Insulin Action Is Associated With Endothelial Function in Hypertension and Type 2 Diabetes

Abstract

Abstract-A primary defect in the vascular action of insulin may be a key intermediate mechanism that links endothelial dysfunction with reduced insulin-mediated cellular glucose uptake in metabolic and cardiovascular disorders. The present study was designed to characterize more fully the relations between insulin action and endothelial function in male patients with essential hypertension (H, nϭ9) or type 2 diabetes (D, nϭ9) along with healthy control subjects (C) matched for age, body mass index, and lipid profile. They attended for measurement of whole-body insulin sensitivity (MCR) by the hyperinsulinemic clamp technique (day 1) and forearm vasoreactivity in response to intra-arterial infusions of insulin/glucose (day 2) and N G -monomethyl-L-arginine (L-NMMA) and norepinephrine (day 3) by bilateral venous-occlusion plethysmography. Results expressed as meanϮSE MCR (mL/kg per minute) were 7.22Ϯ0.99 (C), 6.32Ϯ0.78 (H), and 5.06Ϯ0.53 (D). Insulin/glucose-mediated vasodilation (IGMV) was 17.1Ϯ5.6% (C), 17.2Ϯ5.5% (H), and 12.3Ϯ6.4% (D). L-NMMA vasoconstriction (LNV) was 37.9Ϯ5.1% (C), 37.5Ϯ2.3% (H), and 33.6Ϯ2.8% (D). There were no significant differences among groups for these parameters. Pooled correlation analyses revealed associations between MCR and IGMV (rϭ0.46, PϽ0.05), MCR and LNV (rϭ0.44, PϽ0.05), and IGMV and LNV (rϭ0.52, PϽ0.01). This study supports functional coupling between insulin action (both metabolic and vascular) and basal endothelial nitric oxide production in humans. Key Words: insulin Ⅲ endothelium Ⅲ nitric oxide Ⅲ hyperinsulinism Ⅲ hypertension, essential Ⅲ diabetes mellitus A bnormally reduced insulin-stimulated glucose uptake (insulin resistance) and vascular endothelial dysfunction are both features of metabolic syndromes and cardiovascular disorders. However, it is unclear whether this association is causal or a reflection of a common underlying pathophysiological mechanism. In addition to its metabolic and mitogenic actions, insulin is a directly acting vasodilator, an action that is both endothelium dependent 1 and enhanced by D-glucose 2 and L-arginine 3 uptake. It is therefore tempting to speculate that the vascular effect of insulin may be a key intermediate mechanism that links endothelial function with insulinmediated cellular glucose uptake. Indeed, in previous studies involving young healthy volunteers, we have demonstrated associations between insulin sensitivity and both basal endothelial nitric oxide (NO) production 4 and insulin-mediated vasodilation. 5 Others have shown associations between endothelial function and insulin-mediated vasodilation 6 and, recently, between insulin action (both metabolic and vascular) and microvascular function. 7 However, interpretation of results from studies in older volunteers and patient groups is less clear; for example, in type 2 diabetes and hypertension there are data that report blunting of insulin-mediated vasodilation that parallels changes in insulin sensitivity, 8,9 although contrasting data report no defect in the vascular actio...

Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

“…The Type II diabetic patients showed a lower plasma NOx concentration than non-diabetic subjects (23.9±8.2 vs 42.3±31.5 µmol/l, p=0.00003). There is increasing evidence that NO synthesis and the vasodilating properties of insulin are impaired in insulin resistant states, such as Type II diabetes and obesity [31,32]. Thus, our data agree with previous findings [33].…”

Nitric Oxide Synthase Inhibition Reduces Glucose Uptake During Exercise in Individuals With Type 2 Diabetes More Than in Control Subjects

“…Our LBF data are consistent with an impaired vasodilatory response to exercise in individuals with type 2 diabetes and may relate to both vascular endothelium-dependent (52) and -independent (53) mechanisms. Lipid abnormalities, defects in the vascular action of insulin (52), and elevated blood glucose (54) all are likely contributors to impaired vascular control during exercise.…”

Gamma-glutamyltransferase: an effect modifier in the association between age and hypertension in a 4-year follow-up study

“…This finding is consistent with the findings shown in the relationship between age and type II diabetes, 1 supporting the concept that underlying mechanisms of hypertension and type II diabetes Gamma-glutamyltransferase, age, and hypertension D-H Lee et al are closely related, which was suggested by other studies. [12][13][14][15] Although GGT has been used clinically as a marker of alcohol consumption or liver disease, GGT plays an important role in antioxidant systems at a cellular level. [5][6][7] The maintenance of intracellular levels of glutathione is critical for antioxidant defence mechanisms of the cell, but intact extracellular glutathione is poorly transported across cell membranes.…”

“…12 Recent studies suggest that excessive production of reactive oxygen species, outstripping endogenous antioxidant defence mechanisms, may be involved in the pathogenesis and complications of both conditions. [13][14][15] Therefore, the interaction between age and serum GGT level might be interpreted as a synergic action of two markers of oxidative stress. Alternatively, we are interested in the possibility that body iron storage plays a role in this interaction between GGT and age, because the cellular role of GGT differs depending on iron storage.…”

“…[12][13][14][15] So, by analogy with type II diabetes, the association between age and hypertension might also depend on GGT level. Therefore, we performed this prospective study with the hypothesis that the relationship between age and hypertension was modified by baseline GGT level.…”