HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus.
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.
Carper
Michael J
MJ
Washington University School of Medicine, Department of Internal Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Southwest Tower, Room #846A, Campus Box 8127, 660 South Euclid Drive, St. Louis, MO 63110, USA.
Cade
W Todd
WT
Cam
Margaret
M
Zhang
Sheng
S
Shalev
Anath
A
Yarasheski
Kevin E
KE
Ramanadham
Sasanka
S
D000273:Adipose Tissue / Q000737:chemistry / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced*; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D005951:Glucose Tolerance Test; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D019469:Indinavir / Q000009:adverse effects; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects; D010919:Placebos; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000032:analysis; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D001786:Blood Glucose; D017320:HIV Protease Inhibitors; D007328:Insulin; D010919:Placebos; C491589:Socs1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019469:Indinavir