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Background The cumulative effect of postpartum weight retention from each pregnancy in a woman’s life may contribute to her risk of ultimately developing type 2 diabetes and cardiovascular disease. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiovascular risk factors over the first 5-years after pregnancy. Methods In this prospective observational cohort study, 330 women (mean age 35.7±4.3 years, mean prepregnancy body mass index 25.2±4.8 kg/m2 , 50.9% primiparous) underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, oral glucose tolerance test, insulin sensitivity/resistance (Matsuda index, HOMA-IR), C-reactive protein (CRP), adiponectin) at 1-year, 3-years, and 5-years postpartum. Based on the magnitude of weight change between pre-pregnancy and 5-years postpartum, they were stratified into the following 3 groups: weight loss (n=100), weight gain 0–6% (n=110), and weight gain≥6% (n=120). Results At 1-year postpartum, cardiovascular risk factors did not differ between the groups. However, an adverse risk factor profile progressively emerged in the weight retention groups at 3- and 5-years. Indeed, after covariate adjustment, there was stepwise worsening (from the weight loss group to weight gain 0–6% to weight gain≥6% group) of the following cardiovascular risk factors at 5-years: triglycerides (p=0.001), HDL (p=0.02), LDL (p=0.01), apolipoprotein-B (p=0.003), Matsuda index (p<0.0001), HOMA-IR (p<0.0001), fasting glucose (p=0.07), and CRP (p=0.01). Moreover, on logistic regression analyses, weight gain≥6% emerged as an independent predictor of prediabetes/diabetes at 5-years (adjusted OR=3.40, 95%CI: 1.63–7.09). Conclusion Postpartum weight retention predicts trajectories of worsening cardiovascular risk factors and glucose intolerance over the first 5-years after delivery, consistent with its postulated contribution to future vascular disease in women. [ABSTRACT FROM AUTHOR]

Background: Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity. Methods: ASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration. Results: ASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function. Conclusion: ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein (LDL)-cholesterol is positively associated with cardiovascular disease (CVD) and inversely associated with type 2 diabetes, which could detract from lipid modification. Here, we examined whether lipid traits potentially relevant to CVD aetiology, i.e. apolipoprotein B (apoB), triglycerides (TG) and lipoprotein(a) [Lp(a)] exhibited the same associations. We investigated sex-specifically, including the role of sex hormones, because sex disparities exist in lipid profile and type 2 diabetes. We also replicated where possible. Methods: We used Mendelian randomization (MR) to examine sex-specific associations of apoB, TG and Lp(a) with type 2 diabetes, HbA1c, fasting insulin, fasting glucose, testosterone and estradiol in the largest relevant sex-specific genome-wide association studies (GWAS) in people of European ancestry and replicated where possible. We also assessed sex-specific associations of liability to type 2 diabetes with apoB, TG and Lp(a). Results: Genetically predicted apoB and Lp(a) had little association with type 2 diabetes or glycemic traits in women or men. Genetically predicted higher TG was associated with higher type 2 diabetes risk [odds ratio (OR) 1.44 per standard deviation (SD), 95% confidence interval (CI) 1.26 to 1.65], HbA1c and fasting insulin specifically in women. Higher TG was associated with lower testosterone in women and higher testosterone in men, but with lower estradiol in men and women. Genetic liability to type 2 diabetes was associated with higher TG in women, and possibly with lower apoB in men. Conclusions: Lipid traits potentially relevant to CVD aetiology do not exhibit contrasting associations with CVD and type 2 diabetes. However, higher TG is associated with higher type 2 diabetes risk and glycemic traits, which in turn further increases TG specifically in women, possibly driven by sex hormones. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein (LDL)-cholesterol is positively associated with cardiovascular disease (CVD) and inversely associated with type 2 diabetes, which could detract from lipid modification. Here, we examined whether lipid traits potentially relevant to CVD aetiology, i.e. apolipoprotein B (apoB), triglycerides (TG) and lipoprotein(a) [Lp(a)] exhibited the same associations. We investigated sex-specifically, including the role of sex hormones, because sex disparities exist in lipid profile and type 2 diabetes. We also replicated where possible. Methods: We used Mendelian randomization (MR) to examine sex-specific associations of apoB, TG and Lp(a) with type 2 diabetes, HbA1c, fasting insulin, fasting glucose, testosterone and estradiol in the largest relevant sex-specific genome-wide association studies (GWAS) in people of European ancestry and replicated where possible. We also assessed sex-specific associations of liability to type 2 diabetes with apoB, TG and Lp(a). Results: Genetically predicted apoB and Lp(a) had little association with type 2 diabetes or glycemic traits in women or men. Genetically predicted higher TG was associated with higher type 2 diabetes risk [odds ratio (OR) 1.44 per standard deviation (SD), 95% confidence interval (CI) 1.26 to 1.65], HbA1c and fasting insulin specifically in women. Higher TG was associated with lower testosterone in women and higher testosterone in men, but with lower estradiol in men and women. Genetic liability to type 2 diabetes was associated with higher TG in women, and possibly with lower apoB in men. Conclusions: Lipid traits potentially relevant to CVD aetiology do not exhibit contrasting associations with CVD and type 2 diabetes. However, higher TG is associated with higher type 2 diabetes risk and glycemic traits, which in turn further increases TG specifically in women, possibly driven by sex hormones. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes. Methods: The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use. Results: Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01–1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67–0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70–0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59–0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58–0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04–1.68], p = 0.02), was associated with an increased risk. Conclusions: Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: Assessing the spectrum of disease risk associated with hypertriglyceridemia is needed to inform potential benefits from emerging triglyceride lowering treatments. We sought to examine the associations between a full range of plasma triglyceride concentration with five clinical outcomes. Methods: We used linked data from primary and secondary care for 15 M people, to explore the association between triglyceride concentration and risk of acute pancreatitis, chronic pancreatitis, new onset diabetes, myocardial infarction and all-cause mortality, over a median of 6–7 years follow up. Results: Triglyceride concentration was available for 1,530,411 individuals (mean age 56·6 ± 15·6 years, 51·4% female), with a median of 1·3 mmol/L (IQR: 0.9.to 1.9). Severe hypertriglyceridemia, defined as > 10 mmol/L, was identified in 3289 (0·21%) individuals including 620 with > 20 mmol/L. In multivariable analyses, a triglyceride concentration > 20 mmol/L was associated with very high risk for acute pancreatitis (Hazard ratio (HR) 13·55 (95% CI 9·15–20·06)); chronic pancreatitis (HR 25·19 (14·91–42·55)); and high risk for diabetes (HR 5·28 (4·51–6·18)) and all-cause mortality (HR 3·62 (2·82–4·65)) when compared to the reference category of ≤ 1·7 mmol/L. An association with myocardial infarction, however, was only observed for more moderate hypertriglyceridaemia between 1.7 and 10 mmol/L. We found a risk interaction with age, with higher risks for all outcomes including mortality among those ≤ 40 years compared to > 40 years. Conclusions: We highlight an exponential association between severe hypertriglyceridaemia and risk of incident acute and chronic pancreatitis, new diabetes, and mortality, especially at younger ages, but not for myocardial infarction for which only moderate hypertriglyceridemia conferred risk. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance is a risk factor for cardiovascular disease. Recently, we have developed a novel index, FLAIS (Fasting Laboratory Assessment of Insulin Sensitivity), which accurately reflects insulin sensitivity, measured with hyperinsulinemic-euglycemic clamp, in different groups of subjects. The aim of the present study was to assess the relationship of FLAIS with cardiovascular risk factors in a population-based study. Methods: The study group comprised 339 individuals from the ongoing Białystok Plus study, without previously known diabetes. Clinical examination, oral glucose tolerance test and the measurement of blood laboratory parameters were performed. Results: Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) was diagnosed in 165 individuals whereas type 2 diabetes was diagnosed in 19 subjects. FLAIS was lower in individuals with prediabetes and diabetes in comparison with individuals with normal glucose tolerance. FLAIS was significantly related to waist circumference, systolic and diastolic blood pressure, triglycerides, HDL-cholesterol and LDL-cholesterol in the entire study group and in the subgroups with normal glucose tolerance and with prediabetes/diabetes. HOMA-IR, QUICKI and Matsuda index were not related to blood pressure and LDL-cholesterol in individuals with normal glucose tolerance. Majority of the adjusted models with FLAIS were characterized by better fit with the data in comparison with other indices for all cardiovascular risk factors except waist circumference. Conclusions: FLAIS represents useful index to assess the cluster of insulin resistance-associated cardiovascular risk factors in general population. [ABSTRACT FROM AUTHOR]

Background: Distinguishable sex differences exist in fat mass and muscle mass. High fat mass and low muscle mass are independently associated with cardiovascular disease (CVD) risk factors in people living with type 2 diabetes; however, it is unknown if the association between fat mass and CVD risk is modified by muscle mass, or vice versa. This study examined the sex-specific interplay between fat mass and muscle mass on CVD risk factors in adults with type 2 diabetes living with overweight and obesity. Methods: Dual-energy X-ray absorptiometry (DXA) measures were used to compute fat mass index (FMI) and appendicular muscle mass index (ASMI), and participants were separated into high-fat mass vs. low-fat mass and high-muscle mass vs. low-muscle mass. A two-way analysis of covariance (ANCOVA: high-FMI vs. low-FMI by high-ASMI vs. low-ASMI) was performed on CVD risk factors (i.e., hemoglobin A1C [A1C]; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; triglycerides; systolic and diastolic blood pressure; cardiorespiratory fitness, depression and health related-quality of life [HR-QoL]) at baseline and following a 1-year intensive lifestyle intervention (ILI) for females and males separately, with a primary focus on the fat mass by muscle mass interaction effects. Results: Data from 1,369 participants (62.7% females) who completed baseline DXA were analyzed. In females, there was a fat mass by muscle mass interaction effect on A1C (p = 0.016) at baseline. Post-hoc analysis showed that, in the low-FMI group, A1C was significantly higher in low-ASMI when compared to high-ASMI (60.3 ± 14.1 vs. 55.5 ± 13.5 mmol/mol, p = 0.023). In the high-FMI group, there was no difference between high-ASMI and low-ASMI (56.4 ± 12.5 vs. 56.5 ± 12.8 mmol/mol, p = 0.610). In males, only high-FMI was associated with higher A1C when compared to low-FMI (57.1 ± 14.4 vs. 54.2 ± 12.0 mmol/mol, p = 0.008) at baseline. Following ILI, there were significant fat mass by muscle mass interaction effects on changes in the mental component of HR-QoL in males. Conclusion: Considering that A1C predicts future CVD, strategies to lower A1C may be especially important in females with low fat and low muscle mass living with type 2 diabetes. Our results highlight the complicated and sex-specific contribution of fat mass and muscle mass to CVD risk factors. [ABSTRACT FROM AUTHOR]