OBJECTIVE -To observe the relationship of fasting plasma glucose (FPG), postchallenge plasma glucose (PG) (30, 60, 90, and 120 min during an oral glucose tolerance test [OGTT], as well as maximal PG during an OGTT, postchallenge glucose spikes [PGS], and glucose under the OGTT curve), and HbA 1c to intima-media thickness (IMT) as a marker of atherosclerosis.RESEARCH DESIGN AND METHODS -OGTT, ultrasound measurement of carotid IMT, and various atherosclerosis risk factors, such as family history of diabetes, obesity, and/or hyperlipoproteinemia, but without known diabetes, were analyzed in 582 individuals aged 40-70 years and at risk for type 2 diabetes.RESULTS -In univariate analysis, all examined glycemic parameters were significantly correlated to IMT. The 2-h postchallenge plasma glucose showed the strongest odds ratio (OR) of 1.88 (1.34-2.63) in relation to abnormal IMT. All PG variables, except for 30-min glucose in OGTT, showed a significant OR, whereas the OR for HbA 1c and FPG was not significant. In logistic regression analysis, 2-h PG was identified as the strongest determinant of IMT from all glycemic parameters. The 2-h PG and PGS, but not FPG, were associated with a significant rise of IMT in tertiles of HbA 1c . Glycemic parameters were strongly related to each other and to many atherosclerosis risk factors. In multivariate analysis including a variety of atherosclerosis risk factors, 2-h PG was a significant independent determinant of IMT.CONCLUSIONS -PG and PGS are more strongly associated with carotid IMT than FPG and HbA 1c level and modify substantially the risk for atherosclerosis, estimated by HbA 1c alone, in a cohort at risk for diabetes and in the early diabetes stage.

OBJECTIVE -Isolated impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two risk categories for type 2 diabetes. This study compared both categories with respect to the degree of insulin secretion abnormalities and insulin resistance. RESEARCH DESIGN AND METHODS-This is a crossover comparison of a population at high risk for type 2 diabetes. The subjects were recruited from the Risk Factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) study. They underwent a 75-g oral glucose tolerance test, with measurement of specific insulin, C-peptide, proinsulin, and free fatty acids at baseline and every 30 min after load for 2 h. Factor analysis was performed to evaluate the importance of insulin resistance and secretion abnormalities in both categories.RESULTS -All categories of prediabetic hyperglycemia had a higher cardiovascular risk factor level when adjusted for sex, age, and BMI compared to control subjects with normal glucose tolerance. Subjects with isolated IFG were more insulin resistant than those with IGT. By contrast, subjects with isolated IGT exhibited a more severe deficit in early-and late-phase insulin secretion versus IFG subjects. As shown with factor analysis, in IFG the insulin resistance factor explained 28.4% of the variance, whereas in IGT the insulin secretion factor was dominant, explaining 31.1% of the total variance. CONCLUSIONS -Our cross-sectional data from the RIAD study demonstrate that isolated IFG and isolated IGT are different with respect to the degree of insulin resistance and anomalies in insulin secretion, and that subjects with IGT exhibit a deficit in the early and late phases of insulin secretion. This finding may be important for a differential approach in primary prevention of type 2 diabetes.

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 ...

The RIAD study population at high risk for Type 2 diabetes mellitus, post-challenge hyperglycaemia was found to relate more strongly than fasting hyperglycaemia with carotid IMT.

Oxidized LDL (oxLDL) is a key mediator in atherogenesis and a marker of coronary artery disease (CAD).Type 2 diabetes is associated with excessive cardiovascular morbidity and mortality. Because atherogenesis starts before diabetes is diagnosed, we investigated whether circulating oxLDL levels are increased in impaired glucose tolerance (IGT). OxLDL levels were measured in 376 subjects with normal glucose tolerance (NGT), 113 patients with IGT, and 54 patients with newly diagnosed type 2 diabetes. After correction for age and BMI, serum levels of oxLDL were significantly increased in IGT versus NGT subjects (P ‫؍‬ 0.002). OxLDL levels were not associated with the following parameters of the oxidative/antioxidative balance in the blood: total antioxidant capacity, urate-to-allantoin ratio, and circulating phagocyte oxygenation activity. In stepwise multivariate analysis, LDL cholesterol (P < 0.0005) and triglycerides (P < 0.0005) were the strongest predictors of circulating oxLDL levels, followed by HDL cholesterol (P ‫؍‬ 0.003), 2-h postchallenge C-peptide (P ‫؍‬ 0.011), fasting free fatty acids (P ‫؍‬ 0.013), and serum paraoxonase activity (P ‫؍‬ 0.035). The strong correlation of oxLDL with LDL cholesterol and triglycerides indicates that LDL oxidation in IGT is preferentially associated with dyslipidemia. OxLDL increase may explain the high atherogenic potency of dyslipidemia in the prediabetic state. Diabetes 51:3102-3106, 2002

Hyperglycaemia has been convincingly shown to be associated with increased occurrence of atherosclerosis [1±4]. Epidemiological studies found that patients with Type II (non-insulin-dependent) diabetes mellitus have a two-to four-fold increased relative risk of cardiovascular disease (CVD) in comparison to nondiabetic subjects [3]. Poorly controlled Type II diabetic patients have a higher risk than patients with good glycaemic control [1,4]. Furthermore, there is evidence that non-diabetic plasma glucose levels are also continuously associated with CVD [5±7], though this relationship has not been confirmed for only moderate degrees of hyperglycaemia [8±10]. So far, Diabetologia (1998) 41: 706±712

Our results show a more substantial improvement of glucose control under glibenclamide than under acarbose which, however, was not associated with an increase of insulin sensitivity.

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