Diabetes, Insulin Resistance, and HIV Colleen Hadigan, MD, MPH

Corresponding author Colleen Hadigan, MD, MPH Harvard Medical School, Program in Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit Street, LON 207, Boston MA, 02114, USA. E-mail: [email protected] Current Infectious Disease Reports 2006, 8:69 –75 Current Science Inc. ISSN 1523-3847 Copyright © 2006 by Current Science Inc.

The transformation of HIV infection into a chronically managed illness through the widespread use of highly active antiretroviral therapy has brought with it comorbid conditions such as increased risk of cardiovascular disease. Diabetes and insulin resistance have emerged as important comorbidities associated with HIV infection and the use of antiretroviral therapy. Significant inroads have been made towards understanding the etiology of insulin resistance and diabetes in association with HIV and highly active antiretroviral therapy, and there are also emerging data on the prevalence and incidence of this problem. The recognition and management of diabetes mellitus, insulin resistance, and related complications will be an important part of long-term health maintenance for HIV-infected patients.

Introduction The advent of highly active antiretroviral therapy (HAART) revolutionized the care of HIV infection and introduced marked improvements in life expectancy with significant reductions in HIV-associated morbidity and mortality. In the face of these noteworthy advances, newly recognized morbidities associated with HIV infection and its therapy have emerged. Recent research has identified increased insulin resistance and type 2 diabetes mellitus among individuals with HIV infection who are receiving antiretroviral therapy [1,2•,3]. As in the non–HIV-infected population, one important consequence of type 2 diabetes mellitus is the increased risk of cardiovascular disease conveyed with this diagnosis [4•]. In a large prospective cohort study to evaluate the health consequences of HAART in over 20,000 adults with HIV infection, Friis-Moller et al. [4•] identified increased rates of acute myocardial infarction with increased duration of exposure to HAART. In addition to the risk of HAART, traditional independent risk

factors for cardiovascular disease were identified and a diagnosis of diabetes was associated with a 2.38-fold increased relative risk for acute myocardial infarction (95% CI 1.38–4.10, P = 0.002). These findings highlight the important potential contribution of insulin resistance and diabetes in the long-term health of persons living with HIV. The present report will highlight recent reports in the literature which 1) evaluate and characterize the prevalence of diabetes and insulin resistance in patients with HIV infection, 2) elucidate the mechanisms of insulin resistance and diabetes in this population, and 3) assess various approaches to the management of these metabolic complications.

Prevalence of Diabetes and Insulin Resistance in HIV As the first reports of metabolic complications and lipodystrophy associated with HAART began to appear, investigations of disturbances in glucose and insulin regulation in patients with HIV were also conducted. Early reports of hyperinsulinemia among men and women with HIV infection suggested that insulin resistance may have preceded HAART to some extent. For example, compared with weight-matched healthy controls, HIV-infected men and women with a history of wasting or prior weight loss had increased fasting insulin levels and markers of insulin resistance [5,6]. In both studies, there was no association between insulin levels and the use of protease inhibitors (PI), the component of HAART most often associated with insulin resistance. Furthermore, more than 40% of the men [6] and 75% of the women [5] were not on HAART regimens in these studies. Although not designed to assess lipodystrophy per se, the investigators identified increased truncal fat in relationship to hyperinsulinemia in this population of nonobese HIV-infected patients with a history of weight loss [5,6]. At the same time, a number of studies emerged describing insulin resistance among HIV-infected patients using HAART regimens containing a PI [7,8]. Most of these early reports were cross-sectional studies, conducted retrospectively or completed on selected small cohorts of patients and, therefore, did not provide an overall assessment of the prevalence of insulin resistance and/or diabetes in the HIV population as a whole. More recently, Brown et al. [2•] published data on the prevalence and incidence of diabetes mellitus in a

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Figure 1. Prevalence of diabetes mellitus among HIV-infected men on highly active antiretroviral therapy (HAART) compared with those not on HAART and HIV-seronegative controls. Asterisk indicates analyses are adjusted for age and body mass index. PR—prevalence ratio relative to control. (Adapted from Brown et al. [2•].)

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large cohort of HIV-infected men who participated in mass index, a fourfold increased incidence of diabetes ������������������������������������������������������� the Multicenter AIDS Cohort Study. In this study of 710 compared with HIV-seronegative men. ������������������������������������ ������������������������������������������������������������ Although the frequency of abnormalities of glucose HIV-seronegative men and 568 HIV-infected men, the prevalence of diabetes was significantly greater among metabolism appears to be increased among women with men with HIV infection based on a fasting glucose more HIV infection, there are several conflicting reports on the than 126 mg/dL or self-reported diabetes mellitus (over- prevalence of diabetes and insulin resistance among this all prevalence of diabetes: 12% HIV+ vs 5% HIV-) (Fig. group. Justman et al. [3] reported a threefold increase of 1). When subjects were further categorized according to incident diabetes mellitus among HIV-infected women current use of HAART, HIV-infected men not on HAART using a PI compared with women using non–PI-based had a prevalence ratio of 2.21 (95% CI 1.12–4.38) antiretroviral therapy in a cohort of 1785 women folcompared with controls and men on HAART a preva- lowed in the Women’s Interagency HIV Study (WIHS) lence ratio of 4.64 (95% CI 3.03–7.10) after adjusting between 1994 and 1998. In this study, in addition to for age and body mass index. Similarly, the incidence PI use, increasing age and body mass index were also of diabetes between April 1999 and March 2003 was identified as significant independent risk factors for selfsignificantly increased among the HIV-infected men reported diabetes mellitus. More recently, Howard et al. on HAART compared with HIV seronegative controls [9] reported oral glucose tolerance test results from a large (incidence rate: 4.7 cases per 100 person-years and the cohort of women with HIV infection (n = 133) and ageadjusted rate ratio was 4.11 [95% CI 1.85–9.16]). In a matched controls without HIV infection (n = 88) without subanalysis to identify potential risk factors associated a history of diabetes. Here 13.5% of women with HIV with diabetes mellitus and insulin resistance, if diabetes had impaired glucose tolerance (ie, 2-hour post-challenge or impaired fasting glucose (ie, fasting blood glucose glucose level ≥ 140 mg/dL and < 200 mg/dL) and 4.5% between 100 and 125 mg/dL) were considered together, had previously unrecognized diabetes. Whereas these ritonavir was the only PI associated with increased rates did not differ significantly from the control popularisk (rate ratio 1.70 [95% CI 1.08–2.68]). However, the tion, women in the control group had higher body mass investigators note that 94% of the participants using index and waist circumference and, therefore, may have ritonavir were also receiving another PI in combina- had greater risk for abnormal glucose metabolism based tion with ritonavir, likely for the low dose “boosting” on these characteristics. In order to more carefully assess the prevalence of diaeffects of ritonavir to improve the pharmacokinetic profile of other PIs, thereby limiting the interpretation betes and insulin resistance in the WIHS cohort, Danoff et of this finding. Brown et al. [2•] also noted that men al. [10] published a subsequent study evaluating prospecwith a lower CD4 nadir had a greater risk of incident tive oral glucose tolerance testing in 258 women (88 HIV glucose abnormalities, suggesting that severity of HIV seronegative, 74 HIV-infected women not on HAART, and disease may be related to an increased risk of diabetes 96 women with HIV on HAART). Reminiscent of the findor insulin resistance. In a 4-year follow-up period, this ings of impaired glucose tolerance by Howard et al. [9], 14% large, carefully conducted cohort study identified newly of the participants with HIV had “pre-diabetes” defined as diagnosed diabetes mellitus in 10% of HIV-infected a fasting blood sugar greater than 100 mg/dL or a 2-hour men on HAART and, after adjusting for age and body post challenge glucose level between 140 mg/dL and 200

Diabetes, Insulin Resistance, and HIV Hadigan

mg/dL. The prevalence of diabetes was not increased in the HIV-infected women on HAART (4%) or the HIV-infected women not on HAART (8%) compared with the control women (10%). In this study, body mass index emerged as the single most important predictor of diabetes and prediabetes, but the study groups were not matched for body mass index; the HIV seronegative subjects had significantly higher body mass index compared with HIV-infected women. However, the authors report that, in a sub-analysis in which subjects were matched for body mass index, the prevalence of diabetes or prediabetes did not differ based on HIV status. In summary, even though abnormalities in glucose metabolism may be as common as 14% women with HIV infection, there are currently limited data to support an increased prevalence of diabetes mellitus in women living with HIV compared with a well-matched HIV-uninfected control group. Children with HIV infection do not appear to be immune to the problem of insulin resistance. Although there are considerably fewer data available on children, preliminary studies indicate that insulin resistance may be increased, particularly among HIV-infected children on HAART. For example, in a small cross-sectional study of HIV-infected children on a PI-containing regimen (n = 33) compared with PI-naïve children (n = 15), Bitnun and colleagues [11] identified lower insulin sensitivity in children after adjusting for potential confounders. In a larger multicenter 2-year prospective study of 130 children with HIV infection designed to assess lipodystrophy and associated metabolic complications, Beregszaszi et al. [12], found 13.2% of children to have hyperinsulinemia (defined as an insulin level greater than the 95th percentile from a normoglycemic healthy population matched for pubertal status) and this percentage doubled to 25.6% after 2 years of follow-up (P = 0.01) [12]. Although no child in this study was found to have diabetes mellitus by fasting hyperglycemia, fasting hyperinsulinemia may represent a precursor to, or an increased risk for, subsequent diabetes in this vulnerable population. It is important to recognize that hepatitis C infection is a known risk factor for insulin resistance and diabetes in the non–HIV-infected population [13], and therefore, HIV with hepatitis C co-infection may also predispose patients to diabetes. In a cross-sectional analysis of 1389 antiretroviral-naïve HIV-infected subjects with and without hepatitis C co-infection, Visnegarwala et al. [14] reported that individuals with HIV and hepatitis C co-infection had a significantly increased prevalence of type 2 diabetes compared with patients with HIV monoinfection (5.9% vs 3.3%, respectively) and this increased prevalence persisted after correcting for differences in age and body weight. Additional awareness of the risk of insulin resistance and diabetes in the HIV-hepatitis C co-infected population may, therefore, be indicated in the care and management of such patients.

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Factors Contributing to Insulin Resistance and Diabetes in HIV As noted in a number of the studies described above, the use of antiretroviral therapy, and in particular PIs, has been the focus of many investigations seeking to identify the etiology of insulin resistance and diabetes in association with HIV. Indeed, recognition of lipodystrophy and metabolic complications associated with antiretroviral therapy in the mid to late 1990s was coincident with the widespread introduction of PIs and HAART. In the past 5 years, there has been increasing evidence that, even though antiretroviral medications can have direct effects on insulin sensitivity and glucose metabolism, indirect effects of antiretroviral medications on body fat distribution and lipids, as well as HIV infection and chronic inflammation, may contribute to impair insulin sensitivity in patients with HIV infection. In an early cross-sectional study designed to characterize the metabolic disturbances associated with lipodystrophy in patients with HIV infection, 71 HIVinfected men and women who were complaining of changes in body fat distribution were compared with 213 healthy age-, sex-, and weight-matched control subjects [1]. HIV-infected patients with abnormal fat distribution had significantly increased rates of previously unrecognized diabetes (7% vs 0.5% in the control subjects) and increased rates of impaired glucose tolerance (35.2% vs 5.2% in control subjects). In a substudy of 30 HIVinfected subjects without changes in body fat, there was no increase in diabetes or impaired glucose tolerance compared with 90 age-, sex-, and weight-matched control subjects. Although the use of a PI was not associated with increased insulin resistance or diabetes in this study, HIV-infected subjects with lipodystrophy had increased waist-to-hip ratio compared with control subjects, and the overall influence of antiretroviral medications cannot be separated from the potential effects of body fat distribution on these observations. Lipoatrophy of the peripheral subcutaneous fat, as well as increased central adiposity may contribute to insulin resistance in HIV. Mynarcik et al. [15] identified a direct relationship between insulin sensitivity and peripheral limb fat in a study of HIV-infected subjects with and without lipodystrophy in comparison with healthy volunteers. Changes in fat distribution, particularly lipoatrophy, are increasingly recognized as a direct of effect of antiretroviral therapy, including nucleoside reverse transcriptase inhibitors (NRTI) [16] and represent one mechanism for the observed increased insulin resistance and diabetes in HIV-infected patients on HAART. Indeed, cumulative exposure to NRTIs, and not PIs, was identified as the strongest drug class association with markers of insulin resistance in the Multicenter AIDS Cohort Study of 755 men with HIV infection [17]. The putative mechanism for this observation is through lipoatrophy and mitochondrial toxicity to adipocytes.

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Figure 2. Relationship between insulin stimulated whole body ������������������������������������������������������������� glucose disposal and visceral adipose tissue area in HIV-infected ����������������������������������� men with lipodytrophy (n = 6) and healthy controls (n = 5). ������������������������������������������������������������ (From Hadigan et al. [20], with permission.)

Several studies have also identified a strong positive relationship between visceral adiposity and insulin resistance in HIV [5,11,18–20]. For example, using positron emission tomography with administration of 2-deoxy-2[18F]fluoro-D-glucose, we were able to assess insulin-stimulated glucose uptake in subcutaneous and visceral fat as well as skeletal muscle in patients with HIVassociated lipoatrophy and healthy controls [20]. Under insulin-stimulated conditions, visceral adipose depot size was robustly correlated with whole-body glucose uptake (Fig. 2), as well as regional muscle and fat glucose uptake. Therefore, as is noted in the general population with obesity and the metabolic syndrome, increased visceral adiposity may be an important determinant of insulin sensitivity in the HIV population. In order to separate the direct effects of antiretroviral medications on insulin sensitivity from potential long-term effects on body fat distribution and from the potential confounding effects of HIV, a series of experiments have been conducted, in tissue culture and in vivo in healthy HIV-seronegative volunteers. For example, interleukin-6 and tumor necrosis factor-α, circulating inflammatory cytokines known to be associated with muscle and adipose tissue insulin resistance, are increased in adipocyte cultures after exposures to NRTIs and PIs [21]. Also utilizing 3T3-L1–cultured adipocytes, Murata et al. [22] demonstrated a direct effect of various PIs to inhibit insulin-mediated glucose uptake by adipocytes, presumably via inhibition of glucose transporter GLUT4. Short-term and single-dose administration of a PI, indinavir, was associated with significant reductions in whole-body glucose disposal measured by hyperinsulinemic clamp techniques among HIV-seronegative

volunteers and in the absence of any significant changes in fat distribution [23,24]. A similar well-controlled study of the short-term effects of lopinavir/ritonavir and atazanavir in healthy volunteers demonstrated decreased insulin sensitivity with lopinavir/ritonavir but not atazanavir [25]. Taken together, these data support a direct effect of certain HIV PIs to impair insulin stimulated glucose disposal, independent of HIV infection and alterations in body composition. Abnormalities in circulating lipids as well as increased circulating fatty acids and inappropriate lipid accumulation in muscle and liver are recognized metabolic disturbances associated with insulin resistance in obesity and type 2 diabetes [26]. In the context of lipodystrophy and the use of HA ART, patients with HIV infection also demonstrate increased lipids [1], increased rates of lipolysis and circulating fatty acids [27,28] and increased intramyocellular lipid content which may contribute to decreased insulin sensitivity in this population [29]. In a recent report by Reeds et al. [30], HIV-infected men with dyslipidemia demonstrated impaired suppression of lipolysis as well as impaired glucose disposal in response to insulin stimulation. Conversely, acute suppression of lipolysis and reduction in circulating fatty acids have been shown to improve insulin sensitivity in HIV-infected men with lipodystrophy [31]. Adipocytokines, in particular adiponectin, may play an important role in the relationship between adipocyte and lipid metabolism and insulin sensitivity [20,30].

Strategies for the Treatment of Insulin Resistance and Diabetes in HIV Currently there are no published reports evaluating the efficacy of treatment strategies for type 2 diabetes in patients with HIV infection. A number of randomized, controlled trials have been completed to evaluate the benefits of insulin sensitizing agents, namely metformin and rosiglitazone, in the treatment of HIV-infected patients with lipodsytrophy, with or without insulin resistance (Table 1). The use of metformin was associated with improvements in markers of insulin resistance in each trial and was also noted to reduce triglyceride levels in several cases [32,33]. Administration of rosiglitazone also resulted in improvements in insulin resistance in each study evaluating this agent; however, rosiglitazone use was also associated with significant increases in lipid levels in each study. The improvements in insulin sensitivity in the studies of metformin tended to coincide with reductions in central adiposity [32,34], whereas increased insulin sensitivity with the use of rosiglitazone in the setting of lipoatrophy was observed in several studies in association with increases in subcutaneous adipose tissue [35,36] and with increased levels of adiponectin [35–

Diabetes, Insulin Resistance, and HIV Hadigan

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Table 1. Summary of randomized trials evaluating the efficacy of insulin sensitizing agents in HIV-infected patients Randomized placebo controlled

IR required*

Duration

N

Effect on insulin resistance

RZ

Yes

12 wks

27

Improved

Hadigan et al. [34]

RZ–PC

Yes

12 wks

26

Improved

Martinez et al. [44]

RZ–PC

No

48 wks

108

Improved

Metformin Saint-Marc and Touraine [32]

Rosiglitazone Sutinen et al. [38]

RZ–PC

No

24 wks

30

Improved

Carr et al. [37]

RZ–PC

No

48 wks

108

Improved

Hadigan et al. [35]

RZ–PC

Yes

12 wks

28

Improved

van Wijk et al. [36]

RZ

No

24 wks

39

Both arms improved

Tomazic et al. [33]

RZ

Yes

48 wks

90

Both arms improved

Metformin vs Rosiglitazone

”Yes” indicates a marker of insulin resistance was required for enrollment in the study. IR—insulin resistance; PC—placebo controlled; RZ—randomized treatment assignment.

*

38]. Combined these studies demonstrate the potential utility, as well as limitations, of insulin sensitizing agents in the treatment of insulin resistance in patients with HIV infection. However, it is not known whether the long-term use of these agents will reduce the risk of developing type 2 diabetes mellitus or the cardiovascular sequelae of chronic insulin resistance. With the increased recognition that a number of antiretroviral classes and agents directly contribute to metabolic disturbances such as lipodytrophy, dyslipidemia and insulin resistance, efforts are underway to evaluate the benefits of alternative HA ART regimens that may minimize these effects. Several studies have demonstrated improvements in hyperlipidemia with institution of PI-sparing regimens, but few have been able to identify benefits in insulin sensitivity with changes in HA ART [39]. Similarly, a large, randomized trial designed to decrease the mitochondrial toxicity and potentially reverse lipoatrophy with replacement of stavudine or zidovudine with abacavir showed increases in limb fat after 24 weeks but did not identify any beneficial effects on insulin sensitivity [40]. Although diet and lifestyle modification including increased physical activity remain the first-line recommendations for the management of insulin resistance and type 2 diabetes, there are little data available directly evaluating the potential benefits of this approach in patients with HIV infection. Regular physical activity appears to be protective against the development of insulin resistance and hyperlipidemia in HIV [41], but prospective studies of exercise effects on metabolic parameters are limited and with mixed results with regard to insulin sensitivity. Yarasheski

and colleagues [42] showed that 16 weeks of resistance exercise training reduced triglyceride levels, but did not change insulin concentration in 18 HIV-infected men on antiretroviral therapy but these subjects were not selected for specific metabolic abnormalities. In contrast, Driscoll et al. [43] showed significant added reductions in insulin resistance with aerobic and resistance training above and beyond the benefits of metformin therapy in HIV-infected patients with lipodystrophy and hyperinsulinemia. Additional studies are needed to more fully assess the role of diet and exercise in the amelioration or prevention of insulin resistance and type 2 diabetes in HIV-infected patients on antiretroviral therapy.

Conclusions Insulin resistance and diabetes are increasingly recognized as potential consequences of chronic HIV infection and long-term exposure to antiretroviral therapy. These metabolic disturbances, alone and in combination with hyperlipidemia, confer increased risk of cardiovascular disease and constitute an important challenge facing health care providers managing patients with HIV infection. Although there is growing evidence that antiretroviral therapies contribute to insulin resistance by both direct and indirect toxicities, the mechanism of insulin resistance in patients with HIV infection is likely to be multifactorial. Prompt recognition and management of diabetes in this patient population will be important for maximizing longterm health, but further research is need to determine optimal strategies for screening and therapy.

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References and Recommended Reading

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2.•

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This large cohort study provides useful data on the prevalence and incidence of type 2 diabetes in men with HIV infection compared with a well-matched control population. 3.

4.•

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