The role of protease inhibitors in the pathogenesis of HIV-associated insulin resistance: Cellular mechanisms and clinical implications

Abstract

HIV-associated insulin resistance frequently presents as relative lack of peripheral adipose tissue storage associated with dyslipidemia. This review discusses explanations for the links between acute and subacute abnormalities in glucose metabolism and chronic changes in adipose tissue distribution. Specifically, the molecular mechanisms by which the HIV protease inhibitor class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage are reviewed. It is proposed that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on glucose metabolism. The physiologic outcome is such that total energy storage in the adipocytes is decreased, and the remaining adipocytes resist further energy storage. The excess circulating and dietary lipid metabolites, normally "absorbed" by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue where they impair insulin action. This leads to a pathologic cycle of insulin resistance, lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome.

Antiretroviral Therapy – Changes of Basic Laboratory Parameters in Hiv-Infected Bulgarian Patients

“…According to most studies protease inhibitors are the antiretroviral medicaments which mainly lead to deviations in the lipid profi le [29,44,45,54]. Those of our patients who were treated with non-nucleoside inhibitors showed dyslipidemia in higher percentage.…”

Dyslipidemia in Patients with Lipodystrophy in the Use of Antiretroviral Therapy

“…Several studies investigate ways of relating to HAART the effects of dyslipidemia like type of drug used by the patient and how the treatment regimen it has been implemented, but is still lacking a precise explanation for the lipid profile origin. Protease inhibitors (PI) are associated with dyslipidemia and insulin resistance for a considerable time, specifically ritonavir, and a variety of hypotheses (albeit not conclusive) it is presented to explain this association (Noor, 2007;Dubé et al, 2003). One proposed mechanism to emergence of dyslipidemia is the lipoprotein lipase inhibition by PI, responsible for LDL-C increased, due to difficulty in capturing chylomicrons, resulting in lower hepatic clearance of triglycerides (Sprinz et al, 2010, as cited in Carr & Mooser, 2001).…”

“…Thus, the increase in triglycerides caused by ritonavir that could be related to elevation in hepatic lipoprotein, inhibiting degradation mediated by apolipoprotein B and SREBP-1c in liver (Riddle et al, 2001;Liang et al, 2001). As regard the insulin resistance promoted by PI, this class of antiretroviral drugs has been related to inhibition of GLUT-4 in the transmembrane transport of glucose, leading to reduced glucose uptake mediated by insulin in peripheral tissue (skeletal muscle and adipocytes), which can lead the modification of lipid levels (Noor, 2007). The fact that some patients had a clinical and laboratory profile more or less flowered depending on the effects that PI has on the lipids metabolism may be related to genetics, suggesting that certain people are more prone to PI effects through manifestation of certain genes so far not identified (Shahmanesh et al, 2001).…”

Dyslipidemia in HIV-infected individuals

“…22,23 Generally speaking, PIs are associated with dyslipidemia, which is highest with ritonavir and boosted PIs. 9,14,24 Several theories have been proposed to explain the contribution of PIs in dyslipidemia, although none of them explains all aspects. Carr et al 7 proposed a theory based on the finding of molecular structural homology between the catalytic site of HIV protease and two human proteins involved in lipid metabolism, the protein binding of retinoic acid cytoplasmic type I (CRABP-1 -Cellular Retinoic Acid Binding Protein 1) and protein related to the receptor for low-density lipoprotein (LDL-R).…”

“…Protease inhibitors (PI) show direct effect on human adipose and specific effects on insulin resistance which may contribute to the overall adipose imbalance and development of lipodystrophy, and metabolic syndrome in HIV-positive individuals. [7][8][9] In addition, nucleoside reverse transcriptase inhibitors (NRTIs) may induce mitochondrial dysfunction, which could result in effects on adipose tissue, lactic acidosis, myopathy, peripheral neuropathy, hepatic steatosis and pancreatitis as well. 8,10,11 Although less involved, nonnucleoside reverse transcriptase inhibitors (NNRTIs), mainly efavirenz, might be associated with metabolic disorders, including dyslipidemia.…”