Risk factors that contribute to development of metabolic syndrome in HIV-infected patients are age, gender, duration of HIV infection, CD4 count, viral burden, body mass index, and waist circumference, waist-to-hip ratio, socioeconomic class, and culture.[3
Impaired glucose tolerance and insulin resistance are noted to precede weight loss in patients with HIV.[3
] Insulin resistance, rather than insulin deficiency, is implicated in the pathogenesis of diabetes in HIV-infected patients. According to early reports, evidence of islet cell autoimmunity or beta cell destruction is not seen in HIV patients.[6
] However, autoimmune diabetes has recently been reported in HIV-infected patients.[7
Concurrent use of opiates, however, may alter beta cell function,[8
] while heroin addiction is associated with insulin resistance.
HIV infection is linked with hepatitis C infection, which is associated with insulin resistance and diabetes due to increased intrahepatic tumor necrosis factor (TNF-α) and hepatic steatosis.[8
HIV is also associated with various endocrine abnormalities, including those of the growth hormone axis. Growth hormone deficiency may contribute to insulin resistance in HIV-infected patients.[9
The increased accumulation of visceral fat, with wasting of subcutaneous fat, noted in these patients, creates higher levels of inflammatory cytokines such as TNF-α and increases insulin resistance.[10
Viral factors which contribute to diabetes risk are an increase in viral burden of 0.5 log over a 6-month period, a lower CD4 count, and longer duration of HIV infection.
The major contributor to hyperglycemia in HIV/AIDS, however, is iatrogenic.[11
] The past few decades have seen remarkable improvement in the clinical outcome of HIV patients, thanks to highly active antiretroviral therapy (HAART). Benefits include suppression of viral load, improvement in CD4 count, decrease in opportunistic infections and length of hospital stay, and reduction in mortality.[12
HAART, however, has also led to an increase in metabolic dysfunction, including insulin resistance, diabetes dyslipidemia and lipodystrophy.[12
A recent analysis has found that diabetes is fourfold more common is HIV-infected men exposed to HAART than in HIV-seronegative men.[13
] PIs which have been used extensively as antiretroviral agents are the mainstay of HAART. This class of drugs includes atazanavir, darunavir and saquinair.
PIs have been shown to increase insulin resistance and reduce insulin secretion by interfering with GLUT-4 mediated glucose transport. A positive family history of diabetes, weight gain, lipodystrophy, old age and hepatitis C infection[12
] predisposes to diabetes. PIs interfere with cellular retinoic acid-binding protein type 1 (CRABP 1) that interacts with peroxisomal proliferator-activated receptor (PPAR)-γ. Inhibition of PPAR-γ promotes adipocyte inflammation, release of free fatty acids and insulin resistance.[10
] Hyperglycemia due to PIs usually resolves when the offending drug is stopped.
All PIs do not have the same metabolic effects . Indinavir induces insulin resistance with no effect on lipid metabolism, while lopinavir and ritonavir increase fasting triglycerides and free fatty acids, without affecting insulin sensitivity. Indinavir and ritonavir both block GLUT-4, but no such effect is noted with amprenavir and atazanazvir. Patients treated with nelfinavir, indinavir, liponavir or saquinavir demonstrate alterations in first-phase insulin release with a 25% reduction in β-cell dysfunction.[14
Drug treatment for human immunodeficiency virus and the impact of drugs on pathogenesis of diabetes mellitus
Thus, there is no class effect of PIs on diabetes and various PIs should be studied individually with respect to their metabolic effects.[15
The other class of drugs which is used is the nucleoside analogs (Nucleoside Reverse Transcriptase Inhibitors or NRTIs). It was earlier felt that NRTIs were less likely to cause metabolic abnormalities. A recent study which analyzed 130,151 p erson years of exposure, however, has shown that these drugs increase the risk of diabetes.[16
The risk is highest with stavudine, but is also significant with zidovudine and didanosine. Proposed mechanisms include insulin resistance, lipodystrophy, and mitochondrial dysfunction.[17
PIs seem to confer acute metabolic risks, while NRTIs confer cumulative risks of diabetes in predisposed, exposed persons. Exposure to a combination of NRTI and indinavir (a PI) has been shown to be an additional risk factor for the onset of diabetes.[16
Drugs used to manage comorbid conditions associated with AIDS may also cause diabetes. Pentamidine, which is used to prevent and treat Pneumocystis jiroveci
associated pneumonia, can cause β-cell toxicity, with acute hypoglycemia followed by later diabetes. Factors associated with increased risk of hypoglycemia are longer and higher dosage of pentamidine, as well as renal insufficiency. The group of patients who progressed to diabetes had low C peptide levels, suggestive of β-cell destruction.[17
Megestrol acetate, an appetite stimulant, predisposes to diabetes because of its intrinsic glucocorticoid like activity, increased caloric intake and weight gain.[18
] Hypoglycemia has been noted to resolve once megestrol is stopped, and to recur on rechallenging.[19
Patients on HAART may also be predisposed to diabetes because of the improved nutritional status and weight gain that accompanies effective treatment of HIV.