Increased plasma markers of inflammation and endothelial dysfunction and their association with microvascular complications in type 1 diabetic patients without clinically manifest macroangiopathy.

Aims To evaluate whether plasma biomarkers of inflammation and endothelial dysfunction differed in Type 1 diabetic patients as compared with those in non-diabetic subjects, and to examine the association of these biomarkers with early stages of microvascular complications. Methods Plasma biomarkers of inflammation [fibrinogen, hs-C-reactive protein (hs-CRP)] and endothelial dysfunction [von Willebrand factor (v-WF), intercellular adhesion molecule-1, plasminogen activator inhibitor-1 (PAI-1) activity] were measured in 88 non-smoking young patients with Type 1 diabetes without clinical macrovascular disease and in 40 healthy controls. Results Plasma levels of hs-CRP, fibrinogen, v-WF, soluble intracellular adhesion molecule-1 (sICAM-1) and PAI-1 activity were markedly higher (P < 0.01 or less) in Type 1 diabetic patients than in healthy controls; these results were essentially unchanged when healthy controls were compared with patients without complications. After stratification by microvascular complication status, plasma biomarkers of inflammation and endothelial dysfunction were significantly increased in those with more advanced disease compared with those with early complications or without complications, respectively. However, while the significant differences in these biomarkers were little affected by adjustment for sex, age, BMI and blood pressure values, they were totally abolished after additional adjustment for diabetes duration and glycaemic control. Conclusions These results indicate that in Type 1 diabetes there is a subclinical, chronic inflammation which is, at least partly, independent of clinically manifest macro- and microvascular complications, smoking or other traditional cardiovascular risk factors; this subclinical inflammation is closely correlated to the magnitude and duration of hyperglycaemia

Relationship of nonalcoholic hepatic steatosis to cortisol secretion in diet-controlled type 2 diabetic patients.

AimsTo examine the association of non-alcoholic hepatic steatosis (HS) withthe activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabeticindividuals.MethodsThe activity of the HPA axis, as measured by 24-h urinary free cortisol(UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, wasmeasured in 40 diet-controlled, predominantly overweight, Type 2 diabeticpatients with non-alcoholic HS and in 40 diabetic patients without HS whowere comparable for age, sex and body mass index (BMI).ResultsSubjects with non-alcoholic HS had significantly higher 24-h UFCexcretion (191\ub14 vs. 102\ub13 nmol/24 h;P< 0.001) and post-dexamethasonecortisol concentrations (29.1\ub12 vs. 14.4\ub11 nmol/ l;P< 0.001) than thosewithout HS. Patients with HS had significantly higher values for HOMA insulinresistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist\u2013hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressurevalues were not different between the groups. The differences in urinaryand serum cortisol concentrations between the groups remained significant afteradjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasmatriglycerides, HbA1cand liver enzymes. In multiple logistic regression analyses,24-h UFC or serum cortisol concentrations (P <0.05 andP= 0.02, respectively),along with age and HOMA insulin resistance, predicted the presence of HS,independently of potential confounders.ConclusionsThese results demonstrate that non-alcoholic HS is closely associatedwith a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2diabetic individuals

NON-ALCOHOLIC HEPATIC STEATOSIS AND ITS RELATION TO INCREASED PLASMA BIOMARKERS OF INFLAMMATION AND ENDOTHELIAL DYSFUNCTION IN NON-DIABETIC MEN. ROLE OF VISCERAL ADIPOSE TISSUE.

Aims To compare plasma biomarkers of inflammation and endothelial dysfunction in individuals with and without non-alcoholic hepatic steatosis (HS), and to evaluate whether such differences were mediated by the adverse metabolic pattern, typically found in these subjects. Methods HS (by ultrasound and computed tomography), visceral fat (by computed tomography), insulin resistance (by homeostasis model assessment-HOMA), plasma biomarkers of inflammation and endothelial dysfunction (hs-C reactive protein, fibrinogen, von Willebrand factor, plasminogen activator inhibitor-1 activity) were measured in 100 non-smoking, healthy, male volunteers. Results Plasma hs-CRP, fibrinogen, v-WF and plasminogen activator inhibitor-1 (PAI-1) activity levels were markedly higher (P < 0.01 or less) in subjects with non-alcoholic HS (n = 35) than in those without HS (n = 65). The former also had significantly higher values for body mass index (BMI), visceral fat, diastolic blood pressure, HOMA insulin resistance score, plasma insulin (both fasting and after glucose load), triglycerides, liver enzymes, and lower high-density lipoprotein (HDL)-cholesterol concentration. While the marked differences in these pro-inflammatory biomarkers observed between the groups were little affected by adjustment for age, BMI, blood pressure values, HOMA insulin resistance score, plasma triglyceride and liver enzyme concentrations, they were completely abolished after controlling for visceral fat. Similarly, in multivariate regression analyses, increased visceral fat significantly predicted the pro-inflammatory biomarkers, independently of HS and other potential confounders. Conclusions These results indicate that, in non-smoking, non-diabetic men, the significant increase of plasma biomarkers of inflammation and endothelial dysfunction in the presence of non-alcoholic HS is largely mediated by abdominal visceral fat accumulation

Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease.

Objectives To assess associations between the activity of hypothalamo-pituitary-adrenal (HPA) axis and liver histology in patients with nonalcoholic fatty liver disease (NAFLD). Design and patients In a cross-sectional study, we enrolled 50 consecutive, overweight, NAFLD patients and 40 control subjects who were comparable for age, sex and body mass index (BMI). Measurements NAFLD (by liver biopsy), HPA axis activity (by 24-hour urinary free cortisol [UFC] excretion and serum cortisol levels after 1 mg dexamethasone), insulin resistance (by homeostasis model assessment: HOMA-IR), and metabolic syndrome (MetS) features. Results NAFLD patients had markedly higher (P < 0.001) 24-h UFC (149 +/- 24 vs. 90 +/- 16 nmol/day) and postdex suppression cortisol concentrations (32 +/- 10 vs. 16 +/- 7 nmol/l) than controls. The MetS and its individual components were more frequent among NAFLD patients. The marked differences in urinary/serum cortisol concentrations that were observed between the groups were little affected by adjustment for age, sex, BMI, waist circumference, systolic blood pressure, triglycerides, homeostasis model assessment for insulin resistance score and presence of diabetes. Importantly, 24-h UFC and postdex cortisol concentrations strongly correlated to hepatic necroinflammatory grade (P < 0.01) and fibrosis stage (P < 0.001) among NAFLD patients. By logistic regression analysis, 24-h UFC (odds ratio (OR) 1.80, 95%CI 1.3-2.8) or postdex cortisol concentrations (OR 1.95, 95%CI 1.4-3.1) independently predicted the severity of hepatic fibrosis, but not necroinflammation, after adjustment for potential confounders. Conclusions These results suggest that NAFLD patients have a subtle, chronic overactivity in the HPA axis (that is closely associated with the severity of liver histopathology) leading to subclinical hypercortisolism that might be implicated in the development of NAFLD

Plasma homocysteine levels are associated with von Willebrand factor, soluble intercellular adhesion molecule-1, and soluble tumor necrosis factor-alpha receptors in young type 1 diabetic patients without clinical evidence of macrovascular complications

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Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis healthy men. Role of visceral fat accumulation.

Nonalcoholic fatty liver disease(NAFLD) is a clinicopathologicalsyndrome that is closely associatedwith obesity, dyslipidemia, insulin resistance,and type 2 diabetes, thus suggestingthat NAFLD represents anothercomponent of the metabolic syndrome(1,2). Because it is now recognized thatindividuals with the metabolic syndromeare at increased cardiovascular risk (3\u20135),it is possible to hypothesize that NAFLDpatients might portend a greater cardiovasculardisease (CVD) risk. Ultrasonographicallymeasured carotid intimamediathickness (CIMT), as a reliableindex of subclinical atherosclerosis (6),can be used to characterize the CVD riskof patients with NAFLD. However, theavailable data on this specific topic arelacking.We compared CIMT values in subjectswith and without nonalcoholic hepaticsteatosis (HS) and examinedwhether such differences were mediatedby one or more metabolic disorders typicallyclustering in these subjects

Cigarette smoking and plasma total homocysteine levels in young adults with type 1 diabetes

OBJECTIVE - The purposes of this study were to compare plasma total homocysteine (tHcy) levels, a recognized cardiovascular risk factor, in nondiabetic subjects and type I diabetic patients, and to evaluate whether chronic cigarette smoking had a deleterious effect on plasma tHcy levels in type 1 diabetic patients. RESEARCH DESIGN AND METHODS - Plasma tHcy concentrations were measured in 60 young type 1 diabetic patients without clinical evidence of macroangiopathy and in 30 healthy control subjects who were matched for age, sex, BMI, and smoking habit. RESULTS - Plasma tHcy levels were significantly higher in type I diabetic patients than in control subjects (12.5 +/- 4.8 vs. 10.3 +/- 2.2 mu mol/l, P = 0.01). After stratification by smoking status, diabetic smokers had values for age, sex, BMI, lipids, creatinine, blood pressure, glycometabolic control, diabetes duration, and microvascular complications that were superimposable on their nonsmoking counterparts. Nevertheless, plasma tHcy levels were markedly elevated in diabetic smokers Versus nonsmokers (15.5 +/- 5.7 vs. 10.6 +/- 3 mu mol/l, P < 0.0001) in a dose-dependent fashion (P < 0.0001, by analysis of variance when subjects were categorized for the number of cigarettes smoked daily). CONCLUSIONS - Chronic cigarette smoking seems to adversely affect plasma tHcy levels in young adults with type I diabetes

Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients.

Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD)is associated with an increased risk of cardiovascular diseasein type 2 diabetes. Currently, there is a lack of informationon associations between NAFLD and microvascular complicationsof 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 6460 ml min 121 1.73 m 122) were assessed in 2,103 type 2diabetic individuals who were free of diagnosed cardiovasculardisease and viral hepatitis. NAFLD was ascertained by patient history, blood sampling and liver ultrasound.Results NAFLD patients had higher (p<0.001) age- andsex-adjusted prevalence rates of both non-proliferative (39vs 34%) and proliferative/laser-treated retinopathy (11 vs5%), and CKD (15 vs 9%) than counterparts without NAFLD.In logistic regression analysis, NAFLD was associated withincreased rates of CKD (odds ratio 1.87; 95% CI 1.3\u20134.1,p=0.020) and proliferative/laser-treated retinopathy (oddsratio 1.75; 1.1\u20133.7, p=0.031) independently of age, sex,BMI, waist circumference, hypertension, diabetes duration,HbA1c, lipids, smoking status and medications use.Conclusions/interpretation Our findings suggest that NAFLDis associated with an increased prevalence of CKD and proliferative/laser-treated retinopathy in type 2 diabetic individuals independently of numerous baseline confounding factors. Further studies are required to confirm the eproducibilityof these results and to evaluate whether NAFLD contributes to the development or progression of CKD and retinopathy

Diabetic retinopathy is associated with an increased incidence of cardiovascular events in type 2 diabetic patients.

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 64 60 ml/min/1.73 m2), 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.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 64 60 ml/min/1.73 m2), 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. \ua9 2008 The Authors

Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients.

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 6460 ml min 121 1.73 m 122). 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 patientswithNAFLD than in thosewithout (p<0.0001). In multivariate logistic regression analysis, NAFLD was associated with prevalent retinopathy (adjusted OR 3.31, 95% CI 1.4\u20137.6, p=0.005) or CKD (adjusted OR 3.90, 95% CI 1.5\u201310.1, p=0.005). These associations were independent of age, sex, diabetes duration, HbA1c, 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