indinavir-sulfate and Diabetes-Mellitus--Type-2

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Retina; Retinal Diseases; Ritonavir; Saquinavir

Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60-80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty (fa/fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-alpha and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Composition; Diabetes Mellitus, Type 2; Eating; Gene Expression; Glucose Tolerance Test; HIV Protease Inhibitors; Indinavir; Insulin; Insulin Resistance; Liver; Muscle, Skeletal; Placebos; Rats; Rats, Zucker; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Triglycerides; Tumor Necrosis Factor-alpha

Diabetes mellitus was diagnosed in 16 out of 1011 HIV-positive patients over a median follow-up of 289 days (person-year incidence 2.06, 95% confidence interval 1.18-3.33). Significant risk factors for the onset of diabetes were older age and antiretroviral therapy with stavudine or indinavir. Older men with HIV infection should be considered at higher risk of diabetes, and caution maybe warranted in the use of both indinavir and stavudine in these patients.

Topics: Adolescent; Adult; Age Factors; Aged; Anti-HIV Agents; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Indinavir; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine

Hyperglycemia and new-onset diabetes mellitus have been reported to occur in HIV-infected patients treated with protease inhibitors.. To determine the effect of protease inhibitor therapy on serum glucose in a predominantly minority patient population.. Retrospective record review.. Clinical HIV program of an urban Veterans Affairs medical center.. All HIV-infected patients receiving a protease inhibitor over a one-year period from September 1996 through August 1997.. One hundred seventeen patients not previously known to be diabetic received protease inhibitors; seven (6%) developed symptomatic diabetes mellitus. Eight other patients had one or more serum glucose values >150 mg/dL. Mean random glucose values for patients who did not develop diabetes were higher during therapy than prior to initiation of protease inhibitors.. Urban minority HIV-infected patients receiving combination antiretroviral therapy including a protease inhibitor may be at increased risk for the development of hyperglycemia and diabetes mellitus. Risk factors for diabetes mellitus should be identified and blood glucose monitored in all patients receiving protease inhibitors.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperglycemia; Indinavir; Male; Middle Aged; Minority Groups; Retrospective Studies; Risk Factors; Ritonavir; Saquinavir; Urban Population

In three patients, a 36-year-old HIV seropositive homosexual man and two women aged 35 and 59 years who had acquired HIV infection through heterosexual contact, signs of lipodystrophy developed after prolonged anti-HIV triple therapy. The observed syndrome is seen after prolonged use of HIV protease inhibitors: it is characterized by peripheral fat wasting, central fat accumulation, hyperlipidaemia and insulin resistance. Typically the subcutaneous fatty tissue disappears resulting in prominent zygomata, veins and muscles and thinning of extremities and buttocks. In addition to abdominal fat accumulation, there have been reports on the occurrence of a dorsocervical fat pad, the so-called buffalo hump. Lipodystrophy caused by protease inhibitors is a risk factor for cardiovascular disease. Recognition of the syndrome is essential for adequate follow-up and possible treatment.

Topics: Adult; Cardiovascular Diseases; CD4 Lymphocyte Count; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Indinavir; Insulin Resistance; Lipodystrophy; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Treatment Outcome; Wasting Syndrome