Beneficial effect of insulin in hyperhomocysteinemia and diabetes mellitus-induced vascular endothelium dysfunction: role of phosphoinositide dependent kinase and protein kinase B.
A primary defect in the vascular action of insulin may be the key intermediate mechanism that links endothelial dysfunction with diabetes mellitus and hyperhomocysteinemia. This study investigated the downstream targets of insulin, involved in this process. Hyperhomocysteinemia (serum homocysteine > 10 μm/l) was produced in rats by administering L-methionine (1.7% w/w, p.o.x. 4 weeks) and diabetes mellitus (serum glucose > 140 mg/dl) was induced using streptozotocin (55 mg/kg/day, i.v. once) in another group. Four weeks after L-methionine and streptozotocin administration, vascular endothelium dysfunction was assessed in terms of attenuation of acetylcholine-induced, endothelium-dependent relaxation (isolated aortic ring preparation), decrease in serum nitrate/nitrite level, as well as mRNA expression of eNOS (rtPCR), and disruption of integrity of vascular endothelium. Both hyperhomocysteinemia and diabetes mellitus significantly attenuated acetylcholine-induced endothelial-dependent relaxation, and the increase in serum nitrite/nitrate concentration and the expression of eNOS. Insulin (0.4 and 0.6 IU/kg/day, s.c.) and atorvastatin (30 mg/kg/day, p.o.x. 4 weeks) significantly improved all these parameters. However, this ameliorative effect of insulin was blocked by 7-hydroxystaurosporine (UCN-01) [Inhibitor of phosphoinositide dependent kinase (PDK)], and triciribine (API-2) (protein kinase B/Akt inhibitor). It is suggested that amelioration of vascular endothelium dysfunction by insulin may be due to stimulation of PDK and Akt pathways.
Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India. suns.saurabh@gmail.com
Saurabh
S
Sharma
Manjeet
M
Singh
Pyare Lal
PL
Sharma
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000069059:Atorvastatin; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D001786:Blood Glucose; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D009566:Nitrates; D009573:Nitrites; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D014665:Vasodilator Agents; D000069059:Atorvastatin; 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