title: Activation of the PDK-1/Akt/eNOS pathway involved in aortic endothelial function differs between hyperinsulinemic and insulin-deficient diabetic rats.
abstract: In diabetic states, altered plasma insulin is likely to play key roles in 3-phosphoinositide-dependent protein kinase (PDK)/Akt pathway activation, in insulin resistance and in endothelial dysfunction. Since the molecular mechanism(s) remains unclear, we examined the relationship between the PDK/Akt/endothelial nitric oxide synthase (NOS) pathway and endothelial function in aortas from diabetic rats that were either insulin deficient or hyperinsulinemic. Untreated diabetic (diabetic) rats exhibited hyperglycemia and hypoinsulinemia, whereas high-insulin-treated diabetic (HI-diabetic) rats exhibited hyperinsulinemia. Aortas from the diabetic group displayed impaired endothelium-dependent relaxation in response to ACh, whereas the insulin-induced relaxation was increased. In HI-diabetic aortas, the ACh-induced relaxation was normal, but that induced by insulin was impaired. The insulin-induced relaxation was inhibited by treatment with an Akt inhibitor in control and diabetic aortas, but not in the HI-diabetic aorta. This inhibitory effect on insulin-induced relaxation was greater in diabetic aortas than in control aortas. In all groups, ACh-induced relaxation was unaffected by the above inhibitor. In the diabetic group, various insulin-stimulated levels (nitric oxide production, phosphorylation of endothelial NOS at Ser(1177), of Akt at Thr(308), and of PDK-1 at Ser(241)) were significantly increased, whereas, in the HI-diabetic group, these levels were all decreased (vs. control aortas). These results suggest that the plasma insulin level has a close relation to the level of aortic PDK-1/Akt (at Thr(308))/NOS activities, and that reduced actions of the PDK-1/Akt (at Thr(308)) signal pathway may contribute to the impairments of insulin-induced endothelial functions seen in hyperinsulinemic diabetes.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Shingo
authors.initials: S
authors.lastname: Nemoto
authors.forename: Takagoro
authors.initials: T
authors.lastname: Nogami
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation; D006946:Hyperinsulinism / Q000201:enzymology* / Q000503:physiopathology; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D007328:Insulin / Q000097:blood*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012694:Serine; D015398:Signal Transduction; D013912:Threonine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; D009599:Nitroprusside; D013912:Threonine; D009569:Nitric Oxide; D012694:Serine; D007294:Inositol; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000109:Acetylcholine