Selective Insulin Resistance Affecting Nitric Oxide Release But Not Plasminogen Activator Inhibitor-1 Synthesis in Fibroblasts From Insulin-Resistant Individuals

Abstract

Objectives-Insulin activates several processes potentially dangerous for the arterial wall and hyperinsulinemia might be atherogenic. However, other insulin effects are protective for the vessel wall and thus anti-atherogenic. Aim of this study was to investigate whether insulin effects on potentially pro-atherogenic and anti-atherogenic processes were differently affected in cells from insulin-resistant individuals. Methods and Results-We determined insulin effect on nitric oxide (NO) production and plasminogen activator inhibitor (PAI)-1 synthesis in 12 fibroblast strains obtained from skin biopsy samples of 6 insulin-sensitive (IS) (clamp M Ͼ7 mg/kg body weight per minute) and 6 insulin-resistant (IR) (clamp M Ͻ5 mg/kg body weight per minute) healthy volunteers. Insulin effects on NO release and Akt phosphorylation were significantly impaired in fibroblasts from IR as compared with IS individuals. Conversely, there was not any difference between IR and IS strains in insulin ability to increase PAI-1 antigen levels and, after 24-hour insulin incubation, PAI-1 mRNA increase in IR strains was only slightly less than in IS strains. Insulin ability to induce MAPK activation was also comparable in IR and IS cells. Conclusions-We conclude that in cells from IR individuals, insulin action on anti-atherogenic processes, such as NO release, is impaired, whereas the hormone ability to stimulate atherogenic processes, such as PAI-1 release, is preserved. Key Words: diabetes mellitus Ⅲ fibroblasts Ⅲ insulin resistance Ⅲ nitric oxide Ⅲ plasminogen activator inhibitor type 1 M etabolic syndrome is characterized by insulin resistance, hyperinsulinemia, and a cluster of risk factors for cardiovascular disease. Because insulin can activate several processes potentially dangerous for the vascular wall, hyperinsulinemia might contribute to the high cardiovascular risk associated with the syndrome. [1][2][3][4][5] As a matter of fact, insulin promotes vascular smooth muscle cells migration, 6 enhances leukocyte adhesion molecules expression, 7 stimulates endothelin 8 and plasminogen activator inhibitor-1 (PAI-1) 9 -11 synthesis and expression. However, several insulin effects could be considered protective for the vessel wall and thus anti-atherogenic; for instance, insulin inhibits platelet aggregation 12 and stimulates nitric oxide (NO) release. 13,14 In insulin-resistant subjects, molecular pathways leading to the potentially protective insulin effects on the vessel wall could be insulin-resistant as well, thus contributing to the accelerated atherosclerosis associated with insulin resistance. As a matter of fact, different intracellular cascades can transduce insulin signaling 15 and it appears that most of the potentially proatherogenic insulin effects (cell growth stimulation, increased PAI-1 synthesis and expression, etc.) are mainly mediated through a MAPK-dependent signaling pathway, 16 -19 whereas insulin effects on glucose transport and glucose uptake as well as insulin stimulation of NO synthesis and release are me...

Carotid Intima-media thickness in childhood and adolescent obesity relations to abdominal obesity, high triglyceride level and insulin resistance

“…This information demonstrates that an increased insulin levels seem to be an earlier predictor for atherogenic changes than hyperglycemia, and concur with data published by Atabek et al 19. Insulin not only directly stimulates the expression of vascular cell adhesion molecule 20, but disrupts the balance between the production of NO and ET-1 leading to endothelial dysfunction 21. Our regression analysis showed that lg (HOMA-IR) was an independent determinant of mean IMT level, which indicates that insulin resistance was involved in the basic pathological changes associated of obesity 22, and was closely related to cardio-cerebrovascular disease.…”

Insulin activates hypoxia-inducible factor-1α in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling

“…[34]. Finally, in fibroblast strains obtained from skin biopsy samples from nonobese insulin-resistant subjects vs insulin-sensitive subjects, the effects of insulin on PI3-K phosphorylation were impaired in the presence of a comparable insulin-induced MAPK activation [35].…”

Markers of insulin resistance and sedentary lifestyle are predictors of preeclampsia in women with adverse obstetric results

“…In univariate analysis, ROC curve analysis of WAR showed an optimal cut-off value at >0.8 kg/year, with 70% sensitivity and 74% specificity (OR = 7; 95%CI [3][4][5][6][7][8][9][10][11][12][13][14][15]; P < 0.001; c-statistic = 0.74 ± 0.05; P < 0.001).…”

“…Elevated acanthosis nigricans in the neck and hypertriglyceridemia are clinical manifestations related to insulin resistance (6). Furthermore, basic and clinical evidence has linked insulin resistance to impaired fibrinolysis through increased plasminogen activator inhibitor-I (PAI-I) production (7,8). During normal pregnancy, elastic fibers in the walls of the placental spiral arteries are progressively destroyed by matrix metalloproteinases in order to provide a low resistance placental circulation that ensures appropriate fetal growth.…”