scholarly journals HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus

2008 ◽  
Vol 294 (3) ◽  
pp. E558-E567 ◽  
Author(s):  
Michael J. Carper ◽  
W. Todd Cade ◽  
Margaret Cam ◽  
Sheng Zhang ◽  
Anath Shalev ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Signaling Cascade ◽  
Cytokine Signaling ◽  
Hiv Protease Inhibitors ◽  
Suppressor Of Cytokine Signaling ◽  
Zdf Rats

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-α 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.

scholarly journals Molecular mechanisms of insulin resistance in obesity and type 2 diabetes mellitus

2009 ◽  
Vol 150 (17) ◽  
pp. 771-780 ◽  
Author(s):  
Gábor Winkler ◽  
Károly Cseh
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling

A zsírszövetben az inzulinreceptor jelátviteli folyamatait auto-, para- és endokrin hatásokkal szabályozó számos fehérje termelődik és szekretálódik. Ezek közül több, így a tumornekrózis-faktor-α és szolúbilis receptor formái, az sTNFR1 és sTNFR2, a rezisztin, retinolkötő fehérje-4, plazminogénaktivátor-inhibitor, lipokain-1 gátolja az inzulin jelátviteli folyamatait és inzulinrezisztenciát okoz, elsősorban a zsírszövetben, a májban, az izomszövetben, az agyban, az endothelsejtekben, valamint a hasnyálmirigy β-sejtjeiben. Más fehérjék, így az adiponektin, visfatin, vaspin, omentin, apelin és chemerin pedig javítják az inzulinreceptor jelátvitelét. Az összefoglalás áttekinti az inzulinreceptor jelátviteli folyamatainak főbb részleteit és kitér az elhízásban, valamint a 2-es típusú cukorbetegségben észlelhető inzulin- és citokinrezisztenciák patomechanizmusában a közelmúltban megismert molekuláris tényezőkre (például a suppressor of cytokine signaling fehérje család).

scholarly journals Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats

2005 ◽  
Vol 34 (2) ◽  
pp. 299-315 ◽  
Author(s):  
Young Ho Suh ◽  
Younyoung Kim ◽  
Jeong Hyun Bang ◽  
Kyoung Suk Choi ◽  
June Woo Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

scholarly journals Brain injury caused by HIV protease inhibitors: Role of lipodystrophy and insulin resistance

2012 ◽  
Vol 95 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Sunita Gupta ◽  
Alecia G. Knight ◽  
Boriss Y. Losso ◽  
Donald K. Ingram ◽  
Jeffrey N. Keller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Brain Injury ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors

Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors

AIDS ◽  
2003 ◽  
Vol 17 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Ronit Ben-Romano ◽  
Assaf Rudich ◽  
Dóra Török ◽  
Sharon Vanounou ◽  
Klaris Riesenberg ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Cell Type ◽  
Cell Type Specificity
Sign in / Sign up

Export Citation Format

Share Document