Chronic kidney disease in the type 2 diabetic patients: prevalence and associated variables in a random sample of 2642 patients of a Mediterranean area

Background: Kidney disease is associated with an increased total mortality and cardiovascular morbimortality in the general population and in patients with Type 2 diabetes. The aim of this study is to determine the prevalence of kidney disease and different types of renal disease in patients with type 2 diabetes (T2DM). Methods: Cross-sectional study in a random sample of 2,642 T2DM patients cared for in primary care during 2007. Studied variables: demographic and clinical characteristics, pharmacological treatments and T2DM complications (diabetic foot, retinopathy, coronary heart disease and stroke). Variables of renal function were defined as follows: 1) Microalbuminuria: albumin excretion rate & 30 mg/g or 3.5 mg/mmol, 2) Macroalbuminuria: albumin excretion rate & 300 mg/g or 35 mg/mmol, 3) Kidney disease (KD): glomerular filtration rate according to Modification of Diet in Renal Disease < 60 ml/min/1.73 m2 and/or the presence of albuminuria, 4) Renal impairment (RI): glomerular filtration rate < 60 ml/min/1.73 m2, 5) Nonalbuminuric RI: glomerular filtration rate < 60 ml/min/1.73 m2 without albuminuria and, 5) Diabetic nephropathy (DN): macroalbuminuria or microalbuminuria plus diabetic retinopathy. Results: The prevalence of different types of renal disease in patients was: 34.1% KD, 22.9% RI, 19.5% albuminuria and 16.4% diabetic nephropathy (DN). The prevalence of albuminuria without RI (13.5%) and nonalbuminuric RI (14.7%) was similar. After adjusting per age, BMI, cholesterol, blood pressure and macrovascular disease, RI was significantly associated with the female gender (OR 2.20; CI 95% 1.86-2.59), microvascular disease (OR 2.14; CI 95% 1.8-2.54) and insulin treatment (OR 1.82; CI 95% 1.39-2.38), and inversely associated with HbA1c (OR 0.85 for every 1% increase; CI 95% 0.80-0.91). Albuminuria without RI was inversely associated with the female gender (OR 0.27; CI 95% 0.21-0.35), duration of diabetes (OR 0.94 per year; CI 95% 0.91-0.97) and directly associated with HbA1c (OR 1.19 for every 1% increase; CI 95% 1.09-1.3). Conclusions: One-third of the sample population in this study has KD. The presence or absence of albuminuria identifies two subgroups with different characteristics related to gender, the duration of diabetes and metabolic status of the patient. It is important to determine both albuminuria and GFR estimation to diagnose KD

Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 x 10(-4)), maternal height (P = 1.1 x 10(-4)), pregnancy weight gain (P = 2.2 x 10(-3)), prepregnancy alcohol consumption (P = 4.6 x 10(-4)), and tobacco exposure (P = 1.9 x 10(-3)) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.Peer reviewe

Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 x 10(-4)), maternal height (P = 1.1 x 10(-4)), pregnancy weight gain (P = 2.2 x 10(-3)), prepregnancy alcohol consumption (P = 4.6 x 10(-4)), and tobacco exposure (P = 1.9 x 10(-3)) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.Peer reviewe

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Evolving management and improving outcomes of pregnancy-associated spontaneous coronary artery dissection (P-SCAD): a systematic review.

Background: Pregnancy-associated spontaneous coronary artery dissection (P-SCAD) is defined as SCAD occurring during pregnancy or within 3 months post-partum. Earlier systematic reviews have suggested a high maternal and foetal mortality rate. We undertook a structured systematic review of P-SCAD demographics, management and maternal and foetal outcomes. Methods: Case study identification was conducted according to PRISMA guidelines, with screening of all published P-SCAD cases not meeting pre-defined exclusion criteria. Of two hundred and seventy-three publications screened, one hundred and thirty-eight cases met inclusion criteria. Cases were allocated to one of three time periods; 1960-85 (twenty cases) reflecting early management of P-SCAD, 1986-2005 (forty-two cases) reflecting recent management, and 2006-16 (seventy-six cases), reflecting contemporary management. Results: The only significant demographic change in women experiencing P-SCAD over the last 50 years was an increasing proportion of primigravidas (p = 0.02). Management and outcomes, however, have altered significantly. Emergent angiography (p < 0.0001), reduced thrombolysis (p = 0.006) and increasingly conservative or percutaneous management (p < 0.0001) are associated with dramatic reductions in maternal mortality (85% in earliest reports to 4% in the last decade, p < 0.0001) and foetal mortality (50% in earliest reports to 0.0% in the last decade, p = 0.023). Conclusion: This systematic review of temporal changes in presentation, management and outcomes of P-SCAD represents the widest range of variables analysed in the largest cohort of P-SCAD patients to date. In the setting of earlier coronary angiography and increasingly conservative management, maternal and foetal survival rates continue to improve

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained ?25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation

The effect of preventative cardiovascular therapies on coronary artery disease in people with and without type 2 diabetes: a propensity-matched score study

BACKGROUND: Although it is known that patients with Type 2 Diabetes Mellitus (T2DM) are at an increased risk of coronary artery disease (CAD), the actual coronary artery burden of atherosclerotic disease in patients with and without T2DM in a real-world setting and its possible modification by preventative therapies has not been extensively documented. METHODS: Merged coronary angiography and hospital discharge data between 2013 and 2019 were obtained for analysis and a random sub-sample of patient charts were reviewed for medication use. Propensity scores were estimated using logistic regression models and used to match patients, looking at the effect of severity of CAD over time in years in an ordinal logistic regression model. A separate propensity score was estimated and used to inverse probability weight the ordinal logistic regression looking at the effect of medication use on CAD severity in patients with and without T2DM. RESULTS: From 3,016 patients in the coronary angiography database, 1421 with T2DM and 1421 without T2DM were matched on propensity score. T2DM patients had more extensive CAD in 2018 compared to 2013 ((adjusted odds ratio) adjOR: 2.06 95% C.I. 1.38, 2.07), but this risk appeared to be attenuated in 2019. In contrast, there was no effect of time on CAD burden in patients without diabetes. In the sub-sample of 760 patients who underwent a chart review of their medication use, there were 367 (48%) with T2DM. For patients with T2DM 69.8% reported taking statins, 64.0% RAS inhibitors and 64.0% anti-platelet drugs. This was significantly higher than patients without diabetes of whom 46.6% reported taking statins, 49.0% RAS inhibitors and 49.9% anti-platelet drugs. As in the full matched sample, patients with diabetes had more extensive CAD (adjOR: 1.32 95% CI: 1.01, 1.74). However, after adjustment for the use of RAS inhibitors, statins and anticoagulants there was no difference in extent of CAD between patients with and without diabetes (adjOR: 1.14 95% CI: 0.85, 1.53). CONCLUSIONS: Although patients with diabetes have a greater extent of CAD in comparison to those without T2DM, preventative medication use decreases this CAD burden significantly

Exercise capacity in diabetes mellitus is predicted by activity status and cardiac size rather than cardiac function: a case control study

BACKGROUND: The reasons for reduced exercise capacity in diabetes mellitus (DM) remains incompletely understood, although diastolic dysfunction and diabetic cardiomyopathy are often favored explanations. However, there is a paucity of literature detailing cardiac function and reserve during incremental exercise to evaluate its significance and contribution. We sought to determine associations between comprehensive measures of cardiac function during exercise and maximal oxygen consumption ([Formula: see text]peak), with the hypothesis that the reduction in exercise capacity and cardiac function would be associated with co-morbidities and sedentary behavior rather than diabetes itself. METHODS: This case-control study involved 60 subjects [20 with type 1 DM (T1DM), 20 T2DM, and 10 healthy controls age/sex-matched to each diabetes subtype] performing cardiopulmonary exercise testing and bicycle ergometer echocardiography studies. Measures of biventricular function were assessed during incremental exercise to maximal intensity. RESULTS: T2DM subjects were middle-aged (52 ± 11 years) with a mean T2DM diagnosis of 12 ± 7 years and modest glycemic control (HbA1c 57 ± 12 mmol/mol). T1DM participants were younger (35 ± 8 years), with a 19 ± 10 year history of T1DM and suboptimal glycemic control (HbA1c 65 ± 16 mmol/mol). Participants with T2DM were heavier than their controls (body mass index 29.3 ± 3.4 kg/m2 vs. 24.7 ± 2.9, P = 0.001), performed less exercise (10 ± 12 vs. 28 ± 30 MET hours/week, P = 0.031) and had lower exercise capacity ([Formula: see text]peak = 26 ± 6 vs. 38 ± 8 ml/min/kg, P < 0.0001). These differences were not associated with biventricular systolic or left ventricular (LV) diastolic dysfunction at rest or during exercise. There was no difference in weight, exercise participation or [Formula: see text]peak in T1DM subjects as compared to their controls. After accounting for age, sex and body surface area in a multivariate analysis, significant positive predictors of [Formula: see text]peak were cardiac size (LV end-diastolic volume, LVEDV) and estimated MET-hours, while T2DM was a negative predictor. These combined factors accounted for 80% of the variance in [Formula: see text]peak (P < 0.0001). CONCLUSIONS: Exercise capacity is reduced in T2DM subjects relative to matched controls, whereas exercise capacity is preserved in T1DM. There was no evidence of sub-clinical cardiac dysfunction but, rather, there was an association between impaired exercise capacity, small LV volumes and sedentary behavior

HIF3A association with adiposity: the story begins before birth

Aim: determine if the association of HIF3A DNA methylation with weight and adiposity is detectable early in life. Material &amp; methods: we determined HIF3A genotype and DNA methylation patterns (on hybridization arrays) in DNA extracted from umbilical cords of 991 infants. Methylation levels at three CpGs in the HIF3A first intron were related to neonatal and infant anthropometry and to genotype at nearby polymorphic sites. Results &amp; conclusion: higher methylation levels at three previously described HIF3A CpGs were associated with greater infant weight and adiposity. The effect sizes were slightly smaller than those reported for adult BMI. There was also an interaction within cis-genotype. The association between higher DNA methylation at HIF3A and increased adiposity is present in neonates. In this study, no particular prenatal factor strongly influenced HIF3A hypermethylation. Our data nonetheless suggest shared prenatal influences on HIF3A methylation and adiposit