IR results when there is a decreased ability of exogenous or endogenous insulin to stimulate glucose uptake by cells in the muscles, fat, and liver, resulting in the pancreas producing more insulin to enable glucose to enter those cells. When the pancreas is no longer able to produce enough insulin to overcome this resistance, glucose levels increase, which can lead to prediabetes and, subsequently, type 2 diabetes mellitus, as well as other complications. Insulin is transmitted through cells via a series of protein-protein interactions.(2) Two major cascades of such interactions mediate intracellular insulin action. One pathway aids in the regulation of intermediary metabolism, and the other helps control growth processes and mitoses.(2) The 2 pathways appear to be distinct from each other, and some data suggest that although the pathway regulating intermediary metabolism is diminished in type 2 diabetes, the pathway regulating growth processes and mitoses remains normal.(2)
Assessing for IR
The hyperinsulinemic-euglycemic clamp has been considered the gold standard for measuring IR, but it is usually reserved for clinical research because it is time-consuming and costly.(3) Subsequently, various indices of IR have been developed to simplify assessment by using data from the 2-hour oral glucose tolerance test and, sometimes, other common laboratory assessments, such as triglyceride levels. Validated indices that can be used in clinical practice include the homeostasis model assessment of IR (HOMA-IR), the quantitative insulin sensitivity check index, and the Matsuda index. An advantage of HOMA-IR is that it predicts fasting steady-state glucose and insulin levels, whereas the Matsuda index represents hepatic and peripheral tissue sensitivity to insulin.(3) The quantitative insulin sensitivity check index is commonly used in management of patients who are nonobese, obese, and diabetic.(3) The HOMA-IR index is often used in studies of PLWHIV.
Risk Factors for IR in HIV
PLWHIV who are nondiabetic have the same risk factors for IR as people without HIV, as well as some risk factors that are specific to HIV.(4) Two major risk factors for IR, regardless of HIV status, are increased age and obesity. Location of fat deposition has been found to influence the risk for IR, with increased visceral, hepatic, ectopic (including skeletal muscles), and pericardial fat showing the greatest associations.(4) In addition, adipose tissue from individuals who are obese compared with those who are not appears to have more macrophages, resulting in greater production of plasminogen activator inhibitor-1, a circulating factor associated with atherosclerosis and IR.(5) Previous research has demonstrated that both HIV and HAART are associated with IR.(4) HIV infection has been shown to cause chronic immune activation and inflammation, even when HIV replication is suppressed. Inflammation and immune activation have been associated with obesity, metabolic syndrome, and IR.(5)
HAART and IR Risk
Antiretroviral therapy (ART) may cause IR as a result of several mechanisms. One study found significantly more oxidative DNA damage in PLWHIV treated with ART compared with people who were ART-naive.(6) In a linear regression analysis, increased DNA damage was positively associated with increased IR (odds ratio, 3.052; P less than .001).(6) Another major mechanism may be that ART alters fatty acid metabolism, leading to increased fatty acid levels, which can induce IR via mechanisms such as increasing hepatic gluconeogenesis and decreasing hepatic insulin extraction.(7) Certain ART treatments have been associated with a greater risk for IR than others in some studies, including protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs). Level of exposure appears to modulate this risk. In a study of women with HIV, cumulative exposure to NRTIs longer than 3 years was associated with a HOMA-IR that was 1.13 times higher than that of patients without any cumulative NRTI exposure.(8)
IR and Coronary Artery Calcium in HIV
A large study that compared the incidence and progression of coronary artery calcium deposition in men who had HIV (n=541) with those of men who were uninfected (n=284) found that men with HIV were at significantly higher risk of developing coronary artery calcium deposits (hazard ratio, 1.64).(9) In the study, IR and current smoking status were independently associated with an increased incidence of coronary artery calcium deposits. The study investigators suggested that their findings underscored the importance of interventions to improve IR and to facilitate smoking cessation in men with HIV.(9) Similar findings were reported by researchers who analyzed computed tomographic angiography (CTA) data from the Multicenter AIDS Cohort Study.(10) The data showed that HIV infection was associated with the presence of noncalcified coronary artery calcium deposits in men with coronary artery calcium scores of 0. This finding remained significant even after adjusting for CVD risk factors and other variables, including age, race, center, and cohort (before or after 2001); however, this analysis did not adjust for IR.
IR and Coronary Stenosis in HIV
An analysis of Multicenter AIDS Cohort Study data collected between 2003 and 2013 found IR to be more likely in men with HIV (n=448) than in men without HIV (n=306), and to be associated with significant coronary artery stenosis in both groups.(11) During the study, fasting serum insulin and glucose measurements were obtained semiannually during the 10-year period, and used to determine HOMA-IR, whereas computed tomographic angiography (CTA) was performed at the end of the study to characterize coronary pathology. Compared with uninfected men, those with HIV had significantly higher HOMA-IR. When measured near the time of CTA, men with HIV had a HOMA-IR of 3.2 compared with 2.7 for uninfected men (P =.002), and when HOMA-IR was averaged during the study period, they had a HOMA-IR of 3.4 compared with 3.0 for uninfected men (P less than .001). HOMA-IR was associated with greater odds of coronary stenosis of at least 50% in models comparing men with values in the highest vs the lowest tertiles, although the effect was not significantly modified by HIV serostatus.(11)
IR and Cognitive Function
HIV-associated neurocognitive disorders are well known and can range from severe conditions, such as HIV-associated dementia, to asymptomatic neurocognitive impairment.(12) Because IR is a known risk factor for cognitive impairment, a subanalysis of the Women's Interagency Health Study sought to examine associations between IR and cognitive function in women with HIV.(13) In the study, higher HOMA was associated with poorer performance on several cognitive measures, including the Symbol Digit Modalities Test, Stroop Color-Naming trial, and Stroop interference trial. However, after adjusting for several variables, the association remained statistically significant only for the Stroop Color-Naming trial. Another study suggested a possible insulin-related mechanism behind HIV-associated neurocognitive disorders.(14) In the study, changes in soluble insulin-like growth factor-1 receptor (sIGF1-R) levels and insulin binding to soluble insulin receptor (sIR) were associated with HIV-associated neurocognitive disorders.
Physical Activity and IR Risk
Increased physical activity has been shown to lower IR in the general population; however, a subanalysis of Multicenter AIDS Cohort Study data found men with HIV to have more IR, despite maintaining similar physical activity levels as men without HIV.(15) HOMA-IR was higher in men with HIV (P less than .001), and both HIV infection and low physical activity levels were significantly associated with a higher degree of IR (P less than .0001 and P =.0007, respectively).(15) An earlier study that assessed data from the Pitt Men's study reported similar findings, with self-reported low physical activity demonstrating an association with IR and diabetes mellitus in both men with HIV and men without HIV.(16) Multivariate analyses showed physical function/HIV interaction, older age, higher body mass index, HIV infection, and black race to be significantly associated with IR status. CD4 counts and AIDS status were not associated with IR in either univariate or multivariate analyses.(16)
Exercise and Peripheral Insulin Sensitivity in HIV
Various exercise approaches have been shown to improve peripheral insulin sensitivity in patients with HIV. In one study of PLWHIV with lipodystrophy, insulin-mediated glucose uptake was improved with both strength training (49.0 ± 12 to 57.8 ± 18 μmol glucose/kg lean mass·min; P =.005) and endurance training (55.7 ± 11 to 63.0 ± 11 μmol glucose/kg lean mass·min; P =.02); however, only strength training significantly reduced total body fat and increased total lean mass.17 Both exercise modalities also led to improvements in a variety of laboratory parameters, including high-density lipoprotein levels. In another study, adding progressive aerobic and resistance exercise training to a medicine approach with the antidiabetic drug pioglitazone significantly improved peripheral insulin sensitivity compared with pioglitazone alone in PLWHIV with IR and central adiposity.(18) Further studies are needed on how to optimize exercise in individuals with HIV with CVD risk factors.
Gut Microbiota and IR in HIV
Disruptions in gut microbiota composition and function have been implicated in the pathogenesis of obesity, IR, and type 2 diabetes mellitus.(19) HIV infection has been shown to modulate the levels of bacteria that make up the gut microbiota.(1) In treated and untreated PLWHIV, an increase in the gram-negative species Prevotella has been reported, along with a decrease in the levels of the phylum Bacteroidetes.(1) HIV has also been associated with an overabundance of lipopolysaccharide, an endotoxin derived from the outer membrane of Gram-negative bacteria. When an overabundance of lipopolysaccharide enters the circulation, it can lead to chronic inflammation and contribute to IR.20 In a study that included 67 PLWHIV receiving HAART and 10 healthy control participants, circulating levels of lipopolysaccharide were higher in the HIV cohort, with a positive correlation found between lipopolysaccharide and HOMA-IR (P =.0005).(20)
The advent of numerous choices of highly active antiretroviral therapies (HAART) has enabled individuals with HIV who adhere to these treatments to achieve normal life expectancies. In the majority of cases, death occurs secondary to noncommunicable chronic diseases, such as atherosclerotic cardiovascular disease (CVD), that are mediated by HIV or its treatments.1 Insulin resistance (IR) has been identified as a key driver of CVD and other complications in people living with HIV (PLWHIV), making it an important consideration when treating this population.
Compiled by Christina T. Loguidice
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