/- 0.21 vs. 0.85 +/- 0.05 mM, P = 0.0002), 2-hour glucose after oral glucose challenge (6.88 +/- 0.22 vs. 5.72 +/- 0.17 mM, P = 0.0003), and fasting insulin (81 +/- 8 vs. 45 +/- 2 pM, P = 0.0002) and lower high-density lipoprotein cholesterol (1.17 +/- 0.03 vs. 1.45 +/- 0.05 mM, P < 0.0001) and adiponectin (5.4 +/- 0.3 vs. 7.6 +/- 0.5 mg/L, P = 0.0001) levels compared with the control population. HIV-infected women had more abdominal visceral fat and less extremity fat by CT and DXA scan and demonstrated a higher waist-to-hip ratio (WHR) than the control population. Within the HIV group, CRP and other indices were significantly related to body composition in stepwise regression models. Among all subjects, WHR, but not HIV status, was significantly related to CRP and other cardiovascular disease risk indices. HIV-infected women demonstrate significantly increased risk factors for cardiovascular disease in association with abnormal fat distribution.
Absorptiometry, Photon↗
Resistin levels in human immunodeficiency virus-infected patients with lipoatrophy decrease in response to rosiglitazone.
Resistin is a recently recognized adipocytokine thought to contribute to insulin resistance. We determined resistin levels and metabolic parameters in 24 HIV-infected men and women with lipoatrophy and hyperinsulinemia and studied the effect of 12 wk of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone (4-8 mg/d) on resistin in these subjects. Participants completed metabolic testing before and after rosiglitazone including fasting determination of resistin, adiponectin, and leptin levels, serum inflammatory markers, and hyperinsulinemic euglycemic clamp testing. Resistin concentration decreased significantly after rosiglitazone (12.17 +/- 1.15 ng/ml to 10.23 +/- 1.05 ng/ml; P = 0.02), in conjunction with significant increases in adiponectin- (P < 0.001) and insulin- stimulated glucose disposal (P = 0.004). Leptin levels, as well as TNF-alpha, did not change with rosiglitazone. In summary, among HIV-infected subjects with insulin resistance and lipoatrophy, resistin levels decreased significantly after rosiglitazone. Further investigation into the physiological role of this peroxisome proliferator-activated receptor-gamma-responsive adipocytokine in the metabolic abnormalities associated with HIV is warranted.
Adult↗
Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial.
BACKGROUND: Patients with HIV infection who are treated with antiretroviral agents often lose subcutaneous fat and have metabolic abnormalities, including insulin resistance and reduced adiponectin levels, which may be related to disrupted subcutaneous adipogenesis and altered peroxisome proliferator-activated receptor-gamma signaling. OBJECTIVE: To investigate the effects of rosiglitazone (4 mg/d), a peroxisome proliferator-activated receptor-gamma agonist, in HIV-infected men and women with hyperinsulinemia and lipoatrophy. DESIGN: A randomized, double-blind, placebo-controlled, 3-month study. SETTING: University hospital. PATIENTS: 28 HIV-infected men and women with hyperinsulinemia and lipoatrophy. MEASUREMENTS: Insulin sensitivity measured by euglycemic hyperinsulinemic clamp testing; subcutaneous leg fat area measured by computed tomography; adiponectin, free fatty acid, and lipid levels; and safety variables. RESULTS: Rosiglitazone, when compared with placebo, improved insulin sensitivity (mean [+/-SD] change, 1.5 +/- 2.1 mg of glucose/kg of lean body mass per minute vs. -0.4 +/- 1.6 mg/kg per minute; P = 0.02), increased adiponectin levels (mean [+/-SD], 2.2 +/- 2.2 micro g/mL vs. 0.1 +/- 1.1 microg/mL; P = 0.006), and reduced free fatty acid levels (mean [+/-SD], -0.09 +/- 0.1 mmol/L vs. 0.01 +/- 0.1 mmol/L; P = 0.02). Mean percentage (+/-SD) of body fat (1.38% +/- 3.03% vs. -0.83% +/- 2.76%; P = 0.03) and subcutaneous leg fat area (2.3 +/- 8.4 cm2 vs. -0.9 +/- 1.9 cm2; P = 0.02) increased significantly with rosiglitazone compared with placebo. Mean total cholesterol levels (+/-SD) also increased with rosiglitazone compared with placebo (0.6 +/- 1.0 mmol/L [25 +/- 37 mg/dL] vs. -0.4 +/- 0.6 mmol/L [-15 +/- 25 mg/dL]; P = 0.007). LIMITATIONS: The study was relatively small and of short duration. CONCLUSIONS: The authors demonstrated positive effects of rosiglitazone on lipoatrophy; insulin sensitivity; and metabolic indices, including adiponectin levels, in HIV-infected patients with lipoatrophy and insulin resistance. Peroxisome proliferator-activated receptor-gamma agonists may correct the metabolic abnormalities associated with disrupted adipogenesis in this population. Further studies must determine the clinical utility of such agents in HIV-infected patients.
Adiponectin↗
HIV Infection: Working Group Report of the Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.
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Anti-HIV Agents↗
Differential effects of metformin and exercise on muscle adiposity and metabolic indices in human immunodeficiency virus-infected patients.
The HIV-lipodystrophy syndrome is associated with fat redistribution and metabolic abnormalities, including insulin resistance (IR). The mechanisms and treatment strategies for IR in HIV-lipodystrophy are unclear, but data suggest that intramuscular lipids contribute to IR in this population. We previously showed that metformin and exercise improve hyperinsulinemia more than metformin alone in HIV-lipodystrophy. Now we investigate the effects of these treatment strategies on thigh muscle adiposity measured by computed tomography and additional body composition measures. Twenty-five HIV-infected patients on stable antiretroviral therapy with hyperinsulinemia and fat redistribution participated in a prospective, randomized, 3-month study of metformin alone or metformin and resistance training three times a week. Thigh muscle adiposity decreased significantly more as shown by increased muscle attenuation [2.0 (range, 0.5-5.0) vs. -1.0 (-3.5-0), P = 0.04] and sc leg fat tended to decrease more [-3.3 (-7.5-4.3) vs. 0.8 (-2.1-9.5), P = 0.06] in the combined treatment group in comparison with metformin alone. In multivariate analysis, change in thigh muscle adiposity remained a significant predictor of change in insulin (P = 0.04), controlling for changes in other body composition measurements. These data suggest that muscle adiposity, in addition to other fat depots, is an important determinant of hyperinsulinemia and that exercise has complex effects on regional fat depots in HIV-infected patients. Reduction in muscle adiposity may be an important mechanism by which exercise improves hyperinsulinemia in this population.
Adipose Tissue↗
Alanine aminotransferase levels predict insulin resistance in HIV lipodystrophy.
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Adipose Tissue↗
Psoas muscle attenuation measurement with computed tomography indicates intramuscular fat accumulation in patients with the HIV-lipodystrophy syndrome.
The human immunodeficiency virus (HIV)-lipodystrophy syndrome is characterized by abnormalities of lipid metabolism, glucose homeostasis, and fat distribution. Overaccumulation of intramuscular lipid may contribute to insulin resistance in this population. We examined 63 men: HIV positive with lipodystrophy (n = 22), HIV positive without lipodystrophy (n = 20), and age- and body mass index-matched HIV-negative controls (n = 21). Single-slice computed tomography was used to determine psoas muscle attenuation and visceral fat area. Plasma free fatty acids (FFA), lipid profile, and markers of glucose homeostasis were measured. Muscle attenuation was significantly decreased in subjects with lipodystrophy [median (interquartile range), 55.0 (51.0-58.3)] compared with subjects without lipodystrophy [57.0 (55.0-59.0); P = 0.05] and HIV-negative controls [59.5 (57.3-64.8); P < 0.01]. Among HIV-infected subjects, muscle attenuation correlated significantly with FFA (r = -0.38; P = 0.02), visceral fat (r = -0.49; P = 0.002), glucose (r = -0.38; P = 0.02) and insulin (r = -0.60; P = 0.0001) response to a 75-g oral glucose tolerance test. In forward stepwise regression analysis with psoas attenuation as the dependent variable, visceral fat (P = 0.02) and FFA (P < 0.05), but neither body mass index, subcutaneous fat, nor antiretroviral use, were strong independent predictors of muscle attenuation (r2 = 0.39 for model). Muscle attenuation (P = 0.02) and visceral fat (P = 0.02), but not BMI, subcutaneous fat, FFA, or antiretroviral use, were strong independent predictors of insulin response (area under the curve) to glucose challenge (r2 = 0.47 for model). These data demonstrate that decreased psoas muscle attenuation due to intramuscular fat accumulation may contribute significantly to hyperinsulinemia and insulin resistance in HIV-lipodystrophy patients. Further studies are needed to assess the mechanisms and consequences of intramuscular lipid accumulation in HIV-infected patients.
Absorptiometry, Photon↗
Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution.
A metabolic syndrome has been described among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy; the syndrome is characterized by fat redistribution, insulin resistance, and dyslipidemia. We compared the 10-year coronary heart disease (CHD) risk estimates for 91 HIV-infected men and women with fat redistribution with the risk estimates for 273 age-, sex-, and body mass index (BMI)-matched subjects enrolled in the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were also compared with 90 age- and BMI-matched control subjects. The 10-year CHD risk estimate was significantly elevated among HIV-infected patients with fat redistribution, particularly among men; however, when they were matched with control subjects by waist-to-hip ratio, the 10-year CHD risk estimate did not significantly differ between groups. HIV-infected patients without fat redistribution did not have a greater CHD risk estimate than did control subjects. In addition, the CHD risk estimate was greatest in HIV-infected patients who had primary lipoatrophy, compared with those who had either lipohypertrophy or mixed fat redistribution. Therefore, although CHD risk is increased in HIV-infected patients with fat redistribution, the pattern of fat distribution and sex are potential important components in determining the risk in this population.
Adult↗
Dietary habits and their association with metabolic abnormalities in human immunodeficiency virus-related lipodystrophy.
Relatively little is known about the influence of dietary habits on the metabolic complications associated with human immunodeficiency virus (HIV) infection and lipodystrophy. Although recommendations to modify diet and exercise remain a first-line approach to the management of HIV-infected patients with dyslipidemia and glucose intolerance, it is important to determine to what extent, if any, these metabolic abnormalities may be attributed to or modified by dietary behaviors. I review previous work evaluating dietary behaviors and their relationship to lipid levels and insulin resistance in HIV-infected patients with and without lipodystrophy and discuss the implications of possible dietary interventions and results of preliminary studies of the effects of diet on dyslipidemia. Sound dietary guidelines based on investigational research among HIV-infected patients are clearly needed to help face the challenges of the emerging problems of hyperlipidemia, insulin resistance, and the possible increased risk of cardiovascular disease among patients with HIV infection and lipodystrophy.
Diet↗
Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution.
BACKGROUND: Fatty acid concentrations are increased in patients with HIV and fat redistribution and may contribute to insulin resistance in this population. OBJECTIVE: We determined the effects of acute inhibition of lipolysis on insulin sensitivity in HIV-infected patients with fat redistribution who were receiving a protease inhibitor. DESIGN: Seven HIV-infected men [age: 45 +/- 2 y; body mass index (in kg/m(2)): 28.8 +/- 1.9] with a fasting insulin concentration > or= 104 pmol/L (15 micro IU/mL), combined visceral adiposity and peripheral lipoatrophy, and receiving a protease inhibitor were studied. Tolbutamide-modified frequently sampled intravenous-glucose-tolerance tests (FSIGTTs) were performed after randomized double-blind administration of acipimox (500 mg at -90 and 0 min), a potent inhibitor of lipolysis, and placebo. The subjects completed 2 FSIGTTs separated by 3-7 d. RESULTS: At baseline, fasting insulin and fatty acid concentrations were 27.6 +/- 5.0 micro IU/mL and 0.83 +/- 0.08 mmol/L (normal range: 0.1-0.6 mmol/L), respectively. Fatty acid concentrations were significantly reduced after acipimox compared with placebo (fatty acid area under the curve: acipimox = 73 +/- 8 compared with placebo = 122 +/- 12 mmol x 270 min/L, P = 0.002). Acipimox treatment resulted in a significant increase in the insulin sensitivity index (acipimox = 1.63 +/- 0.5 compared with placebo = 0.88 +/- 0.3 x 10(-4) x min(-1) x micro IU/mL, P = 0.015). CONCLUSIONS: Acute inhibition of lipolysis and reduction in fatty acid concentrations are associated with improved insulin sensitivity in patients with HIV lipodystrophy and hyperinsulinemia. Further studies are needed to determine whether long-term antilipolytic strategies to reduce fatty acid concentrations may be useful in treating the metabolic disturbances associated with HIV lipodystrophy.
Adipose Tissue↗
Stimulation with fatty meal (Lipomul) to assess gallbladder emptying in children with chronic acalculous cholecystitis.
OBJECTIVE: Chronic acalculous cholecystitis previously has been diagnosed by hepatobiliary scan stimulated with intravenous octapeptide of cholecystokinin. This compound may soon be unavailable in the United States. The goal of this study was to describe the characteristics of children with chronic acalculous cholecystitis diagnosed by hepatobiliary scintigraphy with oral Lipomul challenge, and to evaluate their clinical response to cholecystectomy. METHODS: Retrospective chart review of patients with no gall stones detected by abdominal ultrasound or computed tomography with gallbladder ejection fraction (GBEF) <35% after Lipomul challenge who subsequently underwent cholecystectomy. Fifteen patients with a mean age of 14.9 +/- 0.9 years were included. The mean duration of symptoms before evaluation was 8.2 +/- 2.5 months. RESULTS: The mean GBEF after Lipomul challenge was 16.7% +/- 2.7%. All patients had abdominal pain. Ninety percent had right upper quadrant pain and 86% had typical biliary colic. Pain was precipitated by fatty meals in 73.3%. Histopathologic analysis of the gallbladder demonstrated chronic cholecystitis in 80% of cases. The mean postoperative follow-up was 20 +/- 5 months. Six months after the surgery, nine patients (60%) were asymptomatic, five (33%) had marked improvement of symptoms, and one (6%) was unchanged. At the time of latest follow-up, symptoms had reappeared in two patients who had been asymptomatic at the 6-month visit (13%). Seven patients (46%) remained asymptomatic, five (33%) had marked improvement but continued to have some persistent symptoms, and one (6%) was unchanged. CONCLUSIONS: Chronic acalculous cholecystitis may be responsible for right upper quadrant pain in children without gallstones. A GBEF <35% at 30 minutes after Lipomul challenge may be useful in identifying patients who could benefit from cholecystectomy. Lipomul may be a good alternative to cholecystokinin for gallbladder stimulation during scintigraphy.
Abdominal Pain↗
Hyperlipidemia in children with HIV infection: an emerging problem.
The introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV infection has transformed HIV/AIDS into a chronic illness and the focus of clinical management has shifted from opportunistic infections to long-term management and toxicities of therapy. Pediatric patients with HIV infection perhaps pose the greatest challenge in this arena as they potentially face many decades of living with HIV/AIDS and its therapies. Although there are numerous emerging medical complications associated with chronic HIV infection and HAART, hyperlipidemia is increasingly recognized among HIV-infected children and adults and will be the focus of this review. The nature and prevalence of lipid abnormalities in children with HIV infection is discussed, as well as possible etiologies for these abnormalities and the future management of this growing challenge for children living with HIV disease.
Antiretroviral Therapy, Highly Active↗
Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution.
Fat redistribution, defined by both increased abdominal visceral fat and/or decreased abdominal, extremity, and facial subcutaneous fat, is increasingly recognized among human immunodeficiency virus (HIV)-infected patients treated with combination antiretroviral therapy. Fat redistribution in this population is associated with insulin resistance and dyslipidemia and is often referred to as the HIV lipodystrophy syndrome (LIPO). Fatty acids are known to modulate insulin resistance in other disease states, but a comprehensive evaluation of fatty acids has not been undertaken among HIV-infected patients with fat redistribution. In this study, we investigated fatty acid concentrations in 64 HIV-infected individuals (45 men and 19 women) with evidence of fat redistribution (LIPO) in comparison to 30 HIV-infected individuals (20 men and 10 women) without evidence of fat redistribution (NONLIPO) and 32 HIV-negative healthy control subjects (C) (21 males and 11 females) of similar age and body mass index (BMI). Glucose, insulin, and free fatty acid (FFA) levels were measured in response to a 75-g oral glucose tolerance test (OGTT) in the LIPO, NONLIPO, and C subjects. In addition, fasting lipids were obtained, and body composition was determined by anthropometric measurements and dual-energy x-ray absorptiometry (DXA). Fasting FFA concentrations were significantly increased in the LIPO group as compared with NONLIPO and C subjects (0.74 +/- 0.03 v 0.60 +/- 0.04 [mean +/- SEM] mmol/L, P =.002, LIPO v NONLIPO; 0.74 +/- 0.03 v 0.59 +/- 0.03 mmol/L, P =.001, LIPO v C). In contrast, fasting FFA concentrations were not increased in the NONLIPO group (0.60 +/- 0.04 v 0.59 +/- 0.03, P =.909, NONLIPO v C). Similarly, fasting triglycerides and 120-minute OGTT FFA were significantly increased in the LIPO group as compared with the NONLIPO and C group. FFA decreased in HIV-infected LIPO, NONLIPO, and C subjects in response to OGTT, but the 120-minute FFA concentrations remained significantly elevated in LIPO patients compared with NONLIPO and C subjects. In a multivariate regression model of LIPO patients, fasting FFA (P =.027) was a strong independent predictor of insulin area under the curve (AUC), controlling for age, BMI, gender, and body composition (r(2) for model =.31). No differences were observed in FFA concentrations in the LIPO group in an analysis based on current protease inhibitor (PI) use. These data suggest that FFA concentrations are increased in HIV-infected patients with fat redistribution. Increased fasting concentrations of fatty acids are associated with abnormal insulin responses to standard glucose challenge in HIV-infected patients with fat redistribution. Further studies are necessary to determine the mechanism of increased fatty acid concentrations and the role played by increased FFA in mediating insulin resistance in this population.
Absorptiometry, Photon↗
Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy.
Human immunodeficiency virus (HIV) lipodystrophy is associated with fat redistribution, dyslipidemia, and insulin resistance; however, the mechanism of insulin resistance remains unknown. We hypothesized that HIV-infected subjects with fat redistribution have increased rates of lipolysis and increased circulating free fatty acid (FFA) levels that contribute to insulin resistance. Anthrompometric and body composition data were obtained and a standard 75-g oral glucose tolerance test (OGTT) was performed on day 1 of the study. Stable isotope infusions of glycerol and palmitate were completed following an overnight fast to assess rates of lipolysis and FFA flux in HIV-infected men (n = 19) with and without fat redistribution and healthy controls (n = 8) on day 2. Total FFA levels after standard glucose challenge were increased among HIV-infected subjects and positively associated with abdominal visceral adipose tissue area. In contrast, fasting total FFA levels were inversely associated with subcutaneous fat area. Rates of basal lipolysis were significantly increased among HIV-infected subjects (rate of appearance [Ra] glycerol, 4.1 +/- 0.2 v 3.3 +/- 0.2 micromol/kg/min in controls; P =.02). Among HIV-infected subjects, use of stavudine (P =.006) and the rate of lipolysis (ie, Ra glycerol, P =.02) were strong positive predictors of insulin resistance as measured by insulin response to glucose challenge, controlling for effects of age, body mass index (BMI), waist-to-hip ratio (WHR), and protease inhibitor (PI) exposure. These data demonstrate increased rates of lipolysis and increased total FFA levels in HIV-infected subjects and suggest that increased lipolysis may contribute to insulin resistance in this patient population.
Adipose Tissue↗
Body-composition measurements as predictors of glucose and insulin abnormalities in HIV-positive men.
BACKGROUND: Fat redistribution and metabolic abnormalities are seen increasingly in HIV-positive patients. However, the degree to which abnormalities in fat distribution predict glucose and insulin concentrations in these patients remains unknown. OBJECTIVE: We determined how well measurements of fat distribution derived from anthropometry, dual-energy X-ray absorptiometry, and computed tomography predicted hyperinsulinemia in HIV-positive men. DESIGN: Body-composition data were analyzed in 41 HIV-positive men (21 with fat redistribution and 20 without) and 20 HIV-negative control subjects matched for age and body mass index (BMI). Multivariate modeling was performed to determine the effects of body composition on fasting insulin and insulin area under the curve (AUC) during standard glucose tolerance testing. RESULTS: WHR was superior to other body-composition measures in predicting fasting hyperinsulinemia and was a strong predictor of insulin AUC in HIV-positive men. Fasting insulin increased by 77.4 pmol/L for each 0.1-unit change in WHR (95% CI: 18.6, 136.1; P = 0.011), overall r(2) = 0.415 in a model also including age, BMI, and protease inhibitor use. Measures of intraabdominal and subcutaneous fat did not predict fasting hyperinsulinemia but were independent predictors of insulin AUC in multivariate modeling. The ratio of visceral to subcutaneous abdominal fat predicted the largest degree of variance in insulin AUC. CONCLUSIONS: Fat redistribution contributes to hyperinsulinemia in HIV-positive men, independent of BMI and protease inhibitor use. WHR is an integrated index of body-composition changes and strongly predicts both fasting hyperinsulinemia and insulin AUC in HIV-positive men.
Adipose Tissue↗
Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance.
The purpose of this study was to evaluate the metabolic and cardiovascular benefits of continued metformin therapy for HIV-infected patients with lipodystrophy. Eligible subjects who participated in the 3-month randomized study received an additional 6-month open label metformin treatment extension. Nineteen of the 25 potential subjects were eligible to receive open label metformin based on preestablished safety and efficacy criteria. Insulin and glucose response to oral glucose challenge, cardiovascular disease risk markers (e.g. tissue plasminogen activator), weight, and anthropometric measurements were the primary outcome measures. Continued treatment with metformin resulted in further significant reductions in tissue plasminogen activator antigen levels (P = 0.02) and body mass index (P = 0.03). Reductions in insulin levels were sustained during the 6-month treatment extension. In addition, waist circumference decreased significantly in subjects continuing metformin treatment (P = 0.01). Metformin was well tolerated and no one discontinued treatment due to side effects. These data demonstrate a sustained benefit of metformin treatment to reduce hyperinsulinemia and certain markers of cardiovascular disease risk in patients with HIV infection and lipodystrophy.
Adipose Tissue↗