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Aims: The natural history of diabetic complications, including diabetic retinopathy (DR), is changing due to improved care. This study aimed at assessing prevalence of advanced DR and its correlation with risk factors and complications in subjects with type 2 diabetes from the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study., Methods: This study enrolled 15,773 patients visiting consecutively 19 Diabetes Clinics in years 2007-2008. DR was assessed by dilated fundoscopy and classified according to the Global Diabetic Retinopathy Project Group., Results: Advanced DR was observed in 9.8% of patients (4.2% pre-proliferative, 4.2% proliferative, 1.3% maculopathy, 0.1% blindness). Advanced DR was independently associated with hemoglobin (Hb) A(1c), diabetes duration and treatment, particularly with insulin, hypertension, previous cardiovascular disease (CVD), albuminuria and, inversely, age, age at diabetes diagnosis, smoking and estimated glomerular filtration rate. Maculopathy alone was associated with female gender, but not HbA(1c), hypertension and age., Conclusions: We found an alarming high prevalence of advanced DR in subjects with type 2 diabetes from the RIACE cohort, suggesting that the expected favorable effect of improved diabetes management has not emerged yet. Independent correlates of advanced DR were indexes of glycemic exposure, hypertension, CVD, albuminuria and, inversely, age at diagnosis and smoking., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased prevalence of cardiovascular disease (CVD) in both non-diabetic and Type 2 diabetic individuals. We sought to examine whether NAFLD is associated with prevalent CVD in patients with Type 1 diabetes., Subjects and Methods: We studied 343 (156 men; mean age ~45 yr) consecutive Type 1 diabetic patients with and without NAFLD, which was diagnosed by ultrasonography. The presence of CVD was diagnosed by patient history, chart review, electrocardiogram, and echo-Doppler scanning of carotid and lower limb arteries., Results: Compared with those without steatosis, patients with ultrasound-diagnosed NAFLD (no.=182) had a remarkably greater age- and sex-adjusted prevalence of coronary (15.4 vs 1.2%, p<0.0001), cerebrovascular (41.7 vs 9.3%, p<0.0001) and peripheral (29.7 vs 6.2%, p<0.0001) vascular disease. A multivariable logistic regression analysis revealed that NAFLD was associated with an ~8-fold higher odds of CVD (composite endpoint), independently of age, sex, body mass index, family history of CVD, smoking status, physical activity, alcohol consumption, diabetes duration, glycated hemoglobin, systolic blood pressure, plasma lipids, estimated glomerular filtration rate, albuminuria, and use of anti-hypertensive, lipid-lowering and anti-platelet medications (adjusted odds ratio 7.6, 95% confidence intervals 3.6-24.0, p<0.001)., Conclusions: Our results demonstrate that NAFLD is associated with an increased prevalence of asymptomatic/symptomatic CVD in patients with Type 1 diabetes, independently of several established risk factors, including the components of metabolic syndrome.

Background and Objectives: This study examined predictors of the annual decline in estimated GFR (eGFR) in patients with type 2 diabetes and preserved kidney function., Design, Setting, Participants, & Measurements: In a prospective, observational cohort study, 1682 individuals with type 2 diabetes and baseline eGFR ≥60 ml/min per 1.73 m(2) (as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation) were followed for 10 years. Linear regression was used to estimate participants' changes in eGFR over time., Results: During follow-up, 263 (15.6%) individuals had a rapid eGFR decline defined as >4.0% per year. Average eGFR decline was -5.8 ± 3 and -0.6 ± 2 ml/min per 1.73 m(2) per year in rapid decliners and nondecliners, respectively. Compared with normotensive, normoalbuminuric patients (-0.2 ± 0.2 ml/min per 1.73 m(2) per year), those with hypertension (-1.0 ± 0.1 ml/min per 1.73 m(2) per year), hemoglobin A(1c)≥7% (-1.0 ± 0.1 ml/min per 1.73 m(2) per year), longer diabetes duration (-1.0 ± 0.1 ml/min per 1.73 m(2) per year), obesity (-1.2 ± 0.1 ml/min per 1.73 m(2) per year), insulin treatment (-1.5 ± 0.1 ml/min per 1.73 m(2) per year), microalbuminuria (-1.3 ± 0.2 ml/min per 1.73 m(2) per year), or macroalbuminuria (-2.7 ± 0.4 ml/min per 1.73 m(2) per year) had significantly faster age-adjusted annual eGFR declines. Multivariable linear regression analyses revealed that albuminuria (P<0.001) was the strongest predictor of annual eGFR decline. Other independent predictors of annual eGFR decline were older age, hypertension, insulin treatment, and lower baseline eGFR., Conclusions: Annual eGFR decline is predicted by multiple modifiable risk factors in patients with type 2 diabetes and preserved kidney function.

Background: Non-alcoholic fatty liver disease (NAFLD) and left ventricular hypertrophy (LVH) are highly prevalent in Type 2 diabetes and both conditions are associated with an increased risk of incident cardiovascular disease. The aim of this study is to evaluate whether there is an association between NAFLD and echocardiographically detected LVH in Type 2 diabetes., Methods: We studied 116 consecutive patients with hypertension and Type 2 diabetes after excluding those with pre-existing history of cardiovascular disease, advanced kidney disease, excessive alcohol consumption and other known causes of chronic liver disease (e.g., virus, medications, autoimmunity, iron overload). NAFLD was diagnosed by means of ultrasonography, whereas LVH was diagnosed by means of conventional trans-thoracic echocardiography in all patients., Results: The prevalence of LVH was markedly higher among diabetic patients with NAFLD than among those without this disease (82% vs 18%; p=0.01). Multivariate logistic regression analysis revealed that NAFLD was associated with LVH independently of age, sex, body mass index, systolic blood pressure, glycated hemoglobin, duration of diabetes, and parameters of kidney function., Conclusions: Our findings suggest that hypertensive Type 2 diabetic patients with NAFLD have a remarkably higher frequency of LVH than do hypertensive diabetic patients without steatosis, and that NAFLD is associated with LVH independently of classical cardiovascular risk factors and other potential confounders.

Aims: We determined whether non-alcoholic fatty liver is associated with an increased prevalence of chronic kidney disease in Type 1 diabetes., Methods: We studied 343 patients with Type 1 diabetes, who had no history of excessive alcohol consumption or other secondary causes of chronic liver disease. Non-alcoholic fatty liver was diagnosed by ultrasonography. Chronic kidney disease was defined as presence of either abnormal albuminuria (i.e., urinary albumin/creatinine ratio ≥ 30 mg/g) or estimated glomerular filtration rate of less than 60 ml min(-1)  1.73 m(-2) ., Results: Compared with those without steatosis, patients with non-alcoholic fatty liver (n = 182) had significantly lower estimated GFR (83.0 ± 27 vs. 93.3 ± 29 ml min(-1)  1.73 m(-2) , P < 0.001) and a greater prevalence of abnormal albuminuria (50.0 vs. 20.5%, P < 0.0001) and chronic kidney disease (54.4 vs. 24.2%, P < 0.0001). Multivariable logistic regression analysis revealed that non-alcoholic fatty liver was associated with an increased risk of either abnormal albuminuria (adjusted odds ratio 2.21, 95% CI 1.2-4.1, P = 0.01) or chronic kidney disease (adjusted odds ratio 1.93, 95% CI 1.1-3.6, P = 0.02), independently of age, gender, smoking status, physical activity, diabetes duration, HbA(1c) , BMI, systolic blood pressure, plasma lipids and use of anti-hypertensive and lipid-lowering medications., Conclusions: Our findings demonstrate that ultrasound-diagnosed non-alcoholic fatty liver is associated with a higher prevalence of chronic kidney disease in patients with Type 1 diabetes, independently of several risk factors, including the components of the metabolic syndrome., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

The purpose of this study was to evaluate whether a high triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio is associated with an increased incidence of retinopathy and chronic kidney disease (CKD) in type 2 diabetes mellitus. Individuals with type 2 diabetes mellitus (n = 979) with an estimated glomerular filtration rate greater than 60 mL/min and without retinopathy and cardiovascular disease at baseline were followed up for the incidence of diabetic retinopathy (diagnosed by retinography) and CKD (diagnosed by estimated glomerular filtration rate ≤60 mL/min/1.73 m(2)). On follow-up (mean, 4.9 years), 217 (22.2% of total) subjects experienced CKD and/or diabetic-specific retinal lesions (microvascular complication). Of these, 111 subjects developed isolated retinopathy, 85 developed CKD alone, and 21 developed both complications. The TG/HDL-C ratio was positively associated with an increased risk of incident retinopathy and/or CKD (composite microvascular end point) independently of age, sex, body mass index, diabetes duration, hemoglobin A(1c), hypertension, smoking history, low-density lipoprotein cholesterol, albuminuria, and current use of hypoglycemic, antihypertensive, lipid-lowering, or antiplatelet drugs (multivariable-adjusted odds ratio, 2.15; 95% confidence intervals, 1.10-4.25; P = .04). These findings suggested that the TG/HDL-C ratio was associated with an increased incidence of microvascular complications in individuals with type 2 diabetes mellitus without prior cardiovascular disease, independently of several potential confounders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The role of serum uric acid (UA) as a marker or risk factor of cardiovascular disease (CVD) is still controversial. The strong association of serum UA with established risk factors such as hypertension, Type 2 diabetes, dyslipidemia, and chronic kidney disease makes it difficult to establish a direct causal role of serum UA in the development and progression of CVD. The main aims of this review are: 1) to briefly summarize the most relevant studies concerning the association of serum UA with hypertension, chronic kidney disease, CVD events, and death both in patients without diabetes and in those with Type 2 diabetes; and 2) to briefly discuss the putative underlying mechanisms that link serum UA to adverse CVD outcomes. A search was conducted to identify relevant studies in the major electronic databases (MEDLINE and EMBASE, from January 1990 to December 2010) using Medical Subjects Headings and keywords. Collectively, by reviewing the published data in the literature, it emerges that serum UA may exert a number of potentially adverse cardiovascular effects. Nevertheless, the prognostic role of elevated serum UA level as a causal risk factor of adverse CVD outcomes remains still controversial, especially in patients with Type 2 diabetes. At this time, the treatment of asymptomatic hyperuricemia for the primary prevention of CVD is not recommended.

Background: We assessed the risk of coronary heart disease (CHD) in subjects with metabolic syndrome using different reference categories and focusing on the number of traits in the cluster., Methods: For 15 years, we followed 840 subjects from the general population living in Bruneck, northeastern Italy, aged 40-79 years, without CHD at baseline. Metabolic syndrome was diagnosed at baseline using American Heart Association/National Heart, Lung, and Blood Institute criteria. Subjects with the syndrome were compared to subjects without, as well as to subjects without any metabolic abnormality, using Cox models adjusted for sex, age, smoking, and low-density lipoprotein-cholesterol. There were 89 incident CHD cases., Results: In subjects with the metabolic syndrome, the risk of CHD was1.5-fold higher when subjects without the syndrome were the reference category. CHD risk, however, was 12.5-fold higher (95% confidence interval [CI], 1.7-92.7, P=0.014) when subjects without any metabolic abnormality composed the reference category. As compared to subjects with no abnormalities (who had a trivial number of CHD events), the risk increased from subjects with one (hazard ratio 7.6, 95% CI 1.0-56.5, P=0.047) to those with 2, 3, and 4/5 abnormalities (11.6, 1.6-84.9, P=0.016; 12.9, 1.7-96.0, P=0.013; and 10.1, 1.3-79.2, P=0.028), respectively., Conclusions: When compared to the reference category of people without any metabolic abnormality, those with the metabolic syndrome had high cardiovascular risk. However, in the Bruneck population, the risk of CHD seems to be similar in subjects having two or three to five clinical features of metabolic syndrome. Therefore, the clinical utility of identifying subjects with the syndrome using current diagnostic criteria remains uncertain and might be the focus of further specific studies.

Non-alcoholic fatty liver disease (NAFLD) is estimated to afflict ~20-30% of the general population, and over 70% of the patients with Type 2 diabetes. Given the expected rise in the prevalence of obesity and diabetes, NAFLD will be, if not already there, an epidemic. The consequences of NAFLD are numerous, and range from progression to chronic liver disease with its associated morbidity and mortality, to worsening insulin resistance and Type 2 diabetes, to being a contributor to both cardiovascular disease (CVD) and chronic kidney disease (CKD). NAFLD is, therefore, a complex problem with implications far beyond the liver. This review focuses on the rapidly expanding body of clinical evidence suggesting that NAFLD is associated with an increased prevalence and incidence of both CVD and CKD in patients with diabetes. This association appears to be independent of obesity, hypertension, and other potential confounding factors. However, given the heterogeneity and small number of observational studies, further research is urgently required to corroborate the prognostic role of NAFLD in the development and progression of CVD and CKD among patients with diabetes, and to further elucidate the complex and intertwined mechanisms that link NAFLD with these adverse outcomes.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a growing public health problem worldwide. Increasing recognition of the importance of NAFLD and its association with the features of the metabolic syndrome has stimulated an interest in its putative role in the development and progression of chronic kidney disease (CKD). Accumulating evidence suggests that NAFLD and CKD share many important cardio-metabolic risk factors and common pathogenetic mechanisms and that NAFLD is associated with an increased prevalence and incidence of CKD. This association appears to be independent of obesity, hypertension, and other potentially confounding factors, and it occurs both in patients without diabetes and in those with diabetes. Although further research is needed to establish a definitive conclusion, these observations raise the possibility that NAFLD is not only a marker of CKD but also might play a part in the pathogenesis of CKD, possibly through the systemic release of several pro-inflammatory/pro-coagulant mediators from the steatotic/inflamed liver or through the contribution of NAFLD itself to insulin resistance and atherogenic dyslipidemia. However, given the heterogeneity and small number of observational longitudinal studies, further research is urgently required to corroborate the prognostic significance of NAFLD for the incidence of CKD, and to further elucidate the complex and intertwined mechanisms that link NAFLD and CKD. If confirmed in future large-scale prospective studies, the potential adverse impact of NAFLD on kidney disease progression will deserve particular attention, especially with respect to the implications for screening and surveillance strategies in the growing number of patients with NAFLD., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: To assess all-cause and cardiovascular mortality in type 2 diabetic individuals according to estimated glomerular filtration rate (eGFR) and albuminuria., Methods and Results: We followed 2823 type 2 diabetic outpatients for a median period of 6 years for the occurrence of all-cause and cardiovascular mortality. eGFR was estimated using the abbreviated Modification of Diet in Renal Disease study equation. At baseline, an eGFR < 60 ml/min/1.73 m² and abnormal albuminuria were present in 22.5% and 26.0% of participants, respectively. During follow-up, a total of 309 patients died, 53% of deaths were secondary to cardiovascular causes. Risks of all-cause and cardiovascular mortality increased progressively with decreasing eGFR and increasing albuminuria. After adjustment for age, sex, body mass index, smoking, hypertension, diabetes duration, hemoglobin A1c, plasma lipids, medications use (hypoglycemic, anti-hypertensive, anti-platelet or lipid-lowering drugs) and albuminuria, the hazard ratios of all-cause and cardiovascular mortality per 1-SD decrease in eGFR were 1.53 (95%CI 1.2-2.0; p < 0.0001) and 1.51 (95%CI 1.05-2.2; p=0.023), respectively. A similar pattern in the risk of all-cause and cardiovascular mortality was seen for albuminuria (1.14, 1.01-1.3, p=0.028 and 1.19, 1.01-1.4, p=0.043 per 1-SD increase in albuminuria, respectively) after adjustment for eGFR and other potential confounders., Conclusions: These findings suggest that both decreasing eGFR and rising albuminuria are associated with all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of traditional risk factors and diabetes-related variables., (Copyright © 2009 Elsevier B.V. All rights reserved.)

This review summarizes current knowledge of the adverse effects of type 1 diabetes mellitus on coagulation and fibrinolysis. Although further larger studies are needed to provide more definitive information, patients with type 1 diabetes exhibit a proinflammatory/procoagulant condition deriving from increased platelet adhesiveness, activation of the coagulation system, and decreased plasma fibrinolytic potential. This review also focuses on recent data from large prospective studies suggesting a strong association between procoagulant imbalance and development of chronic vascular complications in people with type 1 diabetes. It is likely that a greater appreciation of the intimate interactions between endothelial integrity, coagulation and fibrinolytic factors, and platelets in type 1 diabetes will provide a greater understanding of the risk of developing cardiovascular disease and microvascular complications such as nephropathy and retinopathy in this patient population., (© Thieme Medical Publishers.)

Background and Objectives: We assessed whether nonalcoholic steatohepatitis (NASH) diagnosed by liver biopsy is associated with decreased kidney function and whether such association is independent of insulin resistance and features of the metabolic syndrome., Design, Settings, Participants, & Measurements: We enrolled 80 consecutive overweight patients with biopsy-proven NASH and 80 nonsteatotic control subjects who were matched for age, gender, and body mass index. Chronic kidney disease (CKD) was defined as the presence of estimated GFR (eGFR) of ≤60 ml/min per 1.73 m(2) and/or abnormal albuminuria (i.e., urinary albumin/creatinine ratio ≥30 mg/g)., Results: NASH patients had significantly (P < 0.001) lower eGFR (75.3 ± 12 versus 87.5 ± 6 ml/min per 1.73 m(2)) and a greater frequency of abnormal albuminuria (14 versus 2.5%) and CKD (25 versus 3.7%) than control subjects. The significant differences in eGFR, albuminuria, and CKD that were observed between the two groups were only slightly weakened after adjustment for age, gender, body mass index, smoking status, insulin resistance (by homeostasis model assessment), and components of the metabolic syndrome. Notably, histologic severity of NASH (i.e., fibrosis stage) was strongly associated with either decreasing eGFR or increasing albuminuria (P < 0.01 or less), independently of potential confounding factors., Conclusions: Our findings suggest that patients with biopsy-proven NASH have moderately decreased eGFR and a higher frequency of abnormal albuminuria and CKD than matched control subjects and that the severity of NASH histology is associated with decreased kidney function, independently of traditional risk factors, insulin resistance, and components of the metabolic syndrome.

Background & Aims: To estimate the prevalence of non-alcoholic fatty liver disease (NAFLD) in type 1 diabetic individuals, and to evaluate whether NAFLD is associated with increased prevalence of cardiovascular disease (CVD)., Methods: All patients with diagnosed type 1 diabetes with available liver ultrasound data (n=250), who regularly attended our diabetes clinic, were enrolled. Main study measures were detection of NAFLD (by patient history and liver ultrasound) and asymptomatic/symptomatic CVD (by patient history, chart review, electrocardiogram, and echo-Doppler scanning of carotid and lower limb arteries)., Results: The prevalence of NAFLD was 44.4%, and NAFLD was the most common cause (69.8%) of hepatic steatosis on ultrasound examination. Patients with NAFLD had a remarkably higher (p<0.001) age- and sex-adjusted prevalence of coronary (10.8% vs. 1.1%), cerebrovascular (37.3% vs. 5.5%) and peripheral (24.5% vs. 2.5%) vascular disease than their counterparts without NAFLD. In logistic regression analysis, NAFLD was associated with prevalent CVD (as composite endpoint), independently of age, sex, diabetes duration, hemoglobin A(1c), smoking history, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and medication use (adjusted odds ratio 7.36, 95% confidence intervals 1.60-34.3, p<0.01)., Conclusions: Our findings suggest that NAFLD is very common in type 1 diabetic subjects and is associated, independently of several confounding factors, with a higher prevalence of CVD. Future prospective studies are needed to evaluate whether NAFLD predicts incident CVD events in type 1 diabetes., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: An increased level of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been identified as an independent predictor for cardiovascular events in the general population and in some groups of high-risk patients, such as type 2 diabetes. The aim of this study was to evaluate whether a high TG/HDL-C ratio is associated with an increased risk of all-cause and cardiovascular mortality in type 2 diabetic subjects, and whether this risk is modified by the presence of kidney dysfunction., Methods: We followed 3084 type 2 diabetic outpatients for a mean period of 4.9 years for the occurrence of mortality. The independent association between the TG/HDL-C ratio and all-cause and cardiovascular mortality was analyzed by Cox proportional hazard models and adjusted for several potential confounders, including kidney function measures., Results: During follow-up, 356 (12%) participants died, 46% of whom from cardiovascular causes. Higher TG/HDL-C ratio (third vs. first tertile) was associated with an increased hazard ratio of all-cause (hazard ratio 1.51, CI 95% 1.13-2.00, p=0.005) and cardiovascular (hazard ratio 1.70, 1.12-2.59, p=0.015) mortality after adjustment for traditional risk factors, body mass index, hemoglobin A1c and medication use. After additional adjustment for renal function measures (estimated glomerular filtration rate or albuminuria), the association between the TG/HDL-C ratio and the risk of mortality was abolished., Conclusion: Our findings suggest that the predictive role of a high TG/HDL-C ratio in type 2 diabetes on cardiovascular and all-cause mortality might be largely mediated by the presence of kidney dysfunction., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Aims/hypothesis: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased prevalence of chronic kidney disease (CKD) and retinopathy in patients with type 2 diabetes. Information on this issue is lacking for type 1 diabetes. We evaluated whether NAFLD is associated with increased prevalence of retinopathy and CKD in type 1 diabetic patients., Methods: All type 1 diabetic patients (n = 202) who regularly attended our diabetes clinic and did not have any clinical evidence of cirrhosis or other secondary causes of chronic liver disease were studied. Main study measures were detection of NAFLD (by patient history and liver ultrasound), diabetic retinopathy (diagnosed by ophthalmoscopy) and CKD (defined as abnormal albuminuria or estimated GFR of < or =60 ml min(-1) 1.73 m(-2))., Results: The age- and sex-adjusted prevalence of diabetic retinopathy (53.2 vs 19.8%) and CKD (37.8 vs 9.9%) was markedly higher in patients with NAFLD than in those without (p < 0.0001). In multivariate logistic regression analysis, NAFLD was associated with prevalent retinopathy (adjusted OR 3.31, 95% CI 1.4-7.6, p = 0.005) or CKD (adjusted OR 3.90, 95% CI 1.5-10.1, p = 0.005). These associations were independent of age, sex, diabetes duration, HbA(1c), medication use and presence of the metabolic syndrome., Conclusions/interpretation: Our findings suggest that ultrasound-diagnosed NAFLD is associated, independently of several confounding factors, with a higher prevalence of CKD and retinopathy in type 1 diabetic individuals.

Objective: There is limited and controversial information on whether anaemia is a risk factor for cardiovascular mortality in type 2 diabetes, and whether this risk is modified by the presence of chronic kidney disease (CKD). We assessed the predictive role of lower hemoglobin concentrations on all-cause and cardiovascular mortality in a cohort of type 2 diabetic individuals., Methods: The cohort included 1153 type 2 diabetic outpatients, who were followed for a mean period of 4.9 years. The independent association of anaemia (i.e., hemoglobin <120 g/l in women and <130 g/l in men) with all-cause and cardiovascular mortality was evaluated by Cox proportional hazards regression models and adjusted for several potential confounders, including kidney function measures., Results: During follow-up, 166 (14.4%) patients died, 42.2% (n=70) of them from cardiovascular causes. In univariate analysis, anaemia was associated with increased risk of all-cause (hazard ratio HR 2.62, 95% confidence intervals 1.90-3.60, p<0.001) and cardiovascular mortality (HR 2.70, 1.67-4.37, p<0.001). After adjustment for age, sex, body mass index, smoking, hypertension, dyslipidemia, diabetes duration, hemoglobin A1c, medication use (hypoglycemic, anti-hypertensive, lipid-lowering and anti-platelet drugs) and kidney function measures, the association of anaemia with all-cause (adjusted HR 2.11, 1.32-3.35, p=0.002) and cardiovascular mortality (adjusted HR 2.23, 1.12-4.39, p=0.020) remained statistically significant., Conclusions: Anaemia is associated with increased risk of all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of the presence of CKD and other potential confounders. The advantage to treat anaemia in type 2 diabetes for reducing the risk of adverse cardiovascular outcomes remains to be demonstrated., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Abdominal obesity represents a public health concern because its prevalence is reaching epidemic proportions worldwide, and it is associated with an increased risk of cardiovascular morbidity and mortality and other pathological conditions. A large body of evidence suggests that abdominal obesity is associated with a prothrombotic tendency, which may, at least in part, contribute to the increased risk of atherothrombosis in these individuals. This review briefly summarizes the evidence of direct and indirect effects of the accumulation of excess lipid in visceral adipose tissue on coagulation and fibrinolysis. In addition, this article critically appraises the rapidly expanding body of experimental and clinical data that support a potential direct contribution for the accumulation of excess lipid in the liver (i.e., nonalcoholic fatty liver disease, a very frequent pathological condition in subjects with abdominal obesity) in the pathogenesis of the obesity-induced disorders of coagulation and fibrinolysis.

Purpose: Leprechaunism is a rare congenital syndrome caused by mutations of the insulin receptor gene, transmitted in an autosomal recessive pattern. Insulin growth factor-1 (IGF-1) treatment can be a therapeutic option in this syndrome by its insulin-like effects. Nevertheless, it is of note that IGF-1 has also an angiogenic activity., Methods: Fundus examination by ophthalmoscopy, fluorangiography, and laser treatment were performed., Results: A 17-year-old girl with leprechaunism, under treatment with high doses of insulin, presented a florid diabetic retinopathy. The large neovascularization of the disk regressed after treatment with argon laser panretinal photocoagulation. Five years after treatment, the patient maintained good vision., Conclusions: This clinical case is of interest for 2 reasons: 1) the large retinal neovascularization was likely due to the high insulin dosages; 2) this is the first case in which a sustained regression of retinal neovascularization has been observed after laser treatment in leprechaunism.

Objective: Increased serum C-reactive protein (CRP), an independent predictor of coronary heart disease, was reported in women with polycystic ovary syndrome (PCOS). It remains unclear whether this finding is due to the association between PCOS and either insulin resistance, obesity, or androgen excess, which are all common features of this condition. The aims of this study were to assess whether increased serum CRP is a specific feature of PCOS and to investigate the mechanisms underlying this association., Design and Methods: Serum high-sensitivity CRP (hs-CRP) was measured in 86 hyperandrogenic women (age 21.6+/-4.2 years, body mass index (BMI) 23.6+/-3.5 kg/m2), 50 with PCOS and 36 with idiopathic hyperandrogenism (HA). Thirty-five BMI-matched healthy women were also studied as controls. In these subjects, endocrine and metabolic profiles were assessed. In all hyperandrogenic subjects and 14 controls, insulin sensitivity was measured by the glucose clamp technique. Body fat was measured by bioelectrical impedance., Results: Hs-CRP concentrations were higher in PCOS women (3.43+/-2.01 mg/l) than in HA subjects and healthy women (2.43+/-1.04, P<0.005; and 2.75+/-0.86 mg/l, P<0.05 respectively versus PCOS). In multiple regression analyses, increased serum hs-CRP was independently predicted by higher body fat and lower insulin sensitivity. However, in lean women, serum-free testosterone was an additional, negative, predictive variable., Conclusions: PCOS is accompanied by a low-grade chronic inflammation. Body fat appears the main determining factor of this finding, which is only partly explained by insulin resistance. At least in lean women, androgen excess per se seems to play an additional, possibly protective, role in this association.

This review summarizes current knowledge of the effects of polycystic ovary syndrome, Cushing's syndrome, thyrotoxicosis, hypothyroidism, primary hyperparathyroidism, acromegaly, hypopituitarism, and growth hormone deficiency on coagulation and fibrinolysis. Several abnormalities of the coagulation-fibrinolytic system have been described among patients affected by these endocrine disorders. Although further larger studies are needed to provide more definitive information, clinically overt hypothyroidism appears to be associated with a bleeding tendency, whereas all other endocrine diseases appear to be associated with a thrombotic tendency. The disorders of coagulation and fibrinolysis observed in these endocrine pathologies usually range from mild to moderate and, rarely, to potentially severe laboratory abnormalities (e.g., bleeding diathesis in overt hypothyroidism mainly due to an acquired von Willebrand's syndrome type 1), are reversible after pharmacologic treatment of the hormonal dysfunction, and are usually of limited consequence in clinical practice. Nevertheless, the prompt recognition of potentially severe disorders of blood coagulation is mandatory for the correct management of these patients., ((c) Thieme Medical Publishers.)

Background/aims: Non-alcoholic fatty liver disease (NAFLD) and chronic plaque psoriasis are both associated with metabolic syndrome and increased risk of incident cardiovascular disease. We assessed the frequency and characteristics of NAFLD in patients with chronic plaque psoriasis., Methods: One hundred and thirty consecutive patients with chronic plaque psoriasis and 260 apparently healthy controls matched for age, sex and body mass index were enrolled. NAFLD was diagnosed by abdominal ultrasound after excluding other secondary causes of chronic liver disease., Results: The frequency of NAFLD was remarkably greater in psoriasis patients than in controls (47% vs. 28%; p<0.0001). Patients with psoriasis and NAFLD (n=61) were more likely to have metabolic syndrome and had higher serum C-reactive protein concentrations and greater severity of psoriasis according to the Psoriasis Area and Severity Index (PASI) score (14.2+/-12.6 vs. 9.6+/-7.4; p<0.01) than those with psoriasis alone (n=69). In a subgroup of psoriasis patients (n=43), those with NAFLD (n=21) also had significantly higher serum interleukin-6 and lower serum adiponectin levels. Notably, in multivariate regression analysis, NAFLD was associated with higher PASI score independently of age, gender, body mass index, psoriasis duration, and alcohol consumption., Conclusions: NAFLD is frequent in patients with chronic plaque psoriasis - affecting up to nearly half of these patients - and is strongly associated with psoriasis severity. Early recognition of NAFLD by radiological imaging tests in this group of patients is warranted.

Background and Aims: Type 2 diabetes is one of the most important risk factor for the development of chronic kidney disease (CKD). Recently, it has been shown that lower high-density lipoprotein cholesterol (HDL-C) levels predicted the development of microalbuminuria in type 2 diabetic individuals. We have prospectively assessed the effects of plasma HDL-C levels on the incidence of CKD in a large cohort of type 2 diabetic patients., Methods and Results: We followed 1987 type 2 diabetic outpatients with normal or near-normal kidney function at baseline for 5 years for the occurrence of incident CKD defined as glomerular filtration rate < or = 60 mL/min/1.73 m(2) (as estimated by the abbreviated Modified Diet and Renal Disease Study equation). Cox proportional hazards models were used to examine the independent relationship between plasma HDL-C levels and incident CKD. During a median follow-up of 5 years, 11.8% (n=234) of participants developed incident CKD. In multivariate regression analysis, higher HDL-C levels were associated with a lower risk of incident CKD (multiple-adjusted hazard ratio 0.76; 95% coefficient intervals 0.61-0.96; p=0.025) independently of age, gender, body mass index, hypertension, smoking history, diabetes duration, hemoglobin A1c, plasma triglycerides, LDL-cholesterol, presence of diabetic retinopathy, baseline albuminuria, and current use of medications (anti-hypertensive, anti-platelet, lipid-lowering and hypoglycemic drugs)., Conclusions: Higher plasma levels of HDL-C are associated with a lower risk of incident CKD in a large cohort of type 2 diabetic adults independently of numerous confounding factors.

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are both associated with insulin resistance.We assessed whether NAFLD is associated with impaired insulin sensitivity in PCOS women independently of age and total adiposity., Subjects and Methods: We enrolled 14 young PCOS women with NAFLD, 14 women with PCOS alone and 14 healthy controls, who were matched for age, body mass index, and total body fat (by bio-impedance analyzer). NAFLD was diagnosed by the surrogate measure of abnormal serum alanine aminotransferase (ALT) concentrations (defined as ALT>19 U/l) after excluding other secondary causes of liver disease (alcohol, virus, and medications). Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp., Results: Insulin sensitivity was markedly decreased (p<0.001) in PCOS women with abnormal ALT levels, whereas it was similar between PCOS women with normal ALT levels andmatched healthy controls (8.3+/-2.5 vs 12.1+/-1.7 vs 13.2+/-1.8 mg/min x kg of fat-free mass, respectively). PCOS women with abnormal ALT levels also had higher plasma triglycerides and lower HDLcholesterol concentrations than those with PCOS alone. There was a strong inverse association between serum ALT levels and insulin sensitivity in the whole group of PCOS women (r=-0.59, p=0.0013)., Conclusions: Abnormal serum ALT levels, as surrogate measure of NAFLD, are closely associated with impaired insulin sensitivity in young PCOS women in a manner that is independent from the contribution of age and total adiposity. Early recognition of NAFLD by radiological imaging tests in this group of young patients is warranted.

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.

Aims: Fasting plasma glucose variability strongly predicts the incidence of cardiovascular events in type 2 diabetic patients. We prospectively assessed whether fasting plasma glucose variability predicts the development/progression of retinopathy in a large cohort of type 2 diabetic outpatients., Methods: In the period 1996-1999, 1019 type 2 diabetic participants (aged 69+/-11 years) in the Verona Diabetes Study underwent at least 3 fasting plasma glucose (FPG) determinations and an eye examination by retinography. Of these, 746 underwent a 2nd eye examination in the period 2000-2004, while 273 did not (102 patients had died before undergoing the 2nd eye examination). For each patient, the mean (M-FPG) and the coefficient of variation of FPG (CV-FPG) were computed., Results: By the 2nd eye examination, 124 patients had either developed new retinopathy (79 patients) or progressed to a more severe degree of retinopathy (45 patients). In a multivariable logistic regression analysis, the development/progression of retinopathy was independently predicted by average glycaemia over time, expressed as glycated haemoglobin (odds ratio [OR] 1.82, 95%CI 1.40-2.38 for 1 SD increase) or M-FPG (OR 1.88, 1.47-2.41), but not by CV-FPG. Among other independent variables, HDL-cholesterol was inversely associated with the development/progression of retinopathy., Conclusions: These results suggest that in elderly type 2 diabetic patients the magnitude of hyperglycaemia, but not fasting plasma glucose variability, strongly predicts the development/progression of diabetic retinopathy independently of other known risk factors.

Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

Context: A strong independent association has been recently observed between elevated red blood cell distribution width (RDW) and increased incidence of cardiovascular events., Objective: To assess whether RDW is associated with plasma markers of inflammation since the mechanism(s) underlying this association remain unknown., Design: We retrospectively analyzed results of RDW, hemoglobin, mean corpuscular volume, ferritin, high-sensitivity C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) in a large cohort of unselected adult outpatients who were consecutively referred by general practitioners for routine medical check-up., Results: Cumulative results of RDW and other factors were retrieved from the database of our laboratory information system for 3845 adult outpatients during a 3-year period. When participants were grouped according to RDW quartiles, there were strong, graded increases of ESR and hsCRP (P < .001), both parameters being up to 3-fold higher in the fourth versus the first quartile. Accordingly, the percentages of those with hsCRP greater than 3 mg/L (from 28% to 63%; P < .001) and ESR greater than 40 mm/h (from 8% to 40%; P < .001) increased steadily across RDW quartiles. In multivariable regression analysis, ESR and hsCRP predicted RDW independently of age, sex, mean corpuscular volume, hemoglobin, and ferritin., Conclusions: To our knowledge, our study demonstrates for the first time a strong, graded association of RDW with hsCRP and ESR independent of numerous confounding factors. If confirmed in future follow-up studies, this association might provide a rationale to introduce the easy, inexpensive RDW in algorithms for cardiovascular risk prediction.

Background: The prevalence of thyroid autoimmunity and subclinical primary hypothyroidism in persons with chronic kidney disease (CKD) not requiring chronic dialysis is not well defined., Methods: We studied 1000 consecutive adult outpatients who were referred by their general practitioner for blood testing over the last 2 years. We excluded those with abnormal serum free thyroxine (FT4) levels (n=85). No participants required chronic renal replacement therapy. Thyroid autoimmunity was defined as increased concentrations of serum anti-thyroid antibodies. Subclinical primary hypothyroidism was defined as a serum thyrotropin (TSH) concentration >4 mIU/L. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2)., Results: Overall, 53 (5.8%) subjects had eGFR <60 mL/min/1.73 m(2). Of these, 98 (10.7%) had subclinical hypothyroidism, and 213 (23.3%) subjects had increased anti-thyroid antibodies. Approximately 26% and 34% of those with eGFR <60 mL/min/1.73 m(2) had laboratory evidence of subclinical hypothyroidism or thyroid autoimmunity, respectively. In subgroup analysis stratified by TSH and thyroid autoimmunity, decreasing eGFR values appeared to be more strongly related with the increase in TSH rather than antithyroid antibodies., Conclusions: Thyroid autoimmunity and subclinical primary hypothyroidism are highly prevalent in persons with CKD not requiring chronic dialysis.

Background: Ageing is characterized by a decreased functional reserve, a concept defined as homeostenosis. We assessed the impact of long-term exposure to the average value (mean) or to the variability (coefficient of variation) of fasting glycaemia, body mass index (BMI) and pulse pressure on total mortality in a cohort of type 2 diabetic patients., Methods: Fasting glycaemia, BMI and pulse pressure values were collected over a period of 3 years in 1 319 type 2 diabetic patients who were subsequently followed up for 10 years. For each patient, the means and the coefficients of variation of fasting glycaemia, BMI and pulse pressure were computed. The adverse impact of these risk factors on total mortality was assessed in patients aged < 65 years (n = 565) and in those aged > or = 65 years (n = 754), separately., Results: During the 10 years of follow-up, 438 patients died. In younger diabetic patients, the means of fasting glycaemia [hazard ratio (HR) of III tertile versus I tertile = 2.11, 95% confidence interval (CI): 1.22-3.64], BMI (HR = 1.88, 1.12-3.14) and pulse pressure (HR = 2.36, 1.34-4.16) were independently associated with total mortality, while in older patients they were not. In contrast, the coefficients of variation of glycaemia (HR = 1.56, 1.17-2.08), BMI (HR = 1.34, 1.03-1.75) and pulse pressure (HR = 1.34, 1.03-1.74) independently predicted total mortality only in older patients., Conclusions: Our findings suggest that the variability of fasting glycaemia, body weight and blood pressure (BP) is independently associated with an increased risk of all-cause mortality in older type 2 diabetic patients. Future studies are required to confirm the reproducibility of our findings., (Copyright 2008 John Wiley & Sons, Ltd.)

Background and Objectives: Subclinical primary hypothyroidism is highly prevalent in the general population, especially in the elderly. However, the prevalence of subclinical primary hypothyroidism in persons with chronic kidney disease (CKD) not requiring chronic dialysis is not well defined., Design, Setting, Participants, and Measurements: Cross-sectional data from 3089 adult outpatients, who were consecutively referred by general practitioners for routine blood testing over the last two years, were analyzed. Glomerular filtration rate (GFR) was estimated by the abbreviated Modification of Diet in Renal Disease equation. Multivariable logistic regression was used to evaluate the independent association between prevalent subclinical primary hypothyroidism and estimated GFR., Results: Among 3089 adult participants, 293 (9.5%) had subclinical primary hypothyroidism and 277 (9%) had an estimated GFR <60 ml/min per 1.73 m(2). The prevalence of subclinical primary hypothyroidism increased from 7% at an estimated GFR >or=90 ml/min per 1.73 m(2) to 17.9% at an estimated GFR <60 ml/min per 1.73 m(2) (P < 0.0001 for trend). Compared with participants with an estimated GFR >or=60 ml/min per 1.73 m(2), those with estimated GFR <60 ml/min per 1.73 m(2) had an increased odds of subclinical primary hypothyroidism after adjusting for age, gender, fasting plasma glucose, total cholesterol, and triglyceride concentrations., Conclusions: These findings suggest that subclinical primary hypothyroidism is a relatively common condition ( approximately 18%) among persons with CKD not requiring chronic dialysis, and it is independently associated with progressively lower estimated GFR in a large cohort of unselected outpatient adults.

It is unknown whether chronic kidney disease (CKD) is associated with nonalcoholic fatty liver disease among patients with type 2 diabetes. We followed 1760 outpatients with type 2 diabetes and normal or near-normal kidney function and without overt proteinuria for 6.5 yr for the occurrence of CKD (defined as overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m(2)). During follow-up, 547 participants developed incident CKD. Nonalcoholic fatty liver disease, diagnosed by liver ultrasound and exclusion of other common causes of chronic liver disease, was associated with a moderately increased risk for CKD (hazard ratio 1.69; 95% confidence interval 1.3 to 2.6; P < 0.001). Adjustments for gender, age, body mass index, waist circumference, BP, smoking, diabetes duration, glycosylated hemoglobin, lipids, baseline estimated GFR, microalbuminuria, and medications (hypoglycemic, lipid-lowering, antihypertensive, or antiplatelet drugs) did not appreciably attenuate this association (hazard ratio 1.49; 95% confidence interval 1.1 to 2.2; P < 0.01). In conclusion, our findings suggest that nonalcoholic fatty liver disease is associated with an increased incidence of CKD in individuals with type 2 diabetes, independent of numerous baseline confounding factors.

We assessed the differential contribution of nonalcoholic steatohepatitis (NASH) and visceral adiposity to nontraditional cardiovascular risk biomarkers in adult men. We enrolled 45 consecutive, overweight, male patients with biopsy-proven NASH, 45 overweight male patients without ultrasound-diagnosed hepatic steatosis, and 45 healthy male volunteers. All participants were matched for age; NASH and overweight patients were also matched for BMI and visceral adiposity (as estimated by abdominal ultrasonography). Nontraditional cardiovascular risk biomarkers were measured in all participants. Plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) activity, and adiponectin were markedly different among the groups; the lowest values (the highest for adiponectin) were in nonobese healthy subjects, intermediate in overweight nonsteatotic patients, and the highest (the lowest for adiponectin) in those with biopsy-proven NASH. The marked differences in these cardiovascular risk biomarkers that were observed between overweight and NASH patients were only slightly weakened after adjustment for age, BMI, smoking, plasma triglycerides, and insulin resistance (IR) as assessed by homeostasis model assessment (HOMA). In multivariate regression analysis, NASH and visceral adiposity predicted cardiovascular risk biomarkers independently of potential confounders. In conclusion, our results suggest that NASH can predict a more atherogenic risk profile in a manner that is partly independent from the contribution of visceral adiposity in adult men.

Aims/hypothesis: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease in type 2 diabetes. Currently, there is a lack of information on associations between NAFLD and microvascular complications of diabetes. We assessed the associations between NAFLD and both chronic kidney disease (CKD) and retinopathy in a large cohort of type 2 diabetic individuals using a cross-sectional design., Methods: Prevalence rates of retinopathy (by ophthalmoscopy) and CKD (defined as overt proteinuria and/or estimated GFR

Objective: Although overt thyroid dysfunction is associated with some liver abnormalities, there is a dearth of information on liver function tests across thyroid function tests. We assessed the relationship between serum liver enzyme activity and thyroid function tests in a cohort of adult individuals., Design, Patients and Measurements: We performed a retrospective analysis on the database of the Clinical Chemistry Laboratory at the Verona University Hospital to retrieve results of serum liver enzyme activities [alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT)] and thyroid function tests (TSH and free T4), which have been performed on the whole cohort of outpatient adults consecutively referred by general practitioners for routine blood testing during the last 3 years., Results: Cumulative results for serum GGT, ALT and TSH concentrations were retrieved for 10 292 (68.3% females) outpatient adults with a wide range of age and thyroid function tests. Subjects were categorized according to serum TSH concentrations as follows: < 0.1, 0.1-0.35, 0.36-4.5, 4.6-10 and >10 mU/l. Serum GGT and ALT concentrations increased steadily across the increasing TSH categories (P < 0.0001 for trends), ranging from mean values of 36 to 62 U/l for GGT and from 29 to 41 U/l for ALT, respectively. Similarly, there was a negative, graded, relationship between serum GGT and ALT concentrations and free T4 categories. The results did not change after adjusting for gender, age, lipids and fasting glucose concentrations., Conclusions: Our findings suggest that hypothyroidism and thyroid function tests, even within the reference range, are associated with slightly increased serum GGT and ALT activity concentrations.

Aims: We investigated the association of diabetic retinopathy with the risk of incident cardiovascular disease (CVD) events in a large cohort of Type 2 diabetic adults., Methods: Our study cohort comprised 2103 Type 2 diabetic outpatients who were free of diagnosed CVD at baseline. Retinal findings were classified based on fundoscopy (by a single ophthalmologist) to categories of no retinopathy, non-proliferative retinopathy and proliferative/laser-treated retinopathy. Outcomes measures were incident CVD events (i.e. non-fatal myocardial infarction, non-fatal ischaemic stroke, coronary revascularization procedures or cardiovascular death)., Results: During approximately 7 years of follow-up, 406 participants subsequently developed incident CVD events, whereas 1697 participants remained free of diagnosed CVD. After adjustment for age, body mass index, waist circumference, smoking, lipids, glycated haemoglobin, diabetes duration and medications use, patients with non-proliferative or proliferative/laser-treated retinopathy had a greater risk (P < 0.001 for all) of incident CVD events than those without retinopathy [hazard ratio 1.61 (95% confidence interval 1.2-2.6) and 3.75 (2.0-7.4) for men, and 1.67 (1.3-2.8) and 3.81 (2.2-7.3) for women, respectively]. After additional adjustment for hypertension and advanced nephropathy (defined as overt proteinuria and/or estimated glomerular filtration rate < or = 60 ml/min/1.73 m(2)), the risk of incident CVD remained markedly increased in those with proliferative/laser-treated retinopathy [hazard ratio 2.08 (1.02-3.7) for men and 2.41 (1.05-3.9) for women], but not in those with non-proliferative retinopathy., Conclusions: Diabetic retinopathy (especially in its more advanced stages) is associated with an increased CVD incidence independent of other known cardiovascular risk factors.

Objective: A strong, independent, association has recently been shown between higher red blood cell distribution width (RDW) and the risk of all-cause death and cardiovascular events. However, the mechanism(s) underlying this association remains unclear. Since impaired kidney function is a well-known risk factor for cardiovascular disease, we assessed whether RDW is associated with decreased kidney function., Material and Methods: We cross-sectionally assessed results of RDW, haemoglobin, main corpuscular volume (MCV) and serum creatinine levels in a large cohort of unselected adult outpatients consecutively referred by general practitioners for routine medical check-up. Glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) equation., Results: Cumulative results of RDW, creatinine and other variables were retrieved from the database of our Laboratory Information System for 8,585 adult outpatients over a 3-year period. When participants were grouped according to RDW quartiles, there was a strong, graded, decrease in estimated GFR levels (ranging from 87+/-18 to 81+/-32 mL/min/1.73 m(2); p<0.0001). Accordingly, the percentage of participants with estimated GFR<60 mL/min/1.73 m(2) increased steadily across RDW quartiles (from 5 % to 19 %; p<0.0001). In logistic regression analysis, lower estimated GFR strongly predicted higher RDW levels (p<0.0001) independently of age, gender, MCV and haemoglobin values., Conclusions: Our findings suggest that there is an inverse, graded, association between RDW and kidney function tests in a large cohort of unselected adult outpatients.

Aims: The purpose of the study was to determine long-term cardiovascular autonomic adaptation to moderate endurance aerobic exercise in people with Type 2 diabetes in order to test the hypothesis of an enhanced vagal drive., Methods: We analysed the power spectral density of heart rate cyclic variations at rest, while lying, and while standing in 12 sedentary, non-smoking, Type 2 diabetic individuals. Testing was performed before and after a 6-month, supervised, progressive, aerobic training programme, twice weekly. Heart rate variability was assessed by autoregressive power spectral analysis (PSA); this method allows reliable quantification of low-frequency (LF) and high-frequency (HF) components, which are considered to be under mainly sympathetic and purely parasympathetic control, respectively., Results: In 10-min electrocardiogram recordings, mean RR intervals values lying and standing were similar before and after physical exercise. Likewise, total heart rate variability, expressed as total power spectral density (PSD), was not altered by exercise. In contrast, on standing, the HF component, expressed in normalized units, was significantly higher (20.1 +/- 4 vs. 30.4 +/- 5, P < 0.01), whereas the LF component was significantly lower (68.1 +/- 7 vs. 49.8 +/- 8, P < 0.01) after exercise; hence, on standing, the LF/HF ratio, reflecting the sympathetic vs. parasympathetic balance, was markedly lower (16.2 +/- 11 vs. 5.2 +/- 3.2, P = 0.003). No significant exercise-related changes in these PSA components were observed on lying., Conclusions: A twice-weekly, 6-month, moderate, aerobic exercise programme, without a concomitant weight loss diet, is associated with significant improvements in cardiovascular autonomic function in overweight, non-smoking, Type 2 diabetic individuals.

Background/objective: Previous studies conducted both in the general and diabetic population have shown that pulse pressure (PP) can predict mortality from cardiovascular diseases. The aim of the present study was to investigate the relationship between PP and specific cardiovascular mortality, i.e. from cerebrovascular and ischemic heart diseases, in a well-characterized cohort of type 2 diabetic patients., Methods: A cohort of 1,128 known type 2 diabetic patients 56 to 74 years of age with at least 2 blood pressure measurements for each year between 1984-1986 was followed-up for ten years to assess specific causes of death. The analyses were carried out by using the mean and the coefficient of variation (CV) of PP., Results: By the end of the 10-year follow-up period, 375 patients (178 male, 197 female) had died (33%). The mean PP resulted as an independent predictor of all causes and cardiovascular mortality. Remarkably, the mean PP, but not the CV of PP, was highly predictive of mortality from cerebrovascular diseases. The risk of cerebrovascular mortality rose by 86% with a 10 mm Hg increase in mean PP. PP turned out to be the most important predictor of cerebrovascular mortality among various pressure indexes (mean, systolic and diastolic pressure)., Conclusion: The mean pulse pressure, but not the coefficient of variation is a strong predictor of cardiovascular mortality, mainly from cerebrovascular diseases, in type 2 diabetic patients., (Copyright 2007 S. Karger AG, Basel.)

Background and Aims: Some plasma biomarkers of inflammation and endothelial dysfunction have been recently recognized as important cardiovascular risk factors. Currently, there is little information about the effects of aerobic exercise training on these biomarkers in older adults with type 2 diabetes. We have therefore assessed the effects of a twice-weekly moderate, aerobic exercise programme, without a concomitant weight loss diet, on plasma inflammatory and endothelial dysfunction biomarkers in older type 2 diabetic patients., Methods and Results: A group of 16 sedentary, overweight, non-smoking, older patients with type 2 diabetes volunteered to participate in a 6-month, supervised, progressive, aerobic training study, two times per week. Plasma levels of hs-C-reactive protein (hs-CRP), soluble tumour necrosis factor (TNF)-alpha receptors, P-selectin and intercellular adhesion molecule-1 (ICAM-1) were measured before and after physical training. While hs-CRP and soluble TNF-alpha receptors remained essentially unaffected by physical training, plasma concentrations of P-selectin (P<0.001) and ICAM-1 (P<0.01) markedly decreased; physical training also increased HDL cholesterol by 12% (P<0.05) and decreased uric acid levels by approximately 33% (P=0.021). Body weight, waist circumference, blood pressure, haemoglobin A1c, plasma triglyceride and LDL cholesterol concentrations did not change. Interestingly, the exercise-induced changes in ICAM-1 and P-selectin levels remained significant after adjustment for the percent variations of body weight, waist circumference, haemoglobin A1c, HDL cholesterol and uric acid concentrations., Conclusions: A twice-weekly, 6-month, progressive aerobic-training programme, without a concomitant weight loss diet, is associated with significant decreases in circulating P-selectin and ICAM-1 levels and with a less atherogenic lipid profile in overweight, non-smoking, older type 2 diabetic individuals.

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.

Objectives: To explore associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease (NAFLD)., Design and Patients: In a cross-sectional study, we enrolled 60 consecutive NAFLD patients and 60 age-, sex- and body mass index (BMI)-matched healthy controls., Measurements: NAFLD (by liver biopsy), plasma adiponectin concentrations, insulin resistance (by homeostasis model assessment, HOMA-IR) and metabolic syndrome (MetS) features., Results: NAFLD patients had a marked decrease in plasma adiponectin concentration (6.1 +/- 2.8 vs. 13.6 +/- 3.8 microg/ml, P < 0.001) compared with matched controls. MetS, as defined by the Adult Treatment Panel III (ATP III) criteria, and its individual components were more frequent among NAFLD patients. The marked differences in adiponectin concentrations that were observed between the groups were little affected by adjustment for age, sex, BMI, HOMA-IR score and MetS components. Notably, decreased adiponectin levels were closely associated with the degree of hepatic steatosis, necroinflammation and fibrosis (P < 0.001 for all) among NAFLD patients. By logistic regression analysis, low adiponectin levels independently predicted hepatic steatosis [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.5-5.8, P < 0.001] and necroinflammation (OR 3.1, 95% CI 1.9-7, P < 0.001), but not fibrosis (P = 0.07), after adjustment for age, sex, BMI, HOMA-IR and MetS components., Conclusions: NAFLD patients have markedly lower plasma adiponectin concentrations than control subjects. Low adiponectin levels are strongly associated with the severity of liver histology, thus further supporting the hypothesis that adiponectin might be involved in the development of NAFLD.