OBJECTIVE -Insulin resistance is an independent risk factor for arteriosclerosis and cardiovascular mortality. However, the mechanism by which insulin resistance contributes to arteriosclerosis is unknown. Conceivably, endothelial dysfunction could be involved. Therefore, we asked whether therapy for insulin resistance ameliorates any endothelial dysfunction.RESEARCH DESIGN AND METHODS -We performed a double-blind cross-over trial of 12 patients with recently diagnosed type 2 diabetes. They received rosiglitazone 4 mg b.i.d. for 12 weeks and nateglinide 60 mg b.i.d. for the same number of weeks in random order. To assess the degree of endothelial dysfunction, we used venous occlusion plethysmography. We studied vasodilation in response to acetylcholine (ACh) with and without exogenous insulin. The agents were infused into the brachial artery. Furthermore, we determined insulin resistance by euglycemic clamp.RESULTS -Glycemic control was comparable under rosiglitazone and nateglinide. Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide. ACh response was significantly increased after rosiglitazone treatment (maximum forearm blood flow 12.8 Ϯ 1.3 vs. 8.8 Ϯ 1.3 ml/100 ml after rosiglitazone and nateglinide, respectively; P Ͻ 0.05) but did not attain the level of healthy control subjects (14.0 Ϯ 0.7 ml/100 ml). Coinfusion of exogenous insulin increased ACh response further in the rosiglitazone group. N-monomethyl-L-arginineacetate (L-NMMA), an antagonist of nitric oxide synthase, largely prevented the increased vasodilation after rosiglitazone, regardless of the presence or absence of insulin. Insulin sensitivity and blood flow response were found to be correlated (P Ͻ 0.01).CONCLUSIONS -Insulin resistance is a major contributor toward endothelial dysfunction in type 2 diabetes. Both endothelial dysfunction and insulin resistance are amenable to treatment by rosiglitazone.
Diabetes Care 27:484 -490, 2004T ype 2 diabetes is an important risk factor for arteriosclerosis. According to recent literature, insulin resistance is a major aspect of this relationship (1-3). However, the mechanism by which insulin resistance contributes to arteriosclerosis is not known. An intact vascular endothelium is paramount to protection from arteriosclerosis. Endothelial dysfunction is a hallmark of arteriosclerosis. Endothelial dysfunction is most likely involved in both initiation and propagation of arteriosclerosis (4 -6). In type 2 diabetes, impaired endothelial function, both impaired nitric oxide (NO)-mediated vasodilation and vasodilation mediated independent of NO or prostacyclin (PGI 2 ), has been demonstrated (7-9). Therefore, we asked the question whether in type 2 diabetes endothelial dysfunction might be related to insulin resistance and whether insulin sensitization is capable of restoring this dysfunction. To provide an answer, we used rosiglitazone, a peroxisome proliferator-activated receptor-␥ agonist, to bring about insulin sensitization, and we observed its effects on endothelial function in ...
Endothelial dysfunction in patients with RA with low grade inflammation is associated with a reduced number and partial dysfunction of EPC. Further studies are needed to explore whether interventions that potentially ameliorate the number and function of EPC also improve endothelial function in these patients.
Microalbuminuria, an early feature of diabetic nephropathy, indicates intrarenal endothelial damage. In type 2 diabetes, microalbuminuria is strongly related to insulin resistance. We therefore investigated whether rosiglitazone, an insulin-sensitizing drug that is known to improve endothelial dysfunction, was able to improve intrarenal endothelial dysfunction and microalbuminuria. Nineteen type 2 diabetic patients participated in this double-blind cross-over trial. Nine patients with newly diagnosed disease without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks. Ten patients with microalbuminuria were randomized to rosiglitazone or placebo, each for 12 weeks in addition to their previous antidiabetic medication. After each treatment, glomerular filtration rate (GFR), renal plasma flow, and filtration fraction were measured before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine-acetate (L-NMMA). Ten healthy subjects served as control subjects. Type 2 diabetic patients at baseline showed glomerular hyperfiltration compared with healthy control subjects. Rosiglitazone reduced elevated GFR and filtration fraction toward control primarily in patients with microalbuminuria (GFR: 133.4 ؎ 9.8 vs. 119.6 ؎ 8.7 ml/min; filtration fraction: 23.2 ؎ 1.7 vs. 20.5 ؎ 1.6% before and after rosiglitazone, respectively; control subjects: GFR 111.7 ؎ 8.6 ml/min, filtration fraction 20.4 ؎ 1.5%). Rosiglitazone improved intrarenal NO bioavailability in type 2 diabetes toward control as shown by infusion of L-NMMA. Rosiglitazone reduced albumin excretion in type 2 diabetes with microalbuminuria from 116.5 ؎ 31 to 40.4 ؎ 12 mg/day. Rosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes, improved NO bioavailability, and lessened renal end-organ damage in type 2 diabetes with microalbuminuria. Diabetes
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