Mechanisms and Strategies for Insulin Resistance in Acquired Immune Deficiency Syndrome

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1 SUPPLEMENT ARTICLE Mechanisms and Strategies for Insulin Resistance in Acquired Immune Deficiency Syndrome Steven Grinspoon Harvard Medical School, Massachusetts General Hospital, Program in Nutritional Metabolism, Boston Abnormalities of glucose regulation, including impaired glucose tolerance and insulin resistance, are often seen among human immunodeficiency virus (HIV) infected patients receiving highly active antiretroviral therapy. Insulin resistance in this population may result from antiviral medication directly impairing glucose uptake in the muscle, effects of HIV per se, or indirect effects, such as fat redistribution. Insulin resistance may increase the risk of coronary heart disease among this population of patients, in part by inhibiting normal thrombolysis. The optimal treatment for insulin resistance and impaired glucose intolerance in HIV-infected patients is not known, but preliminary studies have suggested that metformin, an insulin sensitizing agent, improves insulin sensitivity, blood pressure, and waist circumference. Initial studies of thiazolidinediones also suggest the potential utility of such agents to improve insulin sensitivity, decrease hepatic steatosis, and increase subcutaneous fat. Further studies are needed to determine the optimal treatment strategy for insulin resistance in this population. Abnormalities of glucose homeostasis, including insulin resistance and related metabolic abnormalities (hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol level, or an atherogenic lipid profile) occur frequently in association with changes in body composition among HIV-infected patients receiving HAART [1 3]. Metabolic abnormalities, including hyperinsulinemia, were also seen among HIV-infected patients prior to the HAART era [4] and may therefore result, in part, from HIV itself. Fat redistribution per se might also have adverse effects on glucose homeostasis. Among HIV-infected patients with fat redistribution, fasting glucose levels are most often normal, but impaired glucose tolerance is a common result of standard oral glucose tolerance testing (OGTT) [1]. Fasting hyperinsulinemia, inappropriate insulin responses to standard glucose challenge, and decreased glucose disposal rates have now been shown both in relationship to changes in body composition (e.g., loss of subcutaneous abdominal and extremity fat and increased abdominal visceral fat) [5, 6] and in response to specific antiviral therapies [7]. In vitro evidence for an effect of protease inhibitors (PIs) on GLUT-4 mediated glucose transport [8] and also in vivo among non HIV-infected patients [7] have been demonstrated. Insulin resistance is associated with an atherogenic lipid profile and impaired thrombolysis in HIV-infected patients with fat redistribution [1, 9] and may contribute independently to an increased risk of cardiovascular disease in this population. Recent data have suggested that insulin-sensitizing agents may improve the metabolic abnormalities among HIV-infected patients receiving HAART. EVIDENCE FOR INSULIN RESISTANCE AND RELATED METABOLIC ABNORMALITIES IN HIV DISEASE Reprints or correspondence: Dr. Steven Grinspoon, Program in Nutritional Metabolism, LON 207, Massachusetts General Hospital, Boston, MA (Sgrinspoon@partners.org). Clinical Infectious Diseases 2003; 37(Suppl 2):S by the Infectious Diseases Society of America. All rights reserved /2003/3705S2-0008$15.00 A number of studies have demonstrated hyperinsulinemia in HIV-infected patients. Although data from Hommes et al. [10] suggested increased insulin sensitivity in HIV-infected patients prior to HAART, significant fasting hyperinsulinemia was demonstrated in Insulin Resistance in AIDS CID 2003:37 (Suppl 2) S85

2 HIV-infected patients before the introduction of PIs, which provides indirect evidence for insulin resistance [4]. Nonetheless, it is difficult to distinguish the relative contribution of HIV per se from the effects of various antiretroviral regimens, because few studies have been done among antiretroviral-naive subjects and significant hyperinsulinemia has been associated with nucleoside reverse-transcriptase inhibitor therapy [11, 12]. Among patients with fat redistribution during the HAART era, fasting glucose levels are not different from those of ageand body mass index (BMI) matched control subjects. In contrast, fasting insulin, 2-h insulin, and 2-h glucose levels on standard glucose challenge are markedly increased. In a recent study, 35% of the HIV-infected patients with fat redistribution demonstrated glucose intolerance, compared with only 5% of age- and BMI-matched control subjects. In contrast, 7% of HIV-infected patients with fat redistribution, compared with 0.5% of control subjects, demonstrated markedly increased 2- h glucose responses diagnostic of diabetes mellitus (2-h glucose, 1200 mg/dl) [1]. It has also been shown that HIV-infected patients with fat redistribution also demonstrate increased diastolic blood pressure, hypertriglyceridemia, low HDL cholesterol levels, increased low-density lipoprotein (LDL) cholesterol levels, and markedly increased levels of tissue-type plasminogen activator (tpa) and plasminogen activator-inhibitor 1 (PAI-1) levels, which are markers of impaired fibrinolysis [1, 9, 13]. Using an insulin clamp technique, Mynarcik et al. [6] demonstrated decreased glucose disposal (insulin resistance) among HIV-infected patients, in association with reduced peripheral fat, as determined by dual-energy x-ray absorptiometry. Furthermore, Hadigan et al. [1] demonstrated that insulin levels are predicted by both increased waist circumference and reduced thigh circumference, which suggests that increased visceral adiposity and reduced peripheral subcutaneous fat contribute independently to hyperinsulinemia in HIV-infected patients. The percentage of HIV-infected patients with fasting hyperinsulinemia who will develop type II diabetes mellitus is not known. The severity of body-composition abnormalities, the use of specific antiretroviral therapies, and family history may all contribute to the development of diabetes mellitus in this population. For example, the addition of PIs and other antiretroviral medications may be sufficient to tip the balance from compensated normoglycemia to diabetes mellitus, but adequate longitudinal studies have not been done in this regard. PATHOGENESIS OF INSULIN RESISTANCE The pathogenesis of insulin resistance in HIV-infected patients receiving HAART is not known. An important question in this regard is whether a single mechanism is likely to account for the complex pattern of metabolic changes in HIV disease. For example, changes in fat distribution (increased visceral adiposity and reduced subcutaneous fat) are often severe in HIVpositive patients and may contribute independently to hyperlipidemia and insulin resistance [1, 5, 14], as has been seen in HIV-negative patients with similar changes [15]. In multivariate modeling, Meininger et al. [5] demonstrated a 1% increase in fasting insulin levels for each 1% increase in visceral fat and an independent 1% increase in fasting insulin levels for each 1% reduction in abdominal subcutaneous fat. These data suggest that increased visceral fat and reduced subcutaneous fat contribute independently to hyperinsulinemia and insulin resistance in HIV-infected patients. Increased lipolysis that results from the direct effects of antiretroviral drugs and changes in body composition may also contribute to insulin resistance in this population. Increased free fatty acid (FFA) levels and lipolytic rates have been shown among HIV-infected patients receiving HAART and predict insulin responses to standard OGTTs [12, 16]. Furthermore, a reduction in FFA levels by the inhibition of lipolysis has been shown to increase insulin sensitivity in acute dosing studies [17]. Further studies are needed to determine whether increased lipolysis contributes to insulin resistance in HIV-infected patients and the mechanisms for such an effect in this population. Among antiretroviral medications, most work has thus far focused on the class of medications known as PIs. These medications are serine inhibitors of the HIV protease enzyme and effectively reduce viral proliferation. Murata et al. [8] demonstrated a specific effect of PI therapy on insulin-stimulated glucose transport and GLUT-4 in 3T3-L1 adipocytes. The PI indinavir did not affect early insulin-signaling events (insulin receptor autophosphorylation and subsequent tyrosine phosphorylation or phosphatidylinositol [PI]-3 kinase activation) or the translocation of intracellular GLUT-4. At physiological concentrations, indinavir was associated in vitro with a 26% reduction in glucose uptake. A similar inhibition of insulinmediated glucose uptake was seen with ritonavir, indinavir, and amprenavir. PI use has also been associated with hypertriglyceridemia [18], and some drugs in this class may have direct stimulatory effects on hepatic triglyceride synthesis. Noor et al. [7] investigated the use of indinavir over 4 weeks in HIV-negative patients. A significant decrease in glucose disposal was seen among patients, without a clinically significant change in body composition. These data suggest more direct effects of antiretroviral agents, particularly PIs, on glucose uptake. In a more recent study, Noor et al. [19] also demonstrated a significant reduction in insulin sensitivity after a single dose of indinavir, which is highly suggestive of a direct effect on glucose metabolism, likely at the level of glucose uptake. However, changes in body composition resulting from PIs and other antiretrovirals may also simultaneously contribute to changes in glucose metabolism among HIV-infected patients receiving S86 CID 2003:37 (Suppl 2) Grinspoon

3 long-term antiretroviral therapy. For example, Meininger et al. [5] demonstrated that 89% of the variability in fasting insulin levels was explained by multivariate modeling that included age, BMI, PI use, and waist:hip ratio. It is most likely that a number of factors contribute to abnormalities in glucose homeostasis among HIV-infected patients receiving HAART. CLINICAL CONSEQUENCES OF INSULIN RESISTANCE AND RELATED METABOLIC ABNORMALITIES Whether the anthropometric (increased wait:hip ratio, increased visceral fat, and reduced subcutaneous fat) and metabolic (hypertriglyceridemia, low HDL cholesterol levels, and modest increases in LDL cholesterol levels and diastolic blood pressure) abnormalities seen among HIV-infected patients receiving HAART contribute to an actual increase in cardiovascular disease remains unknown. The results of two recent crosssectional studies suggested an increased risk of myocardial infarction and cardiovascular events in HIV-infected patients. Mary-Krause et al. [20] demonstrated a substantially increased risk of myocardial infarction among French HIV-infected patients who received a PI for 130 months, compared with those who received a PI for!18 months. In contrast, Klein et al. [21] investigated coronary heart event rates among 4541 persons followed from 1996 to 2000 in the Kaiser Permanante insurance system. Coronary heart disease (CHD) event rates were not significantly different among patients who received PIs versus those who did not (5.8 vs. 5.2 event rates/1000 patient-years), but overall CHD event rates were higher among the HIV-infected patients than among the control subjects (event rate, 2.8/ 1000 patient-years of follow-up). Further longitudinal studies with larger numbers of patients are needed to determine whether HIV-infected patients in the era of HAART are at increased risk for myocardial infarction or CHD secondary to increased risk factors. What role, if any, might insulin resistance play in the increase in cardiovascular risk among patients with HIV lipodystrophy? Numerous studies of HIV-negative individuals have documented that hyperinsulinemia and truncal obesity are strong independent risk factors that contribute to CHD with significant associated morbidity and mortality [22]. Despres et al. [23] demonstrated that the risk of CHD rises with increasing insulin levels when controlling for LDL levels, apolipoprotein B levels, and the total cholesterol:hdl ratio. One mechanism by which hyperinsulinemia and insulin resistance may contribute to increased cardiovascular disease is through an effect on fibrinolysis. Meigs et al. [24] showed, in a multivariate regression analysis that controlled for potential confounding variables such as age, BMI, lipid levels, and waist: hip ratio in the Framingham Offspring Cohort, that both PAI- 1 and tpa are highly correlated with insulin levels among non HIV-infected adults. These data suggest a direct, independent effect of hyperinsulinemia to impair fibrinolysis in glucose-intolerant and diabetic subjects. Increased levels of tpa antigen, a marker of impaired fibrinolysis, predicts an increased risk of [1] coronary artery disease mortality among patients with a history of angina pectoris and CHD and [2] cerebral vascular events among individuals without a history of CHD [25, 26]. Recent data have indicated that patients with HIV infection and fat redistribution have marked elevation in PAI- 1 and tpa antigen levels in association with significant hyperinsulinemia [9]. TREATMENT OF INSULIN RESISTANCE IN HIV LIPODYSTROPHY SYNDROME An initial consideration among patients with HIV lipodystrophy and severe insulin resistance is whether a regimen without PIs will improve insulin resistance. The results of preliminary studies have suggested an improvement in insulin levels with substitution of an nonnucleoside reverse-transcriptase inhibitor for a PI, but further studies are needed to determine the efficacy of switching strategies [27]. Furthermore, the optimal antiviral strategy to mitigate insulin resistance is not known. In addition, metabolic considerations must be balanced against the known beneficial effects of various antiviral regimens on immune function and survival. The initial management approach for non HIV-infected patients with insulin resistance includes recommendations on dietary modification, increased exercise, and sensible weight reduction or weight management, as indicated. Only limited data on the effects of diet and exercise are available for patients with HIV lipodystrophy. Hadigan et al. [28] demonstrated, in a cross-sectional study, that the consumption of a diet with a high ratio of polyunsaturated to saturated fats and that was low in fiber was associated with an increased insulin areaunder-the-curve (AUC) response to standard OGTTs. Although there are currently no published interventional studies investigating the effects of diet and exercise to treat or prevent the metabolic disturbances associated with fat distribution in HIVinfected patients, dietary and lifestyle counseling should be considered to be potential therapies to improve insulin resistance for all patients who present with such disturbances. In HIV-negative patients with hyperinsulinemia, the use of insulin-sensitizing agents is often recommended as an initial medical regimen for patients with impaired glucose tolerance or type II diabetes mellitus and fasting glucose levels that are under reasonable control. Such patients often have significant fasting hyperinsulinemia levels, which compensates for insulin resistance, and therefore maintain normal fasting glucose levels. Similarly, among patients with HIV lipodystrophy, significant Insulin Resistance in AIDS CID 2003:37 (Suppl 2) S87

4 insulin resistance has been shown in association with normal fasting glucose levels but impaired glucose response to standard challenge. Metformin is particularly appropriate for use in patients with significant truncal adiposity, dyslipidemia, and increased BMI. For example, the use of metformin improves glycemic control and weight in type II diabetes mellitus [29]. In addition, metformin modestly lowers lipid levels. In patients with hyperlipidemia, metformin has been demonstrated to decrease triglyceride and LDL levels without adversely affecting other parameters. The modest 10% 20% reduction in plasma triglyceride levels achieved with metformin may be related to an associated decreased hepatic production of very low density lipoprotein cholesterol. The effects of metformin in HIV-infected patients with fat redistribution and fasting hyperinsulinemia were recently reported. The effects of low-dose metformin (500 mg orally, twice per day) were investigated in a randomized, placebo-controlled pilot study over 12 weeks [30]. The insulin AUC result after a 2-h standard 75-g oral glucose challenge was significantly reduced in the group that received metformin, compared with placebo-treated patients. Metformin treatment was also associated with reductions in weight, waist circumference, diastolic blood pressure, and concentrations of tpa and PAI-1 but was not associated with any significant adverse events [9]. Similar beneficial effects on insulin resistance and visceral fat were also reported in an open-label, 8-week study of higher dosages of metformin (850 mg orally, 3 times per day) given to HIVinfected patients with fat redistribution [31]. The development of lactic acidosis is a rare, but potentially serious, adverse effect of metformin, particularly in patients with renal dysfunction. The results of studies to date that have used lower doses of metformin have not suggested an increased occurrence of lactic acidosis in HIV-infected patients, even among those using nucleoside-analogue reverse-transcriptase inhibitors. However, these studies have been small and have carefully selected patients on the basis of normal kidney and liver function. Taken together, the preliminary study results to date on metformin have suggested a beneficial effect on cardiovascular risk parameters, but additional studies are needed to determine the longterm safety and efficacy of metformin and the optimal target population for this intervention. Insulin resistance may also occur in HIV-infected patients because of the loss of subcutaneous fat. Hadigan et al. [1] demonstrated that reduced thigh circumference, a marker of peripheral fat atrophy, was an independent predictor of hyperinsulinemia in HIV-positive patients with fat redistribution. Mynarcik et al. [6] demonstrated decreased insulin sensitivity in association with reduced subcutaneous fat. Metformin, although it is a potent insulin-sensitizing agent, is not believed to restore peripheral adipogenesis but rather to act primarily via a reduction in hepatic insulin resistance [32]. In contrast, a novel class of therapeutic agents, the thiazolidinediones, has been shown to promote adipogenesis, primarily through an action on peroxisome proliferator-activated receptor g. Although the thiazolidinediones have effects on both hepatic and peripheral insulin resistance, the dominant effect is to improve peripheral glucose uptake. For example, troglitazone was shown to significantly increase peripheral glucose uptake, with only modest effects on hepatic insulin sensitivity, in a study of patients with type II diabetes mellitus [32], but the medication was recently withdrawn from the market by the US Food and Drug Administration because of rare but significant hepatic toxicity. The therapeutic efficacy of the thiazolidinediones has been well established among patients with type II diabetes mellitus [33]. The thiazolidinediones also reduce plasma triglyceride levels by 10% 20% and increase HDL cholesterol levels by 5% 10% in patients with diabetes. Patients have demonstrated weight increases in response to thiazolidinediones, in contrast to metformin, which is associated with weight loss. In a recent study among non HIV-infected patients with lipodystrophy, Arioglu et al. [15] demonstrated a significant effect of troglitazone to increase subcutaneous fat and decrease visceral fat, in association with improved triglyceride and FFA levels and insulin resistance. In contrast, in the results of a recently published 16-week randomized study [34], rosiglitazone did not increase abdominal subcutaneous fat but did improve hyperinsulinemia and the hepatic lipid content in HIVinfected patients with fat redistribution. However, patients were not preselected on the basis of a specific fat distribution criterion, and peripheral subcutaneous fat was not assessed. In contrast, Gelato et al. [35] demonstrated increased peripheral subcutaneous fat levels in response to rosiglitazone in a small pilot study of HIV-infected patients. Further clinical trials are needed to determine the safety and efficacy of thiazolidinediones in HIV-infected patients. CLINICAL ASSESSMENT OF GLUCOSE HOMEOSTASIS IN HIV-INFECTED PATIENTS The routine testing of the fasting glucose level is recommended for all HIV-infected patients, particularly those with obesity, with a family history of diabetes, or who are receiving PIs. On the basis of recent data that have demonstrated a high prevalence of impaired glucose tolerance among HIV-infected patients with fat redistribution, a standard 75-g OGTT may also be useful in determining the existence of impaired glucose tolerance in patients, particularly those receiving HAART. The measurement of fasting insulin levels may also be useful but is not generally recommended outside of the research setting. S88 CID 2003:37 (Suppl 2) Grinspoon

5 CONCLUSIONS Abnormalities in glucose homeostasis affect a substantial number of HIV-infected patients receiving HAART, particularly those with evidence of fat redistribution. The primary abnormality of glucose homeostasis in such patients is insulin resistance, which may result in part from severe changes in fat redistribution but also from direct effects of antiretroviral drugs. Insulin resistance, dyslipidemia, and impaired fibrinolysis may contribute to an increased risk of CHD in patients with HIV lipodystrophy. Changes in the dietary intake of fats and fibers and increased exercise may improve insulin indices in such patients, and they may also benefit from insulin-sensitizing agents. Further studies of insulin-sensitizing agents and antiretroviral switching strategies are needed to determine the optimal management strategy for insulin resistance in HIVinfected patients. References 1. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001; 32: Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12:F Vigouroux C, Gharakhanian S, Salhi Y, et al. Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART). Diabetes Metab 1999; 25: Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S. Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus infected women. J Clin Endocrinol Metab 1999; 84: Meininger G, Hadigan C, Rietschel P, Grinspoon S. Use of body composition parameters in predicting glucose and insulin abnormalities in HIV-infected men. Am J Clin Nutr 2002; 76: Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC. Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr 2000; 25: Noor M, Lo J, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001; 15: Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000; 275: Hadigan C, Meigs JB, Rabe J, et al. Increased PAI-1 and tpa antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2001; 86: Hommes MJ, Romijn JA, Endert E, Eeftinck Schattenkerk JK, Sauerwein HP. Insulin sensitivity and insulin clearance in human immunodeficiency virus infected men. Metabolism 1991; 40: Hadigan C, Corcoran C, Stanley T, Piecuch S, Klibanski A, Grinspoon S. Fasting hyperinsulinemia in human immunodeficiency virus infected men: relationship to body composition, gonadal function, and protease inhibitor use. J Clin Endocrinol Metab 2000; 85: Hadigan C, Borgonha S, Rabe J, Young V, Grinspoon S. Increased rates of lipolysis among HIV-infected men receiving highly active antiretroviral therapy. Metabolism 2002; 51: Sattler FR, Qian D, Louie S, et al. Elevated blood pressure in subjects with lipodystrophy. AIDS 2001; 15: Kosmiski LA, Kuritzkes DR, Lichtenstein KA, et al. Fat redistribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. AIDS 2001; 15: Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000; 133: Meininger G, Hadigan C, Laposata M, et al. 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. Metabolism 2002; 51: Hadigan C, Rabe J, Meininger G, Aliabadi N, Breu J, Grinspoon S. Inhibition of lipolysis improves insulin sensitivity in protease inhibitor treated HIV-infected men with fat redistribution. Am J Clin Nutr 2003; 77: Purnell JQ, Zambon A, Knopp RH, et al. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 2000; 14: Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebocontrolled study. AIDS 2002; 16:F Mary-Krause M, Cotte L, Partisani M, Simon A, Costagliola D. Impact of treatment with protease inhibitor (PI) on myocardial infarction (MI) occurrence in HIV-infected men [abstract 657]. In: Programs and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections (Chicago). Alexandria, VA: Foundation for Retrovirology and Human Health, 2001: Klein D, Hurley LB, Quesenberry CP Jr, Sidney S. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV- 1 infection? J Acquir Immune Defic Syndr 2002; 30: Peiris AN, Sothman MS, Hoffman RG, et al. Adiposity, fat distribution and cardiovascular risk. Ann Intern Med 1989; 110: Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 334: Meigs JB, Nathan DM, Wilson PW, Cupples LA, Singer DE. Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance: the Framingham Offspring Study. Ann Intern Med 1998; 128: Johansson L, Jansson JH, Boman K, Nilsson TK, Stegmayr B, Hallmans G. Tissue plasminogen activator, plasminogen activator inhibitor 1, and tissue plasminogen activator/plasminogen activator inhibitor 1 complex as risk factors for the development of a first stroke. Stroke 2000; 31: Thogersen AM, Jansson JH, Boman K, et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS 1999; 13: Hadigan C, Jests S, Anderson E, Tsay R, Cyr H, Grinspoon S. Modifiable dietary habits and their relation to metabolic abnormalities in men and women with HIV-infection and fat redistribution. Clin Infect Dis 2001; 33: Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non insulin-dependent diabetes mellitus. N Engl J Med 1995; 333: Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 2000; 284: Saint-Marc T, Touraine JL. Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor therapy. AIDS 1999; 13: Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic Insulin Resistance in AIDS CID 2003:37 (Suppl 2) S89

6 effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998; 338: Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind placebo-controlled trial. Ann Intern Med 1998; 128: Sutinen J, Hakkinen AM, Westerbacka J, et al. Rosiglitazone in the treatment of HAART-associated lipodystrophy (HAL): a randomized, double-blind, placebo-controlled study [abstract LB13]. In: Programs and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections (Seattle). Alexandria, VA: Foundation for Retrovirology and Human Health, Gelato MC, Mynarcik DC, Quick JL, et al. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study. J Acquir Immune Defic Syndr 2002; 31: S90 CID 2003:37 (Suppl 2) Grinspoon