title: Regulation of IRS-2 signaling by IGF-1 receptor in the diabetic rat heart.
abstract: Cardiovascular disease involves changes in inflammatory markers. Since insulin/insulin-like growth factor 1 receptor (IGF-1R) can activate vascular endothelial growth factor to promote vascular growth, reduced IGF-1R signaling in the type I diabetic heart could be detrimental, leading to reduced, collateral blood vessel growth. This study assessed whether diabetes can induce an inflammatory phenotype to regulate molecules in the IGF-1 signaling cascade, thus mediating apoptosis. Rats were made diabetic using streptozotocin (to render them type I diabetic) for 2 months with no insulin treatment. At 2 months, rats were sacrificed under anesthesia, and the left ventricle was immediately removed and placed into cold lysis buffer for protein analyses. Western blotting, immunoprecipitation, and enzyme-linked immunosorbent assay analyses were completed to evaluate protein levels. Diabetes increased TNF-alpha, interleukin-6 (IL-6), and IL-1alpha levels in the heart. JNK and p42/p44 activity was significantly increased in the diabetic heart, while IGF-1R phosphorylation, IRS-2 tyrosine phosphorylation, and Akt activities were reduced. A significant increase in Bad protein levels and the cleavage of caspase 3 was observed in the diabetic heart. These results suggest that diabetes activates multiple inflammatory markers in the heart, which then signal a decrease in the activities of key players in the insulin-signaling cascade, namely IGF-1R, IRS-2, and Akt, to regulate apoptosis.
authors.affiliation: Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Youde
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D053148:Caspase 3 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D011917:Rats, Inbred Lew; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D053582:Interleukin-1alpha; D015850:Interleukin-6; C526299:Irs2 protein, rat; D014409:Tumor Necrosis Factor-alpha; D017526:Receptor, IGF Type 1; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3