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The prevalence of insulin resistance in the most common metabolic disorders is still an undefined issue. We assessed the prevalence rates of insulin resistance in subjects with impaired glucose tolerance (IGT), NIDDM, dyslipidemia, hyperuricemia, and hypertension as identified within the frame of the Bruneck Study. The study comprised an age- and sex-stratified random sample of the general population (n = 888; aged 40-79 years). Insulin resistance was estimated by homeostasis model assessment (HOMA(IR)), preliminarily validated against a euglycemic-hyperinsulinemic clamp in 85 subjects. The lower limit of the top quintile of HOMA(IR) distribution (i.e., 2.77) in nonobese subjects with no metabolic disorders (n = 225) was chosen as the threshold for insulin resistance. The prevalence of insulin resistance was 65.9% in IGT subjects, 83.9% in NIDDM subjects, 53.5% in hypercholesterolemia subjects, 84.2% in hypertriglyceridemia subjects, 88.1% in subjects with low HDL cholesterol, 62.8% in hyperuricemia subjects, and 58.0% in hypertension subjects. The prevalence of insulin resistance in subjects with the combination of glucose intolerance (IGT or NIDDM), dyslipidemia (hypercholesterolemia and/or hypertriglyceridemia and/or low HDL cholesterol), hyperuricemia, and hypertension (n = 21) was 95.2%. In isolated hypercholesterolemia, hypertension, or hyperuricemia, prevalence rates of insulin resistance were not higher than that in nonobese normal subjects. An appreciable number of subjects (n = 85, 9.6% of the whole population) was insulin resistant but free of IGT, NIDDM, dyslipidemia, hyperuricemia, and hypertension. These results from a population-based study documented that 1) in hypertriglyceridemia and a low HDL cholesterol state, insulin resistance is as common as in NIDDM, whereas it is less frequent in hypercholesterolemia, hyperuricemia, and hypertension; 2) the vast majority of subjects with multiple metabolic disorders are insulin resistant; 3) in isolated hypercholesterolemia, hyperuricemia, or hypertension, insulin resistance is not more frequent than can be expected by chance alone; and 4) in the general population, insulin resistance can be found even in the absence of any major metabolic disorders. [ABSTRACT FROM AUTHOR]

Objective: Data on cardiac function in patients with nonalcoholic fatty liver disease (NAFLD) are limited and conflicting. We assessed whether NAFLD is associated with abnormalities in cardiac function in patients with type 2 diabetes.Research Design and Methods: We studied 50 consecutive type 2 diabetic individuals without a history of ischemic heart disease, hepatic diseases, or excessive alcohol consumption, in whom NAFLD was diagnosed by ultrasonography. A tissue Doppler echocardiography with myocardial strain measurement was performed in all patients.Results: Thirty-two patients (64%) had NAFLD, and when compared with the other 18 patients, age, sex, BMI, waist circumference, hypertension, smoking, diabetes duration, microvascular complication status, and medication use were not significantly different. In addition, the left ventricular (LV) mass and volumes, ejection fraction, systemic vascular resistance, arterial elasticity, and compliance were also not different. NAFLD patients had lower e' (8.2 ± 1.5 vs. 9.9 ± 1.9 cm/s, P < 0.005) tissue velocity, higher E-to-e' ratio (7.90 ± 1.3 vs. 5.59 ± 1.1, P < 0.0001), a higher time constant of isovolumic relaxation (43.1 ± 10.1 vs. 33.2 ± 12.9 ms, P < 0.01), higher LV-end diastolic pressure (EDP) (16.5 ± 1.1 vs. 15.1 ± 1.0 mmHg, P < 0.0001), and higher LV EDP/end diastolic volume (0.20 ± 0.03 vs. 0.18 ± 0.02 mmHg, P < 0.05) than those without steatosis. Among the measurements of LV global longitudinal strain and strain rate, those with NAFLD also had higher E/global longitudinal diastolic strain rate during the early phase of diastole (E/SR(E)). All of these differences remained significant after adjustment for hypertension and other cardiometabolic risk factors.Conclusions: Our data show that in patients with type 2 diabetes and NAFLD, even if the LV morphology and systolic function are preserved, early features of LV diastolic dysfunction may be detected. [ABSTRACT FROM AUTHOR]

Objective: Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes.Research Design and Methods: We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2)).Results: During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71-3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA(1c), eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16-3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD.Conclusions: In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to explore the relation between insulin resistance and plasma levels of soluble adhesion molecules and to examine the effects of acute hyperinsulinemia on these molecules in type 2 diabetic individuals.Research Design and Methods: Intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E- and P-selectin plasma concentrations were measured in 36 nonobese type 2 diabetic patients without cardiovascular disease and in 7 healthy subjects. Insulin sensitivity was assessed by a 4-h euglycemic ( approximately 5 mmol/l)-hyperinsulinemic ( approximately 300 pmol/l) clamp performed in combination with [(3)H]3-D-glucose infusion.Results: Diabetic subjects were insulin resistant but did not show plasma concentrations of adhesion molecules that were significantly higher than control subjects. In diabetic subjects, plasma ICAM-1 and E-selectin were negatively correlated with total glucose disposal during the insulin clamp (r = -0.432, P < 0.01; and r = -0.375, P < 0.05, respectively), whereas plasma VCAM-1 and P-selectin were not. Plasma ICAM-1 as well as E- and P-selectin were positively correlated with BMI, total body fat (TBF), and waist girth (P < 0.05-0.001). In multiple regression analyses, the relation of plasma ICAM-1 and E-selectin with insulin sensitivity was lost after adjustment for potential confounders, including HbA(1c), blood pressure, and/or LDL cholesterol. In these analyses, BMI was the only independent predictor of plasma ICAM-1 (R(2) = 0.244, P < 0.002), whereas TBF was the only independent predictor of plasma E-selectin (R(2) = 0.202, P = 0.01). The 4-h insulin infusion during the glucose clamp did not significantly change plasma levels of adhesion molecules.Conclusions: Overall adiposity, rather than insulin resistance, may be a determinant of plasma levels of ICAM-1 and E-selectin in type 2 diabetic individuals. In these patients, acute hyperinsulinemia does not exert any significant effect on plasma adhesion molecules. These findings support the possibility that adipose tissue releases one or more factors that may adversely affect endothelial function on one hand and insulin sensitivity on the other. [ABSTRACT FROM AUTHOR]

Objective: Glycosylated hemoglobin (HbA(1c)) recently has been recommended for the diagnosis of diabetes by the American Diabetes Association, but its value in the prediction of type 2 diabetes is poorly understood. In this study we evaluated how high-normal HbA(1c) levels predict type 2 diabetes.Research Design and Methods: We measured HbA(1c) in 919 Caucasian subjects, aged 40-79 years, and recorded new cases of type 2 diabetes in the following 15 years. Diabetes was diagnosed with HbA(1c).Results: Subjects were stratified according to baseline HbA(1c) (<5.0, 5.00-5.49 [reference], 5.50-5.99, and 6.00-6.49%). Sex- and age-adjusted hazard ratios (95% CI) for type 2 diabetes were 1.11 (0.30-4.41), 1.00, 3.79 (1.79-8.06), and 12.50 (5.51-28.34), respectively. Results did not change after adjusting for several putative confounding factors and were confirmed when models with updated variables were used.Conclusions: HbA(1c) is an independent risk factor for type 2 diabetes. Subjects with high-normal levels of HbA(1c) deserve particular attention because they have a strong risk of developing diabetes. [ABSTRACT FROM AUTHOR]

Evaluates interleukin-6 levels in type 1 diabetic patients without microvascular and macrovascular complications. Procedure; Differences in fibrinogen concentration; Significance.

Focuses on a study which assessed the effects of chronic smoking on leptin levels in type 1 diabetics. Information on serum leptin; Methods; Conclusions.

Objective: Several studies have explored the impact of nonalcoholic fatty liver disease (NAFLD) on risk of incident type 2 diabetes. However, the extent to which NAFLD may confer risk of incident diabetes remains uncertain. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident diabetes., Research Design and Methods: We collected data using PubMed, Scopus, and Web of Science from January 2000 to July 2017. We included only large ( n ≥500) observational studies with a follow-up duration of at least 1 year in which NAFLD was diagnosed on imaging methods. Eligible studies were selected according to predefined keywords and clinical outcomes. Data from selected studies were extracted, and meta-analysis was performed using random-effects modeling., Results: A total of 19 observational studies with 296,439 individuals (30.1% with NAFLD) and nearly 16,000 cases of incident diabetes over a median of 5 years were included in the final analysis. Patients with NAFLD had a greater risk of incident diabetes than those without NAFLD (random-effects hazard ratio [HR] 2.22, 95% CI 1.84-2.60; I 2 = 79.2%). Patients with more "severe" NAFLD were also more likely to develop incident diabetes; this risk increased across the ultrasonographic scores of steatosis ( n = 3 studies), but it appeared to be even greater among NAFLD patients with advanced high NAFLD fibrosis score ( n = 1 study; random-effects HR 4.74, 95% CI 3.54-5.94). Sensitivity analyses did not alter these findings. Funnel plot and Egger test did not reveal significant publication bias. Study limitations included high heterogeneity, varying degrees of confounder adjustment across individual studies, and lack of studies using liver biopsy., Conclusions: NAFLD is significantly associated with a twofold increased risk of incident diabetes. However, the observational design of the eligible studies does not allow for proving causality., (© 2018 by the American Diabetes Association.)

Objective: Several studies have explored the impact of diabetes on mortality in patients with heart failure (HF). However, the extent to which diabetes may confer risk of mortality and hospitalization in this patient population remains imperfectly known. Here we examine the independent prognostic impact of diabetes on the long-term risk of mortality and hospitalization in patients with HF., Research Design and Methods: PubMed, Scopus, and Web of Science from January 1990 to October 2016 were the data sources used. We included large ( n ≥1,000) observational registries and randomized controlled trials with a follow-up duration of at least 1 year. Eligible studies were selected according to predefined keywords and clinical outcomes. Data from selected studies were extracted, and meta-analysis was performed using random-effects modeling., Results: A total of 31 registries and 12 clinical trials with 381,725 patients with acute and chronic HF and 102,036 all-cause deaths over a median follow-up of 3 years were included in the final analysis. Diabetes was associated with a higher risk of all-cause death (random-effects hazard ratio [HR] 1.28 [95% CI 1.21, 1.35]), cardiovascular death (1.34 [1.20, 1.49]), hospitalization (1.35 [1.20, 1.50]), and the combined end point of all-cause death or hospitalization (1.41 [1.29, 1.53]). The impact of diabetes on mortality and hospitalization was greater in patients with chronic HF than in those with acute HF. Limitations included high heterogeneity and varying degrees of confounder adjustment across individual studies., Conclusions: This updated meta-analysis shows that the presence of diabetes per se adversely affects long-term survival and risk of hospitalization in patients with acute and chronic HF., (© 2017 by the American Diabetes Association.)

Objective: Diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) and death. Because the prevalence of diabetes is rising worldwide and chronic heart failure (CHF) is becoming increasingly common with the aging population, it is timely to examine the impact of diabetes per se on 1-year adverse outcomes in patients with CHF., Research Design and Methods: We prospectively assessed whether diabetes status independently affected the 1-year risk of all-cause and CVD mortality and first hospitalization for worsening heart failure (HF) in a multinational cohort of 9,428 outpatients with CHF enrolled in the European Society of Cardiology and Heart Failure Association Long-Term Registry., Results: Compared with those patients without diabetes, patients with diabetes ( n = 3,440, 36.5%) had higher cumulative rates of 1-year all-cause death (9.4% vs. 7.2%; adjusted hazard ratio [HR] 1.28; 95% CI 1.07-1.54), CVD death (4.8% vs. 3.8%; adjusted HR 1.28; 95% CI 0.99-1.66), and HF hospitalization (13.8% vs. 9.3%; adjusted HR 1.37; 95% CI 1.17-1.60), all independent of age, sex, BMI, smoking, systolic blood pressure, estimated glomerular filtration rate, hemoglobin, HF etiology, left ventricular ejection fraction, hypertension, statin use, and prior stroke or chronic obstructive pulmonary disease. Among CHF patients with HbA 1c measurements available at baseline ( n = 2,567), there was a significant and independent association between increasing HbA 1c levels and the risk of 1-year survival outcomes., Conclusions: The presence of diabetes markedly increases the risk of 1-year adverse clinical outcomes in outpatients with CHF independent of multiple common risk factors. More effective and personalized treatment for diabetes should be considered in this particularly high-risk patient population., (© 2017 by the American Diabetes Association.)

Objective: Recent studies have suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of heart rate-corrected QT interval prolongation and atrial fibrillation in patients with type 2 diabetes. Currently, no data exist regarding the relationship between NAFLD and ventricular arrhythmias in this patient population., Research Design and Methods: We retrospectively analyzed the data of 330 outpatients with type 2 diabetes without preexisting atrial fibrillation, end-stage renal disease, or known liver diseases who had undergone 24-h Holter monitoring for clinical reasons between 2013 and 2015. Ventricular arrhythmias were defined as the presence of nonsustained ventricular tachycardia (VT), >30 premature ventricular complexes (PVCs) per hour, or both. NAFLD was diagnosed by ultrasonography., Results: Compared with patients without NAFLD, those with NAFLD (n = 238, 72%) had a significantly higher prevalence of >30 PVCs/h (19.3% vs. 6.5%, P < 0.005), nonsustained VT (14.7% vs. 4.3%, P < 0.005), or both (27.3% vs. 9.8%, P < 0.001). NAFLD was associated with a 3.5-fold increased risk of ventricular arrhythmias (unadjusted odds ratio [OR] 3.47 [95% CI 1.65-7.30], P < 0.001). This association remained significant even after adjusting for age, sex, BMI, smoking, hypertension, ischemic heart disease, valvular heart disease, chronic kidney disease, chronic obstructive pulmonary disease, serum γ-glutamyltransferase levels, medication use, and left ventricular ejection fraction (adjusted OR 3.01 [95% CI 1.26-7.17], P = 0.013)., Conclusions: This is the first observational study to show that NAFLD is independently associated with an increased risk of prevalent ventricular arrhythmias in patients with type 2 diabetes., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: Cardiovascular autonomic diabetic neuropathy (CAN) is a serious complication of diabetes. No reliable data on the prevalence of CAN among patients with newly diagnosed type 2 diabetes are available. Therefore, the aim of this study was to estimate the prevalence of CAN among patients with newly diagnosed type 2 diabetes., Research Design and Methods: A cohort of 557 patients with newly diagnosed type 2 diabetes with cardiovascular autonomic test results available was selected. Early and confirmed neuropathy were assessed using a standardized methodology and their prevalences determined. A multivariate logistic regression analysis was modeled to study the factors associated with CAN., Results: In the entire cohort, the prevalence of confirmed CAN was 1.8%, whereas that of early CAN was 15.3%. Prevalence did not differ between men and women. In the multivariate analyses BMI results were independently and significantly associated with CAN after adjusting for age, sex, hemoglobin A1c, pulse pressure, triglyceride-to-HDL cholesterol ratio, kidney function parameters, and antihypertensive treatment., Conclusions: CAN could be detected very early in type 2 diabetes. This study may suggest the importance of performing standardized cardiovascular autonomic tests after diagnosis of type 2 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: There is no information about the role of nonalcoholic fatty liver disease (NAFLD) in predicting the development of chronic kidney disease (CKD) in type 1 diabetes., Research Design and Methods: We studied 261 type 1 diabetic adults with preserved kidney function and with no macroalbuminuria at baseline, who were followed for a mean period of 5.2 years for the occurrence of incident CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 and/or macroalbuminuria). NAFLD was diagnosed by ultrasonography., Results: At baseline, patients had a mean eGFR of 92 ± 23 mL/min/1.73 m2; 234 (89.7%) of them had normoalbuminuria and 27 (10.3%) microalbuminuria. NAFLD was present in 131 (50.2%) patients. During follow-up, 61 subjects developed incident CKD. NAFLD was associated with an increased risk of incident CKD (hazard ratio [HR] 2.85 [95% CI 1.59-5.10]; P < 0.001). Adjustments for age, sex, duration of diabetes, hypertension, A1C, and baseline eGFR did not appreciably attenuate this association (adjusted HR 2.03 [1.10-3.77], P < 0.01). Results remained unchanged after excluding those who had microalbuminuria at baseline (adjusted HR 1.85 [1.03-3.27]; P < 0.05). Addition of NAFLD to traditional risk factors for CKD significantly improved the discriminatory capability of the regression models for predicting CKD (e.g., with NAFLD c statistic 0.79 [95% CI 0.73-0.86] vs. 0.76 [0.71-0.84] without NAFLD, P = 0.002)., Conclusions: This is the first study to demonstrate that NAFLD is strongly associated with an increased incidence of CKD. Measurement of NAFLD improves risk prediction for CKD, independently of traditional cardio-renal risk factors, in patients with type 1 diabetes., (© 2014 by the American Diabetes Association.)

Objective: To compare the performance of two glomerular filtration rate (GFR)-estimating equations in predicting the risk of all-cause and cardiovascular mortality in type 2 diabetic patients., Research Design and Methods: We followed 2,823 type 2 diabetic outpatients for a period of 6 years for the occurrence of all-cause and cardiovascular mortality. GFR was estimated using the four-variable Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation., Results: At baseline, an estimated GFR (eGFR) <60 mL/min/1.73 m(2) was present in 22.0 and 20.2% of patients using the MDRD study equation and the CKD-EPI equation, respectively. A total of 309 patients died during the follow-up (152 patients from cardiovascular causes). Both creatinine-based equations were associated with an increased risk of all-cause and cardiovascular mortality. However, the CKD-EPI equation provided a more accurate risk prediction of mortality than the MDRD study equation. Receiving operating characteristic curves showed that the areas under the curve (AUCs) for all-cause mortality (AUC 0.712 [95% CI 0.682-0.741]) and cardiovascular mortality (0.771 [0.734-0.808]) using eGFR(CKD-EPI) were significantly greater (P < 0.0001 by the z statistic) than those obtained by using eGFR(MDRD) (0.679 [0.647-0.711] for all-cause mortality and 0.739 [0.698-0.783] for cardiovascular mortality)., Conclusions: Our findings suggest that the estimation of GFR using the CKD-EPI equation more appropriately stratifies patients with type 2 diabetes according to the risk of all-cause and cardiovascular mortality compared with the MDRD study equation.

Objective: To examine whether baseline pulse pressure (PP), a marker of arterial stiffness, is associated with subsequent development of atrial fibrillation (AF) in type 2 diabetes., Research Design and Methods: A total of 350 type 2 diabetic patients, who were free from AF at baseline, were followed for 10 years. A standard electrocardiogram was performed annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist., Results: During the follow-up, 32 patients (9.1% of total) developed incident AF. After adjustments for age, sex, BMI, diabetes duration, presence of left ventricular hypertrophy, hypertension treatment, kidney dysfunction, and pre-existing history of coronary heart disease, heart failure, and mild valvular disease, baseline PP was associated with an increased incidence of AF (adjusted odds ratio 1.76 for each SD increment [95% CI 1.1-2.8]; P < 0.01)., Conclusions: Our findings suggest that increased PP independently predicts incident AF in patients with type 2 diabetes.

Objective: To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals., Research Design and Methods: We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992-2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality., Results: At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1-4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9-17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality., Conclusions: Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.

Objective: There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals., Research Design and Methods: The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders., Results: During follow-up, 329 (12.1%) patients died, 44.1% (n = 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 [95% CI 1.12-1.27], P < 0.001) and cardiovascular (1.25 [1.16-1.34], P < 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 [1.01-1.61], P = 0.046), whereas the association of serum uric acid with all-cause mortality did not., Conclusions: Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures.

Objective: Nonalcoholic fatty liver disease (NAFLD) is closely associated with several metabolic syndrome features. We assessed whether NAFLD is associated with carotid artery intima-media thickness (IMT) as a marker of subclinical atherosclerosis and whether such an association is independent of classical risk factors, insulin resistance, and metabolic syndrome features., Research Design and Methods: We compared carotid IMT, as assessed by ultrasonography, in 85 consecutive patients with biopsy-proven NAFLD and 160 age-, sex-, and BMI-matched healthy control subjects., Results: NAFLD patients had a markedly greater carotid IMT (1.14 +/- 0.20 vs. 0.82 +/- 0.12 mm; P < 0.001) than control subjects. The metabolic syndrome (according to Adult Treatment Panel III criteria) and its individual components were more frequent in those with NAFLD (P < 0.001). The marked differences in carotid IMT observed between the groups were only slightly weakened after adjustment for age, sex, BMI, smoking history, LDL cholesterol, insulin resistance (by homeostasis model assessment), and metabolic syndrome components. Notably, carotid IMT was strongly associated with degree of hepatic steatosis, necroinflammation, and fibrosis among NAFLD patients (P < 0.001 for all). Similarly, by logistic regression analysis, the severity of histological features of NAFLD independently predicted carotid IMT (P < 0.001) after adjustment for all potential confounders., Conclusions: These results suggest that the severity of liver histopathology among NAFLD patients is strongly associated with early carotid atherosclerosis, independent of classical risk factors, insulin resistance, and the presence of metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is closely correlated to several metabolic syndrome features. We assessed prospectively whether NAFLD predicts future cardiovascular disease (CVD) events among type 2 diabetic individuals, independent of metabolic syndrome features and other classical risk factors. We carried out a prospective nested case-control study in 2,103 type 2 diabetic patients who were free of diagnosed CVD at baseline. During 5 years of follow-up, 248 participants (case subjects) subsequently developed nonfatal coronary heart disease (myocardial infarction and coronary revascularization procedures), ischemic stroke, or cardiovascular death. Using risk-set sampling, 496 patients (control subjects) among those who remained free of diagnosed CVD during follow-up were randomly selected in a 2:1 ratio, matched for age and sex to the case subjects. After adjustment for age, sex, smoking history, diabetes duration, HbA1c, LDL cholesterol, liver enzymes, and use of medications, the presence of NAFLD was significantly associated with an increased CVD risk (odds ratio 1.84, 95% CI 1.4-2.1, P < 0.001). Additional adjustment for the metabolic syndrome (as defined by National Cholesterol Education Program Adult Treatment Panel III criteria) appreciably attenuated, but did not abolish, this association (1.53, 1.1-1.7, P = 0.02). In conclusion, NAFLD is significantly associated with a moderately increased CVD risk among type 2 diabetic individuals. This relationship is independent of classical risk factors and is only partly explained by occurrence of metabolic syndrome.

Objective: To evaluate whether homeostasis model assessment-estimated insulin resistance (HOMA-IR) is an independent predictor of cardiovascular disease (CVD) in type 2 diabetes., Research Design and Methods: Conventional CVD risk factors (sex, age, smoking, plasma lipids, blood pressure, and metabolic control) and insulin resistance (estimated by HOMA) were evaluated at baseline in 1,326 patients with type 2 diabetes examined within the Verona Diabetes Complications Study. At baseline and after a mean follow-up of 4.5 years, CVD was assessed by medical history, physical examination, electrocardiography, and echo-Doppler of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were carefully scrutinized to identify cardiovascular deaths. In statistical analyses, CVD was an aggregate end point including both fatal and nonfatal coronary, cerebrovascular, and peripheral vascular disease as well as ischemic electrocardiographic abnormalities and vascular lesions identified by echo-Doppler., Results: At baseline, 441 subjects were coded positive for CVD (prevalent cases). Incident cases numbered 126. Multiple logistic regression analyses showed that, along with sex, age, smoking, HDL/total cholesterol ratio, and hypertension, HOMA-IR was an independent predictor of both prevalent and incident CVD. A 1-unit increase in (log)HOMA-IR value was associated with an odds ratio for prevalent CVD at baseline of 1.31 (95% CI 1.10-1.56, P = 0.002) and for incident CVD during follow-up of 1.56 (95% CI 1.14-2.12, P < 0.001)., Conclusions: HOMA-IR is an independent predictor of CVD in type 2 diabetes. The improvement of insulin resistance might have beneficial effects not only on glucose control but also on CVD in patients with type 2 diabetes.