title: Hepatic insulin gene therapy prevents deterioration of vascular function and improves adipocytokine profile in STZ-diabetic rats.
abstract: Hepatic insulin gene therapy (HIGT) ameliorates hyperglycemia in diabetic rodents, suggesting that similar approaches may eventually provide a means to improve treatment of diabetes mellitus. However, whether the metabolic and hormonal changes produced by HIGT benefit vascular function remains unclear. The impact of HIGT on endothelium-dependent vasodilation, nitrosyl-hemoglobin content (NO-Hb), and insulin sensitivity were studied using aortic ring preparations, electron spin resonance spectroscopy (ESR), homeostasis assessment of insulin resistance (HOMA-IR) calculations, and insulin tolerance testing (ITT). Data were correlated with selected hormone and adipocytokine concentrations. Rats made diabetic with streptozotocin were treated with subcutaneous insulin pellets dosed to sustain body weights and hyperglycemia or with HIGT; nondiabetic rats served as controls. Hyperglycemic rats demonstrated impaired endothelium-dependent vasodilation, reduced levels of NO-Hb, and diminished insulin, leptin, and adiponectin concentrations compared with controls. In contrast, HIGT treatment significantly reduced blood sugars and sustained both endothelium-mediated vasodilation and NO-Hb at control levels. HOMA-IR calculations and ITT indicated enhanced insulin sensitivity among HIGT-treated rats. HIGT partially restored suppressed leptin levels in hyperglycemic rats and increased adiponectin concentrations to supranormal levels, consistent with indicators of insulin sensitivity. Our findings indicate that the metabolic milieu produced by HIGT is sufficient to preserve vascular function in diabetic rodents. These data suggest that improved glycemia, induction of a beneficial adipocytokine profile, and enhanced insulin sensitivity combine to preserve endothelium-dependent vascular function in HIGT-treated diabetic rats. Consequently, HIGT may represent a novel and efficacious approach to reduce diabetes-associated vascular dysfunction.
authors.affiliation: Endocrinology and Metabolism Section (111) Atlanta VA Medical Center, NE, Decatur, GA 30033, USA. pthule@emory.edu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Thulé
authors.forename: Adam G
authors.initials: AG
authors.lastname: Campbell
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Kleinhenz
authors.forename: Darin E
authors.initials: DE
authors.lastname: Olson
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Boutwell
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.forename: C Michael
authors.initials: CM
authors.lastname: Hart
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D052242:Adiponectin / Q000097:blood; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002320:Cardiovascular Physiological Phenomena; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005934:Glucagon / Q000097:blood; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D036361:Peptide Hormones / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D006454:Hemoglobins; D007328:Insulin; D020738:Leptin; D008055:Lipids; D036361:Peptide Hormones; C008657:nitrosyl hemoglobin; D009599:Nitroprusside; D005934:Glucagon; D019001:Nitric Oxide Synthase; D000109:Acetylcholine