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Objective: Fasting insulin concentrations are often used as a surrogate measure of insulin resistance. We investigated the relative contributions of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis., Design and Methods: The Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort consists of 1326 European non-diabetic, overall healthy men and women aged 30-60 years. We performed standard oral glucose tolerance tests and hyperinsulinemic euglycemic clamps. As a general measure of cardiovascular risk, we assessed the prevalence of the metabolic syndrome in 1177 participants. Carotid artery intima media thickness (IMT) was measured by ultrasound to assess preclinical atherosclerosis., Results: Fasting insulin was correlated with all elements of the metabolic syndrome. Insulin sensitivity (M/I) was correlated with most elements. The odds ratio for the metabolic syndrome of those in the highest quartile of fasting insulin compared with those in the lower quartiles was 5.4 (95% confidence interval (CI) 2.8-10.3, adjusted for insulin sensitivity) in men and 5.1 (2.6-9.9) in women. The odds ratio for metabolic syndrome of those with insulin sensitivity in the lowest quartile of the cohort compared with those in the higher quartiles was 2.4 (95% CI 1.3-4.7, adjusted for fasting insulin) in men and 1.6 (0.8-3.1) in women. Carotid IMT was only statistically significantly associated with fasting insulin in both men and women., Conclusions: Fasting insulin, a simple and practical measure, may be a stronger and independent contributor to cardiometabolic risk and atherosclerosis in a healthy population than hyperinsulinemic euglycemic clamp-derived insulin sensitivity.

Objective: Low-grade chronic inflammation has been hypothesized to underlie the constellation of cardiometabolic risk factors, possibly by inducing insulin resistance. In the present study, we investigated associations between inflammation markers, insulin sensitivity (expressed as the ratio of the M value to the mean plasma insulin concentrations measured during the final 40 min of the clamp [M/I]), and a range of cardiometabolic risk factors in a large, healthy population., Research Design and Methods: The Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort includes 1,326 nondiabetic European men and women, aged between 30 and 60 years. We measured cardiometabolic risk factors and performed a hyperinsulinemic-euglycemic clamp. We determined total white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) as markers of chronic inflammation., Results: WBC and ESR were both strongly associated with M/I. WBC and ESR were further associated with a range of cardiometabolic risk factors. Associations between WBC and HDL cholesterol, triglycerides, heart rate, fasting C-peptide, and insulin and 2-h insulin in men and women and between WBC and 2-h glucose in women remained significant after adjustment for both M/I and waist circumference. Associations between ESR and HDL cholesterol, heart rate, fasting, and 2-h insulin in men and women and between ESR and fat mass in women remained significant after adjustment for M/I and waist circumference., Conclusions: This study showed that low-grade chronic inflammation is associated with the cardiometabolic risk profile of a healthy population. Insulin resistance, although strongly associated with inflammation, does not seem to play a large intermediary role.

Background: To describe the frequency, in some European populations, of the World Health Organisation (WHO) defined metabolic syndrome and to compare the frequency of this syndrome with an alternative definition for non-diabetic subjects, called the insulin resistance syndrome proposed by the European Group for the Study of Insulin Resistance (EGIR)., Methods: Investigators of eight European studies contributed, according to a written protocol, the frequencies of abnormalities of these two syndromes, by sex and age class, as well as the overall frequencies of the syndromes and the average number of abnormalities: 8200 men and 9363 women were included., Results: The frequency of both syndromes increased with age and was almost always higher in men than women for a given age. In non-diabetic subjects the frequency of the WHO syndrome varied between 7% and 36% for men 40 to 55 years; for women of the same age, between 5% and 22%. The EGIR syndrome was less frequent than the WHO syndrome (1% to 22% in men, 1% to 14% in women 40-55 years), and in men this was mainly due to the differing definitions of central obesity, as the WHO definition included overall obesity, BMI > or = 30 kg/m(2)., Conclusions: There is great variability in the frequency of the syndrome between different populations, due to the differing frequencies of the abnormalities and no doubt to the differing methodologies of measurement. Prospective studies and advances in the knowledge of physio-pathological mechanisms are required to determine the most appropriate and practical definition of the syndrome.

Objectives: To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes. Methods: Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial. Participants: Males and females aged 45–74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey. Intervention: Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function. Results: One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%. Conclusions: ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes. Registration: - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39 [ABSTRACT FROM AUTHOR]

Objective To study whether the shape of the oral glucose tolerance test (OGTT)-glucose curve is a stable trait over time; it is associated with differences in insulin sensitivity, ß-cell function and risk of impaired fasting glucose (IFG) and glucose tolerance (IGT) in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort. Methods OGTT-glucose curve shape was classified as monophasic, biphasic, triphasic and anomalous in 915 individuals. Oral glucose insulin sensitivity (OGIS), Matsuda insulin sensitivity index (ISI) and ß-cell function were assessed at baseline and 3 years apart. Results The OGTT-glucose curve had the same baseline shape after 3 years in 540 people (59%; κ = 0.115; p < 0.0001). Seventy percent of the participants presented with monophasic OGTT-glucose curve shape at baseline and after 3 years (percent positive agreement 0.74). Baseline monophasic shape was associated with significant increased risk of IFG (OR 1.514; 95% CI 1.084–2.116; p = 0.015); biphasic shape with reduced risk of IGT (OR 0.539; 95% CI 0.310–0.936) and triphasic shape with reduced risk of IFG (OR 0.493; 95% CI 0.228–1.066; P = 0.043) after 3 years. Increased risks of IFG (OR 1.509; 95% CI 1.008–2.260; p = 0.05) and IGT (OR 1.947; 95% CI 1.085–3.494; p = 0.02) were found in people who kept stable monophasic morphology over time and in switchers from biphasic to monophasic shape (OR of IGT = 3.085; 95% CI 1.377–6.912; p = 0.001). Conclusion After 3 years follow-up, the OGTT-glucose shape was stable in 59% of the RISC cohort. Shapes were associated with different OGIS and ß-cell function; persistence over time of the monophasic shape and switch from biphasic to monophasic shape with increased risk of impaired glucose metabolism. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Confirmatory factor analysis (CFA) was used to test the hypothesis that the components of the metabolic syndrome are manifestations of a single common factor. RESEARCH DESIGN AND METHODS -- Three different datasets were used to test and validate the model. The Spanish and Mauritian studies included 207 men and 203 women and 1,411 men and 1,650 women, respectively. A third analytical dataset including 847 men was obtained from a previously published CFA of a U.S. population. The one-factor model included the metabolic syndrome core components (central obesity, insulin resistance, blood pressure, and lipid measurements). We also tested an expanded one-factor model that included uric acid and leptin levels. Finally, we used CFA to compare the goodness of fit of one-factor models with the fit of two previously published four-factor models. RESULTS -- The simplest one-factor model showed the best goodness-of-fit indexes (comparative fit index 1, root mean-square error of approximation 0.00). Comparisons of one-factor with four-factor models in the three datasets favored the one-factor model structure. The selection of variables to represent the different metabolic syndrome components and model specification explained why previous exploratory and confirmatory factor analysis, respectively, failed to identify a single factor for the metabolic syndrome. CONCLUSIONS -- These analyses support the current clinical definition of the metabolic syndrome, as well as the existence of a single factor that links all of the core components. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the relation of central obesity to markers of insulin resistance, chronic inflammation and coronary heart disease (CHD) in population-based studies from Spain and Mexico City, Mexico. The study found comparable results for C-reactive protein (CRP) and CHD risk estimates. The results of the study suggest that central obesity may not be an essential component of metabolic syndrome.