Use of DPP4 inhibitors in Italy does not correlate with diabetes prevalence among COVID-19 deaths.

In a nationwide study of 3818 charts from patients with fatal COVID-19, we found that geographical differences in Dipeptidyl peptidase 4 (DPP4) inhibitors use did not correlate with diabetes prevalence among COVID-19 deaths, thus not supporting the hypothesis of a clinically relevant involvement of DPP4 inhibition in COVID-19 development and progression.

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.

Current treatment for polycystic ovary syndrome: focus on adolescence.

Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women and it is associated with an increased rate of infertility. Its etiology remains largely unknown, although both genetic and environmental factors play a role. PCOS is characterized by insulin resistance, metabolic disorders and low-grade chronic inflammation. To date, the treatment of PCOS is mainly symptomatic and aimed at reducing clinical signs of hyperandrogenism (hirsutism and acne), at improving menstrual cyclicity and at favoring ovulation. Since PCOS pathophysiology is still largely unknown, the therapeutic interventions currently in place are rarely cause-specific. In such cases, the therapy is mainly directed at improving hormonal and metabolic dysregulations typical of this condition. Diet and exercise represent the main environmental factors influencing PCOS. Thus, therapeutic lifestyle changes represent the first line of intervention, which, in combination with oral contraceptives, represent the customary treatment. Insulin resistance is becoming an increasingly studied target for therapy, most evidence stemming from the time-honored metformin use. Relatively novel strategies also include the use of thiazolidinediones and GLP1-receptor agonists. In recent years, a nutraceutical approach has been added to the therapeutic toolkit targeting insulin resistance. Indeed, emerging data support inositol and alpha-lipoic acid as alternative compounds, alone or in combination with the aforementioned strategies, with favorable effects on ovulation, insulin resistance and inflammation. Nevertheless, additional studies are required in adolescents, in order to assess the effectiveness of diet supplements in preventing negative impacts of PCOS on fertility in adult age. This review focuses on the main therapeutic options for PCOS to date.

Association between non-alcoholic fatty liver disease and risk of atrial fibrillation in adult individuals: An updated meta-analysis.

BACKGROUND & AIMS: Recent studies examined the association between non-alcoholic fatty liver disease (NAFLD) and risk of atrial fibrillation (AF) in adults, but the findings have been inconsistent. We provided a quantitative estimate of the magnitude of the association between NAFLD and risk of AF. METHODS: We searched publication databases using predefined keywords to identify observational studies (published up to December 14, 2018), in which NAFLD was diagnosed by biopsy, imaging or biochemistry and AF was diagnosed by medical history and electrocardiograms. Data from selected studies were extracted and meta-analysis was performed using random-effects modelling. RESULTS: Nine cross-sectional and longitudinal studies were included in the final analysis (n = 364 919 individuals). Meta-analysis of data from 5 cross-sectional studies showed that NAFLD was associated with an increased risk of prevalent AF (random-effects odds ratio 2.07, 95% CI 1.38-3.10; I2  = 54.7%), independent of age, sex, body mass index, hypertension and other common AF risk factors. This risk was particularly high among patients with established diabetes (n = 1 study; random-effects odds ratio 5.17, 95% CI 2.05-13.02). Meta-analysis of data from 4 longitudinal studies showed that NAFLD was independently associated with a 10-year increased risk of incident AF only in type 2 diabetic patients (n = 1 study; random-effects hazard ratio 4.96, 95% CI 1.42-17.28). Sensitivity analyses did not modify these findings. Funnel plots did not reveal significant publication bias. CONCLUSIONS: NAFLD is associated with an increased risk of AF in middle-aged and elderly individuals (especially in those with type 2 diabetes). However, the observational design of the eligible studies does not allow for proving causality.

A Case Report of Insulinoma Relapse on Background Nesidioblastosis: A Rare Cause of Adult Hypoglycemia.

Context: Nesidioblastosis is a rare cause of adult hypoglycemia. Current medical therapy can mitigate disease symptoms. However, side effects and limited efficacy may prevent long-term disease management. Case Description: A 63-year-old white woman presented at our institution on April 2017 with a history of distal spleno-pancreatectomy for well-differentiated insulinoma in 2013. Hypoglycemic events did not resolve after surgery, and residual nesidioblastosis near the pancreatic resection margins was identified. Hypoglycemic episodes increased in frequency and severity despite high-dose diazoxide (DZX) therapy. On April 2016, octreotide was introduced but soon discontinued for inefficacy. When the patient arrived at our attention, add-on pasireotide was started and glucose levels monitored by subcutaneous sensor. Compared with DZX, 225 mg/d alone, sensor glucose during pasireotide + DZX 75 mg/d showed occurrence of severe hypoglycemia. Pasireotide was discontinued, and the instrumental workup (68Ga-DOTATOC CT/positron emission tomography, 99mTc-nanocolloid scintigraphy and echo-endoscopy + fine-needle aspiration biopsy) identified an insulinoma relapse. Subtotal pancreatectomy was performed without further recurrence of hypoglycemia over 9 months of follow-up. Conclusions: Although insulinoma relapses on background nesidioblastosis rarely occur, they should be considered as an alternate diagnosis when medical therapy fails to prevent hypoglycemia. Further studies are warranted to test whether the immunophenotypic signature of nesidioblastosis/insulinoma may provide insights for a tailored use of pasireotide.

Systematic review with meta-analysis: non-alcoholic fatty liver disease is associated with a history of osteoporotic fractures but not with low bone mineral density.

BACKGROUND: Several studies have explored the effect of non-alcoholic fatty liver disease (NAFLD) on bone mineral density (BMD) and risk of osteoporotic fractures in adults. However, the extent to which NAFLD adversely affects bone health remains uncertain. AIM: To provide a quantitative estimation of the magnitude of the association of NAFLD with BMD or history of osteoporotic fractures in adults. METHODS: We searched PubMed, Web of Science, and Scopus using predefined keywords to identify all observational studies, published up to 31 August 2018, in which NAFLD was diagnosed by imaging or histology; BMD was measured by dual energy X-ray absorptiometry; and a self-reported history of osteoporotic fractures was collected with interviewer-assisted questionnaires. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling. RESULTS: Twelve cross-sectional or case-control studies with aggregate data on 30 041 adults of predominantly Asian ethnicity (30% with NAFLD) were included in the final analysis. No significant differences in BMD at different skeletal sites (whole body, lumbar spine, or femur) were observed between individuals with and without NAFLD. Conversely, NAFLD was associated with increased odds of osteoporotic fractures, especially in older Chinese men (n = 2 studies; random-effects odds ratio 2.10, 95% CI 1.36-3.25; I2  = 0%). Sensitivity analyses did not alter these findings. The funnel plot and Egger test did not reveal significant publication bias. CONCLUSIONS: This meta-analysis suggests that imaging-defined or biopsy-proven NAFLD is associated with a self-reported history of osteoporotic fractures (principally in Chinese men), but not with low BMD, in middle-aged and elderly individuals.

Association between nonalcoholic fatty liver disease and colorectal tumours in asymptomatic adults undergoing screening colonoscopy: a systematic review and meta-analysis.

BACKGROUND: It is currently uncertain whether non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of colorectal tumours. We performed a meta-analysis of relevant observational studies to quantify the magnitude of the association between NAFLD and risk of colorectal adenomas and cancer. METHODS: We searched PubMed, Scopus and Web of Science from January 2000 to November 2017 using pre-defined keywords to identify observational studies of asymptomatic adults undergoing screening colonoscopy, in which NAFLD was diagnosed by imaging or histology. Data from selected studies were extracted and meta-analysis was performed using random-effects modelling. RESULTS: Eleven observational studies (8 cross-sectional and 3 longitudinal) with aggregate data on 91,124 asymptomatic adults (32.1% with NAFLD) of predominantly Asian descent accounting for a total of 14,911 colorectal adenomas and 1684 cancers were included in the final analysis. NAFLD was associated with an increased risk of prevalent colorectal adenomas (n = 7 studies using liver imaging techniques; random-effects odds ratio [OR] 1.28, 95% CI 1.11-1.48; I2 = 82.9% or n = 1 study using liver biopsy; random-effects OR 1.61, 95% CI 0.90-2.89) and cancer (n = 4 studies using liver imaging techniques; random-effects OR 1.56, 95% CI 1.25-1.94; I2 = 65.6% or n = 1 study using liver biopsy; random-effects OR 3.04, 95% CI 1.29-7.18). NAFLD was also associated with an increased risk of incident colorectal adenomas (n = 3 studies; random-effects hazard ratio [HR] 1.42, 95% CI 1.18-1.72; I2 = 0%) and cancer (n = 1 study; random-effects HR 3.08, 95% CI 1.02-9.03). These risks were independent of age, sex, smoking, body mass index and diabetes (or metabolic syndrome). Sensitivity analyses did not alter these findings. Funnel plot and Egger's test did not reveal significant publication bias. CONCLUSIONS: This meta-analysis of observational studies (involving asymptomatic individuals of predominantly Asian descent undergoing screening colonoscopy) suggests that NAFLD (detected by imaging or biopsy) is independently associated with a moderately increased prevalence and incidence of colorectal adenomas and cancer. However, the observational design of the studies does not allow for proving causality, and the possibility of residual confounding by some unmeasured factors cannot be ruled out. More prospective studies, particularly in European and American individuals, and mechanistic studies are required to better understand the association between NAFLD and colonic carcinogenesis.

Association Between Diabetes and 1-Year Adverse Clinical Outcomes in a Multinational Cohort of Ambulatory Patients With Chronic Heart Failure: Results From the ESC-HFA Heart Failure Long-Term Registry.

OBJECTIVE: Diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) and death. Because the prevalence of diabetes is rising worldwide and chronic heart failure (CHF) is becoming increasingly common with the aging population, it is timely to examine the impact of diabetes per se on 1-year adverse outcomes in patients with CHF. RESEARCH DESIGN AND METHODS: We prospectively assessed whether diabetes status independently affected the 1-year risk of all-cause and CVD mortality and first hospitalization for worsening heart failure (HF) in a multinational cohort of 9,428 outpatients with CHF enrolled in the European Society of Cardiology and Heart Failure Association Long-Term Registry. RESULTS: Compared with those patients without diabetes, patients with diabetes (n = 3,440, 36.5%) had higher cumulative rates of 1-year all-cause death (9.4% vs. 7.2%; adjusted hazard ratio [HR] 1.28; 95% CI 1.07-1.54), CVD death (4.8% vs. 3.8%; adjusted HR 1.28; 95% CI 0.99-1.66), and HF hospitalization (13.8% vs. 9.3%; adjusted HR 1.37; 95% CI 1.17-1.60), all independent of age, sex, BMI, smoking, systolic blood pressure, estimated glomerular filtration rate, hemoglobin, HF etiology, left ventricular ejection fraction, hypertension, statin use, and prior stroke or chronic obstructive pulmonary disease. Among CHF patients with HbA1c measurements available at baseline (n = 2,567), there was a significant and independent association between increasing HbA1c levels and the risk of 1-year survival outcomes. CONCLUSIONS: The presence of diabetes markedly increases the risk of 1-year adverse clinical outcomes in outpatients with CHF independent of multiple common risk factors. More effective and personalized treatment for diabetes should be considered in this particularly high-risk patient population.

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 ).

Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease.

PURPOSE: Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are two powerful predictors of adverse cardiovascular outcomes in patients with type 2 diabetes, but the etiology of valvular calcification is uncertain. Nonalcoholic fatty liver disease (NAFLD) is an emerging cardiovascular risk factor and is very common in type 2 diabetes, but whether NAFLD is associated with valvular calcification in this group of patients is presently unknown. METHODS: We undertook a cross-sectional study of 247 consecutive type 2 diabetic outpatients with no previous history of heart failure, valvular heart diseases (aortic stenosis, mitral stenosis, moderate or severe aortic and mitral regurgitation) or hepatic diseases. Presence of MAC and AVS was detected by echocardiography. NAFLD was diagnosed by ultrasonography. RESULTS: Overall, 139 (56.3%) patients had no heart valve calcification (HVC-0), 65 (26.3%) patients had one valve affected (HVC-1) and 43 (17.4%) patients had both valves affected (HVC-2). 175 (70.8%) patients had NAFLD and the prevalence of this disease markedly increased in patients with HVC-2 compared with either HVC-1 or HVC-0 (86.1% vs. 83.1% vs. 60.4%, respectively; p < 0.001). NAFLD was significantly associated with AVS and/or MAC (unadjusted-odds ratio 3.51, 95% CI 1.89-6.51, p < 0.001). Adjustments for age, sex, waist circumference, smoking, blood pressure, hemoglobin A1c, LDL-cholesterol, kidney function parameters, medication use and echocardiographic variables did not appreciably weaken this association (adjusted-odds ratio 2.70, 95% CI 1.23-7.38, p < 0.01). CONCLUSIONS: Our results show that NAFLD is an independent predictor of cardiac calcification in both the aortic and mitral valves in patients with type 2 diabetes.

Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.