ritonavir and Glucose-Intolerance

To compare information on body fat changes from questionnaire and clinical examination and to study lipoatrophy in HIV-1 patients on highly active antiretroviral therapy (HAART).. The study was cross-sectional within a randomized trial. One hundred and sixty-eight male HIV-1 patients were examined by questionnaire and clinical examination. Clinical lipoatrophy was studied and defined as fat wasting in the face, legs and/or arms. Fasting blood samples reflecting lipid and glucose metabolism were taken and the role of indinavir, ritonavir (RTV) and RTV/saquinavir (SQV) on lipoatrophy was investigated.. After a median of 17 months on HAART, concordance rates between information on changes in body fat from questionnaire and clinical examination were significant and varied from 70 to 96%. With a positive criteria of lipoatrophy in both assessments, 14% of patients had lipoatrophy. These patients had lower weight (P = 0.0007), weight loss from baseline (P = 0.003), lower circumferences at all measurements (P < 0.01), lower plasma triglycerides and low-density lipoprotein (LDL) (P < 0.05) and longer treatment with stavudine (P = 0.0009). Homeostasis model assessment (HOMA) estimates for insulin resistance and beta-cell function were comparable. Plasma cholesterol, triglycerides and very low-density lipoprotein (VLDL) were higher in patients receiving RTV or RTV/SQV (P < 0.03).. Questionnaire and clinical assessment provide concordant information on changes in body fat. Lipoatrophic patients on HAART with neither increase in abdominal circumference, nor hyperlipidaemia nor glucose intolerance may have side-effects to protease inhibitor treatment, to nucleoside reverse transcriptase inhibitor treatment (stavudine) or suffer from a drug-independent condition.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Composition; Cross-Sectional Studies; Drug Therapy, Combination; Glucose Intolerance; HIV Infections; HIV Protease Inhibitors; HIV Wasting Syndrome; Humans; Hyperlipidemias; Indinavir; Lipodystrophy; Male; Middle Aged; Ritonavir; Saquinavir; Stavudine; Surveys and Questionnaires

treatment of HIV infection with Protease Inhibitors (PIs) and Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can lead to insulin resistance and changes in body fat distribution. Overactivity of the endogenous cannabinoid system produces similar disturbances in metabolic syndrome within the general population. However, Cannabinoid receptor type 1 antagonism, in both human and animal studies, reverses many of these biochemical and physical derangements observed in the metabolic syndrome.. using an experimental study design, fifteen adult male Sprague-Dawley rats housed under standard conditions were randomized into three groups; Control, combined Anti-Retroviral Therapy (cART) only and cART + rimonabant. Drugs were administered daily by oral gavage for four weeks. After four weeks, insulin tolerance tests were conducted, the rats were euthanised and fat depots were excised and weighed. Experimental data were analysed using STATA 16.0 with the significance level set at p<0.05. The Shapiro-Wilk test determined normalcy. In cases of significance, post hoc analysis was performed by either the Dunn test or the Tukey HSD test.. Sprague Dawley rats treated with cART + rimonabant demonstrated better insulin sensitivity (p = 0.0239) and lower body weight (p = 0.044) than rats treated with cART alone. They had leaner body composition with 58% less adiposity than cART-only rats.. the study results suggest a role for the endogenous cannabinoid system in cART induced metabolic derangements and physical changes. Future studies can directly assay ECS activity in cART associated metabolic syndrome.

Topics: Adult; Animals; Anti-HIV Agents; Cannabinoids; Glucose Intolerance; HIV Infections; Humans; Lopinavir; Male; Metabolic Syndrome; Rats; Rats, Sprague-Dawley; Rimonabant; Ritonavir; Zidovudine

HIV protease inhibitors acutely block glucose transporters (GLUTs) in vitro, and this may contribute to altered glucose homeostasis in vivo. However, several GLUT-independent mechanisms have been postulated. To determine the contribution of GLUT blockade to protease inhibitor-mediated glucose dysregulation, the effects of ritonavir were investigated in mice lacking the insulin-sensitive glucose transporter GLUT4 (G4KO). G4KO and control C57BL/6J mice were administered ritonavir or vehicle at the start of an intraperitoneal glucose tolerance test and during hyperinsulinemic-euglycemic clamps. G4KO mice exhibited elevated fasting blood glucose compared with C57BL/6J mice. Ritonavir impaired glucose tolerance in control mice but did not exacerbate glucose intolerance in G4KO mice. Similarly, ritonavir reduced peripheral insulin sensitivity in control mice but not in G4KO mice. Serum insulin levels were reduced in vivo in ritonavir-treated mice. Ritonavir reduced serum leptin levels in C57BL/6J mice but had no effect on serum adiponectin. No change in these adipokines was observed following ritonavir treatment of G4KO mice. These data confirm that a primary effect of ritonavir on peripheral glucose disposal is mediated through direct inhibition of GLUT4 activity in vivo. The ability of GLUT4 blockade to contribute to derangements in the other molecular pathways that influence insulin sensitivity remains to be determined.

Topics: Adipokines; Adipose Tissue; Animals; Blood Glucose; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 4; HIV Protease Inhibitors; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Ritonavir