Insulin resistance and beta-cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10.

AIMS: We investigated quantitative expression, mutual aggregation and relation with hyperglycemia of insulin resistance (IR) and beta-cell dysfunction (BCD) in newly diagnosed type 2 diabetes. METHODS: We assessed IR with euglycemic hyperinsulinemic clamp and BCD with modelled glucose/C-peptide response to oral glucose in 729 mostly drug-naïve patients. We measured glycated hemoglobin, pre-prandial, post-prandial and meal-related excursion of blood glucose. RESULTS: IR was found in 87.8% [95% confidence intervals 85.4-90.2] and BCD in 90.0% [87.8-92.2] of subjects, ranging from mild to moderate or severe. Approximately 20% of subjects had solely one defect: BCD 10.8% [8.6-13.1] or IR 8.6% [6.6-10.7]. Insulin resistance and BCD aggregated in most subjects (79.1% [76.2-82.1]). We arbitrarily set nine possible combinations of mild, moderate or severe IR and mild, moderate or severe BCD, finding that each had a similar frequency (∼10%). In multiple regression analyses parameters of glucose control were related more strongly with BCD than with IR. CONCLUSIONS: In newly-diagnosed type 2 diabetes, IR and BCD are very common with a wide range of expression but no specific pattern of aggregation. Beta-cell dysfunction is likely to play a greater quantitative role than IR in causing/sustaining hyperglycemia in newly-diagnosed type 2 diabetes.

Association of nonalcoholic fatty liver disease with QTc interval in patients with type 2 diabetes.

BACKGROUND AND AIMS: The relationship between nonalcoholic fatty liver disease (NAFLD) and prolonged heart rate-corrected QT (QTc) interval, a risk factor for ventricular arrhythmias and sudden cardiac death, is currently unknown. We therefore examined the relationship between NAFLD and QTc interval in patients with type 2 diabetes. METHODS AND RESULTS: We studied a random sample of 400 outpatients with type 2 diabetes. Computerized electrocardiograms were performed for analysis and quantification of QTc interval. NAFLD was diagnosed by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases. Mean QTc interval and the proportion of those with increased QTc interval (defined as either QTc interval above the median, i.e. ≥416 ms, or QTc interval >440 ms) increased steadily with the presence and ultrasonographic severity of NAFLD. NAFLD was associated with increased QTc interval (odds ratio [OR] 2.16, 95% CI 1.4-3.4, p < 0.001). Adjustments for age, sex, smoking, alcohol consumption, BMI, hypertension, electrocardiographic left ventricular hypertrophy, diabetes-related variables and comorbid conditions did not attenuate the association between NAFLD and increased QTc interval (adjusted-OR 2.26, 95% CI 1.4-3.7, p < 0.001). Of note, the exclusion of those with established coronary heart disease or peripheral artery disease from analysis did not appreciably weaken this association. CONCLUSION: This is the first study to demonstrate that the presence and severity of NAFLD on ultrasound is strongly associated with increased QTc interval in patients with type 2 diabetes even after adjusting for multiple established risk factors and potential confounders.

Non-alcoholic fatty liver disease is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes.

NAFLD (non-alcoholic fatty liver disease) and AF (atrial fibrillation) are two pathological conditions that are highly prevalent in developed countries and share multiple risk factors. The relationship between NAFLD and AF in Type 2 diabetes is currently unknown. We studied a hospital-based sample of 702 patients with Type 2 diabetes discharged from our Division of Endocrinology during 2007-2011. The diagnosis of AF was confirmed in affected participants on the basis of ECGs and medical history by experienced cardiologists. NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases. Of the 702 hospitalized patients included in the study, 514 (73.2%) of them had NAFLD and 85 (12.1%) had persistent or permanent AF. NAFLD was associated with an increased risk of prevalent AF {OR (odds ratio), 3.04 [95% CI (confidence interval), 1.54-6.02]; P<0.001}. Adjustments for age, sex, systolic BP (blood pressure), HbA1c, (glycated haemoglobin), estimated GFR (glomerular filtration rate), total cholesterol, electrocardiographic LVH (left ventricular hypertrophy), COPD (chronic obstructive pulmonary disease), and prior history of HF (heart failure), VHD (valvular heart disease) or hyperthyroidism did not attenuate the association between NAFLD and AF [adjusted OR, 5.88 (95% CI, 2.72-12.7); P<0.001]. In conclusion, our results show that ultrasound-diagnosed NAFLD is strongly associated with an increased prevalence of persistent or permanent AF in patients with Type 2 diabetes, independently of several clinical risk factors for AF. The potential impact of NAFLD on AF deserves particular attention, especially with respect to the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

Vitamin D, thrombosis, and hemostasis: more than skin deep.

Vitamin D(3) deficiency is a highly prevalent condition worldwide. Clinically, vitamin D(3) has a key role in calcium homeostasis and bone mineralization and has recently been implicated in the pathogenesis and/or progression of several acute and chronic illnesses, including cardiovascular disease (CVD). Accumulating evidence from observational, prospective studies suggests that low levels of serum 25-hydroxyvitamin D(3) are independently associated with an increased risk of CVD events and death. The molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a cardiovascular role for the active metabolite of vitamin D(3). 1-α,25-dihydroxyvitamin D(3) regulates the renin-angiotensin system, suppresses proliferation of vascular cell smooth muscle, improves insulin resistance and endothelial cell-dependent vasodilation, inhibits myocardial cell hypertrophy, exerts anticoagulant and antifibrotic activity, and modulates macrophage activity and cytokine generation. Overall, the high prevalence of vitamin D(3) deficiency and the plausible biological mechanisms linking this to CVD risk suggest that the treatment of vitamin D(3) deficiency to prevent CVD is a promising field to explore. Large placebo-controlled randomized clinical trials are urgently needed to determine whether vitamin D supplementation could have any potential benefit in reducing future CVD events and mortality risk.

Glomerular filtration rate decline in T2DM following diagnosis. The Verona newly diagnosed diabetes study-12.

AIMS: Nephropathy is a complication of type 2 diabetes, with increased albuminuria and reduced glomerular filtration rate (GFR) as biomarkers. Rates of progression to end-stage-renal disease are variable among patients. In this study we have examined the GFR decline in newly diagnosed T2DM. METHODS: A cohort of 410 patients with newly diagnosed T2DM and with at least four serum creatinine during the follow-up period were recruited. A linear model was used to calculate the decline in eGFR. A multivariable logistic model was used to identify independent predictors of rapid eGFR decline. RESULTS: Average follow-up was 12.4 years. The eGFR change was -0.80 ±â€¯2.23 ml/min/1.73 m2 per year. Patients were arbitrarily stratified into rapid decliners (≤-3.0 ml/min/1.73 m2 per year), moderate decliners (-2.9/-1 ml/min/1.73 m2 per year) and slow/no decliners (>-1.0 ml/min/1.73 m2 per year). Subjects in the 3 categories were 11.4%, 27.3%, and 61.3%, respectively. Albuminuria was the stronger predictor of rapid eGFR decline. CONCLUSIONS: A rapid decline in eGFR occurs in approximately 1 out of 10 newly diagnosed subjects. This rapid decline can be predicted by widely accessible clinical features, such as albuminuria. Identification of rapid decliners may help to reduce progression toward advanced stages of nephropathy.

Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes.

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.

Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9.

INTRODUCTION: We explored the presence of chronic complications in subjects with newly diagnosed type 2 diabetes referred to the Verona Diabetes Clinic. Metabolic (insulin secretion and sensitivity) and clinical features associated with complications were also investigated. RESEARCH DESIGN AND METHODS: The comprehensive assessment of microvascular and macrovascular complications included detailed medical history, resting ECG, ultrasonography of carotid and lower limb arteries, quantitative neurological evaluation, cardiovascular autonomic tests, ophthalmoscopy, kidney function tests. Insulin sensitivity and beta-cell function were assessed by state-of-the-art techniques (insulin clamp and mathematical modeling of glucose/C-peptide curves during oral glucose tolerance test). RESULTS: We examined 806 patients (median age years, two-thirds males), of whom prior clinical cardiovascular disease (CVD) was revealed in 11.2% and preclinical CVD in 7.7%. Somatic neuropathy was found in 21.2% and cardiovascular autonomic neuropathy in 18.6%. Retinopathy was observed in 4.9% (background 4.2%, proliferative 0.7%). Chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) was found in 8.8% and excessive albuminuria in 13.2% (microalbuminuria 11.9%, macroalbuminuria 1.3%).Isolated microvascular disease occurred in 30.8%, isolated macrovascular disease in 9.3%, a combination of both in 9.1%, any complication in 49.2% and no complications in 50.8%.Gender, age, body mass index, smoking, hemoglobin A1c and/or hypertension were independently associated with one or more complications. Insulin resistance and beta-cell dysfunction were associated with macrovascular but not microvascular disease. CONCLUSIONS: Despite a generally earlier diagnosis for an increased awareness of the disease, as many as ~50% of patients with newly diagnosed type 2 diabetes had clinical or preclinical manifestations of microvascular and/or macrovascular disease. Insulin resistance might play an independent role in macrovascular disease. TRIAL REGISTRATION NUMBER: NCT01526720.

Hemostatic and fibrinolytic abnormalities in endocrine diseases: a narrative review.

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.

Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.

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.

Prevalence of thyroid autoimmunity and subclinical hypothyroidism in persons with chronic kidney disease not requiring chronic dialysis.

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.

Long-Acting GLP-1 Receptor Agonist Exenatide Influence on the Autonomic Cardiac Sympatho-Vagal Balance.

Long-acting glucagon-like peptide 1 receptor agonists are increasingly used to treat type 2 diabetes. An increase of heart rate (HR) has been observed with their use. To elucidate the role of the cardiac sympatho-vagal balance as a possible mediator of the reported increase in HR, we performed power spectral analysis of HR variability (HRV) in patients receiving exenatide extended-release (ER). Twenty-eight ambulatory patients with type 2 diabetes underwent evaluation at initiation of exenatide-ER and thereafter at 3 and at 6 months. To obtain spectral analyses of HRV, a computerized acquisition of 10 minutes of RR electrocardiogram intervals (mean values of ~700 RR intervals) were recorded both in lying and in standing positions. All patients showed a substantial increase of HR both in lying and in standing positions. Systolic blood pressure, body weight, and glycated hemoglobin A1c significantly decreased both at 3 and 6 months compared with basal levels. The low-frequency/high-frequency ratio varied from 3.05 ± 0.4 to 1.64 ± 0.2 (P < 0.001) after 3 months and to 1.57 ± 0.3 (P < 0.001) after 6 months in a lying position and from 4.56 ± 0.8 to 2.24 ± 0.3 (P < 0.001) after 3 months and to 2.38 ± 0.4 (P < 0.001) after 6 months in a standing position compared with basal values, respectively. HR variations, induced by exenatide-ER treatment, do not appear to be related to sympathetic autonomic tone. Of note, we observed a relative increase of vagal influence on the heart.

Relation of elevated serum uric acid levels to first-degree heart block and other cardiac conduction defects in hospitalized patients with type 2 diabetes.

AIMS: Several studies have reported that moderately elevated serum uric acid levels are associated with an increased risk of tachyarrhythmias (mainly atrial fibrillation) in patients with and without type 2 diabetes mellitus (T2DM). It is currently unknown whether an association also exists between elevated serum uric acid levels and cardiac conduction defects in patients with T2DM. METHODS: We retrospectively analyzed a hospital-based sample of 967 patients with T2DM discharged from our Division of Endocrinology over the years 2007-2014. Standard electrocardiograms were performed on all patients and were interpreted by expert cardiologists. RESULTS: Overall, 267 (27.6%) patients had some type of conduction defects on electrocardiograms (defined as at least one block among first-degree atrio-ventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block). Patients in the 3rd serum uric acid tertile had a higher prevalence of any cardiac conduction defects than those belonging to 2nd or 1st tertile, respectively (35.8% vs. 25.0% vs. 22.6%; p<0.0001). Elevated serum uric acid levels were associated with a nearly twofold increased risk of cardiac conduction defects after adjustment for age, sex, hemoglobin A1c, diabetes duration, metabolic syndrome, chronic kidney disease, chronic obstructive pulmonary disease, ischemic heart disease, valvular heart disease and medication use (adjusted-odds ratio 1.84, 95% confidence intervals 1.2-2.9; p=0.009). CONCLUSIONS: Moderately elevated serum uric acid levels are associated with an increased prevalence of any cardiac conduction defects in hospitalized patients with T2DM, independent of multiple risk factors and potential confounding variables.

Nonalcoholic fatty liver disease is associated with an increased risk of heart block in hospitalized patients with type 2 diabetes mellitus.

Recent studies suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiac tachyarrhythmias (mainly atrial fibrillation) in patients with and without type 2 diabetes mellitus. The aim of this study was to examine whether an association also exists between NAFLD and heart block. We have retrospectively evaluated a hospital-based cohort of 751 patients with type 2 diabetes discharged from our Division of Diabetes and Endocrinology during years 2007-2014. Standard electrocardiograms were performed on all patients. Diagnosis of NAFLD was based on ultrasonography, whereas the severity of advanced hepatic fibrosis was based on the fibrosis (FIB)-4 score and other non-invasive fibrosis markers. Overall, 524 (69.8%) patients had NAFLD and 202 (26.9%) had heart block (defined as at least one block among first-degree atrio-ventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block) on electrocardiograms. Patients with NAFLD had a remarkably higher prevalence of any persistent heart block than those without NAFLD (31.3% vs. 16.7%, p<0.001); this prevalence was particularly increased among those with higher FIB-4 score. NAFLD was associated with a threefold increased risk of prevalent heart block (adjusted-odds ratio 3.04, 95% CI 1.81-5.10), independently of age, sex, hypertension, prior ischemic heart disease, hemoglobin A1c, microvascular complication status, use of medications and other potentially confounding factors. In conclusion, this is the largest cross-sectional study to show that NAFLD and its severity are independently associated with an increased risk of prevalent heart block in hospitalized patients with type 2 diabetes.

Primary cutaneous B-cell lymphoma and chronic leg ulcers in a patient with type 2 diabetes.

The incidences of type 2 diabetes mellitus and many cancers are rapidly increasing worldwide. Diabetes is a strong risk factor for some cancers (including lymphomas) and is also associated with adverse cancer outcomes. After gastrointestinal tract, the skin is the second most frequent extranodal site involved by non-Hodgkin lymphomas and the cutaneous B-cell lymphomas (CBCLs) range from 25% to 30% of all primary cutaneous lymphomas. The primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) is an aggressive lymphoma with a poor prognosis, representing roughly 20% of all primary CBCLs. Classically, the cutaneous manifestation of this lymphoma is a red or violaceous tumors arising on a leg. To date, despite the large body of evidence suggesting that diabetes is strongly associated with an increased risk of some cancers, very little information is available regarding a possible association between type 2 diabetes and primary cutaneous diffuse large B-cell lymphoma. In this report, we will present the case of a white adult patient with type 2 diabetes with chronic leg ulcers complicated by a primary cutaneous diffuse large B-cell lymphoma. LEARNING POINTS: Diabetes mellitus is increasing worldwide as well as the incidence of many cancers.Diabetes mellitus is a powerful risk factor for some cancers (including lymphomas) and is strongly associated with adverse cancer outcomes.Seen that diabetes is strongly associated with an increased risk of cancers (including cutaneous lymphomas), clinicians should always keep in mind this complication in elderly patients with type 2 diabetes, even in a chronic leg ulcer with hypertrophy of the wound edge, which is hard to heal and does not have the typical characteristics of a diabetic or vascular ulcer. In these cases, a biopsy should be performed to rule out a neoplasm.Early diagnosis and correct management of cancer in a patient with type 2 diabetes are crucial to improve clinical outcomes.

Nonalcoholic fatty liver disease is associated with an increased prevalence of distal symmetric polyneuropathy in adult patients with type 1 diabetes.

AIMS: Presently, data on the association between nonalcoholic fatty liver disease (NAFLD) and distal symmetric polyneuropathy in people with diabetes are scarce and conflicting. The aim of this retrospective, cross-sectional study was to examine whether NAFLD was associated with an increased prevalence of distal symmetric polyneuropathy in type 1 diabetic adults. METHODS: We studied all white type 1 diabetic outpatients (n = 286, 42.3% male, mean age 43 ± 14 years, median diabetes duration 17 [10-30] years), who participated in a foot screening program at our adult diabetes clinic after excluding those who had excessive alcohol consumption and other known causes of chronic liver disease. NAFLD was diagnosed by ultrasonography. Distal symmetric polyneuropathy was detected using the Michigan Neuropathy Screening Instrument method and the biothesiometer Vibrotest. RESULTS: Overall, the prevalence rates of NAFLD and distal symmetric polyneuropathy were 52.4% and 35.3%, respectively. Patients with NAFLD had a substantially increased prevalence of distal symmetric polyneuropathy compared to their counterparts without NAFLD (51.0% vs. 17.1%, p < 0.001). In univariate analysis, NAFLD was associated with an approximately 5-fold increased risk of prevalent distal symmetric polyneuropathy (odds ratio [OR] 5.32, 95% confidence interval [CI] 3.1-9.3, p < 0.001). This association remained significant even after adjustment for age, sex, diabetes duration, hemoglobin A1c, diabetic retinopathy, smoking, metabolic syndrome, chronic kidney disease and carotid artery stenoses ≥ 40% (adjusted-OR 2.23, 95% CI 1.1-4.8, p < 0.05). CONCLUSIONS: Our results show that NAFLD, diagnosed by ultrasonography, is strongly associated with an increased risk of distal symmetric polyneuropathy in type 1 diabetic adults, independently of several cardio-metabolic risk factors.

Interleukin-6 as a potential positive modulator of human beta-cell function: an exploratory analysis-the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 6.

AIMS: Recent studies in mouse models of T2D showed that interleukin-6 (IL-6), released from skeletal muscle, is associated with increased glucose-dependent insulin secretion. Few data currently exist exploring the relationship between IL-6 and beta-cell function in humans. We investigated whether IL-6 is positively associated with beta-cell function in newly diagnosed T2D. We extended the same analyses to IL-10, because it regulated similarly to IL-6 in skeletal muscle, and TNF-α and C-reactive protein (CRP), as general biomarkers of inflammation. METHODS: In 330 VNDS participants, we assessed (1) basal plasma concentrations of IL-6, IL-10, TNF-α, and CRP; (2) beta-cell function, estimated by OGTT minimal modeling and expressed as derivative (DC) and proportional control (PC); (3) insulin sensitivity, by euglycemic insulin clamp. RESULTS: IL-6 was positively associated with PC in both univariate analysis (p = 0.04) and after adjustment for age, sex, BMI, HbA1c, and M-clamp (p = 0.01). HbA1c was the major independent contributor to the overall variance of PC (16 %), followed by BMI and IL-6 (~2 % each). Similar results were obtained for IL-10 (p = 0.048, univariate; p = 0.04, fully adjusted). TNF-α and CRP were not significantly associated with any component of beta-cell function. CONCLUSIONS: Our data are the first evidence in human subjects that an endocrine loop involving IL-6 may act as positive modulator of glucose-dependent insulin secretion. Further functional studies are needed to corroborate IL-6 system as a potential druggable target in diabetes. CLINICAL TRIAL REGISTRATION NUMBER: NCT01526720 ( http://www.clinicaltrial.gov ).

Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular disease in adult patients with type 1 diabetes.

BACKGROUND: Recent studies suggested that nonalcoholic fatty liver disease (NAFLD) is associated with an increased prevalence of cardiovascular disease (CVD) in type 1 diabetes. We assessed whether NAFLD also predicts the risk of incident CVD events in type 1 diabetic adults. METHODS: We studied a retrospective cohort of 286 type 1 diabetic outpatients (mean age 43±14years; median duration of diabetes 17 [10-30] years) without secondary causes of chronic liver diseases, who were followed for a mean period of 5.3years for the occurrence of incident CVD events (a combined endpoint inclusive of nonfatal ischemic heart disease, nonfatal ischemic stroke or coronary/peripheral artery revascularizations). NAFLD was diagnosed by ultrasonography. RESULTS: Overall, 150 patients (52.4%) had NAFLD at baseline. During a mean follow-up of 5.3±2.1years, 28 patients developed incident CVD events. Patients with NAFLD had a higher incidence of CVD events than those without NAFLD (17.3% vs. 1.5%, p<0.001). NAFLD was associated with an increased risk of CVD events (hazard ratio [HR] 8.16, 95% confidence interval [CI] 1.9-35.1, p<0.005). Adjustments for age, sex, body mass index, smoking, diabetes duration, hemoglobin A1c, dyslipidemia, hypertension, chronic kidney disease, prior ischemic heart disease and serum gamma-glutamyltransferase levels did not appreciably attenuate the association between NAFLD and incident CVD (adjusted-HR 6.73, 95% CI 1.2-38.1, p=0.031). CONCLUSIONS: This is the first observational study to demonstrate that NAFLD is associated with an increased risk of incident CVD events in type 1 diabetic adults, independently of established CVD risk factors and diabetes-related variables.

Nonalcoholic Fatty Liver Disease Is Associated With Ventricular Arrhythmias in Patients With Type 2 Diabetes Referred for Clinically Indicated 24-Hour Holter Monitoring.

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.

Lower levels of 25-hydroxyvitamin D3 are associated with a higher prevalence of microvascular complications in patients with type 2 diabetes.

OBJECTIVE: Low levels of serum 25-hydroxyvitamin D [25(OH)D] are commonly found in type 2 diabetes. We examined whether there is an association between circulating 25(OH)D concentrations and the presence of microvascular complications in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 715 outpatients with type 2 diabetes who regularly attended our clinic. Participants were evaluated for the presence of microvascular complications (namely retinopathy and/or nephropathy) by clinical evaluation, fundus examination, urine examination and biochemical tests. Serum 25(OH)D levels were also measured for each participant. RESULTS: Hypovitaminosis D (ie, a serum 25(OH)D level <30 ng/mL) was found in 75.4%, while deficiency (ie, a 25(OH)D level <20 ng/mL) was found in 36.6% of these patients. Serum 25(OH)D levels decreased significantly in relation to the severity of either retinopathy or nephropathy or both. In multivariate logistic regression analysis, lower 25(OH)D levels were independently associated with the presence of microvascular complications (considered as a composite end point; OR 0.758; 95% CI 0.607 to 0.947, p=0.015). Notably, this association remained significant even after excluding those with an estimated glomerular filtration rate <60 mL/min/1.73 m(2). CONCLUSIONS: We found an inverse and independent relationship between circulating 25(OH)D levels and the prevalence of microvascular complications in patients with type 2 diabetes. However, vitamin D may be simply a marker and causality cannot be implied from our cross-sectional study. Whether vitamin D supplementation in patients with type 2 diabetes may have beneficial effects on the risk of microvascular complications remains to be investigated.

Nonalcoholic Fatty Liver Disease Is Independently Associated with Early Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes.

Accumulating evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with left ventricular diastolic dysfunction (LVDD) in nondiabetic individuals. To date, there are very limited data on this topic in patients with type 2 diabetes and it remains uncertain whether NAFLD is independently associated with the presence of LVDD in this patient population. We performed a liver ultrasonography and trans-thoracic echocardiography (with speckle-tracking strain analysis) in 222 (156 men and 66 women) consecutive type 2 diabetic outpatients with no previous history of ischemic heart disease, chronic heart failure, valvular diseases and known hepatic diseases. Binary logistic regression analysis was used to examine the association between NAFLD and the presence/severity of LVDD graded according to the current criteria of the American Society of Echocardiography, and to identify the variables that were independently associated with LVDD, which was included as the dependent variable. Patients with ultrasound-diagnosed NAFLD (n = 158; 71.2% of total) were more likely to be female, overweight/obese, and had longer diabetes duration, higher hemoglobin A1c and lower estimated glomerular filtration rate (eGFR) than those without NAFLD. Notably, they also had a remarkably greater prevalence of mild and/or moderate LVDD compared with those without NAFLD (71% vs. 33%; P<0.001). Age, hypertension, smoking, medication use, E/A ratio, LV volumes and mass were comparable between the two groups of patients. NAFLD was associated with a three-fold increased odds of mild and/or moderate LVDD after adjusting for age, sex, body mass index, hypertension, diabetes duration, hemoglobin A1c, eGFR, LV mass index and ejection fraction (adjusted-odds ratio 3.08, 95%CI 1.5-6.4, P = 0.003). In conclusion, NAFLD is independently associated with early LVDD in type 2 diabetic patients with preserved systolic function.