Elevated circulating follistatin associates with an increased risk of type 2 diabetes
Ontology highlight
ABSTRACT:
SUBMITTER: Wu C
PROVIDER: S-EPMC8580990 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD). METHODS:We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available. Elevated MMP-9 was defined based on >95th percentile plasma values from control (non-COPD) sample in SPIROMICS. COPD subjects were classified as having elevated or nonelevated MMP-9. Logistic, Poisson, and Kaplan-Meier analyses were used to identify associations with prospective AECOPD in both cohorts. RESULTS:Elevated MMP-9 was present in 95/1,053 (9%) of SPIROMICS and 41/140 (29%) of COPDGene participants with COPD. COPD subjects with elevated MMP-9 had a 13%-16% increased absolute risk for AECOPD and a higher median (interquartile range; IQR) annual AECOPD rate (0.33 [0-0.74] versus 0 [0-0.80] events/year and 0.9 [0.5-2] versus 0.5 [0-1.4] events/year for SPIROMICS and COPDGene, respectively). In adjusted models within each cohort, elevated MMP-9 was associated with increased odds (odds ratio [OR], 1.71; 95%CI, 1.00-2.90; and OR, 3.03; 95%CI, 1.02-9.01), frequency (incidence rate ratio [IRR], 1.45; 95%CI, 1.23-1.7; and IRR, 1.24; 95%CI, 1.03-1.49), and shorter time-to-first AECOPD (21.7 versus 31.7 months and 14 versus 21 months) in SPIROMICS and COPDGene, respectively. CONCLUSIONS:Elevated MMP-9 was independently associated with AECOPD risk in 2 well-characterized COPD cohorts. These findings provide evidence for MMP-9 as a prognostic biomarker and potential therapeutic target in COPD. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene). FUNDING:This work was funded by K08 HL123940 to JMW; R01HL124233 to PJC; Merit Review I01 CX000911 to JLC; R01 (R01HL102371, R01HL126596) and VA Merit (I01BX001756) to AG. SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C,HHSN268200900015C HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals Inc.; Chiesi Farmaceutici; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Therapeutics Inc.; Ikaria Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. COPDGene is funded by the NHLBI (R01 HL089897 and R01 HL089856) and by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.
| S-EPMC6302944 | biostudies-literature
Project description:Background:The 22q11.2 microdeletion is the pathogenic copy number variation (CNV) associated with 22q11.2 deletion syndrome (22q11.2DS, formerly known as DiGeorge syndrome). Familiar endocrinological manifestations include hypoparathyroidism and hypothyroidism, with recent elucidation of elevated risk for obesity in adults. In this study, we aimed to determine whether adults with 22q11.2DS have an increased risk of developing type 2 diabetes (T2D). Methods:We studied the effect of the 22q11.2 microdeletion on risk for T2D, defined by history and glycosylated hemoglobin (HbA1c), using weighted survey data from the adult Canadian population (based on n = 11,874) and from a clinical cohort of adults with 22q11.2DS (n = 314), aged 17-69 years. Binomial logistic regression models accounted for age, sex, non-European ethnicity, family history of T2D, obesity, and antipsychotic medication use. Findings:The 22q11.2 microdeletion was a significant independent risk factor for T2D (OR 2·44, 95% CI 1·39-4·31), accounting for other factors (p < 0·0001). All factors except sex were also significant within 22q11.2DS. The median age at diagnosis of T2D was significantly younger in 22q11.2DS than in the Canadian population sample (32 vs 50 years, p < 0·0001). In adults without T2D, HbA1c was significantly higher in 22q11.2DS than the population (p = 0·042), after accounting for younger age of the 22q11.2DS group. Interpretation:The results support the 22q11.2 microdeletion as a novel independent risk factor and potential model for early onset T2D. The findings complement emerging evidence that rare CNVs may contribute to risk for T2D. The results have implications for precision medicine and research into the underlying pathogenesis of T2D.
| S-EPMC7565196 | biostudies-literature
Project description:Trimethylamine N-oxide (TMAO), a novel cardiovascular (CV) disease and mortality risk marker, is a gut microbiota-derived metabolite as well. Recently, plasma concentrations of branched-chain amino acids (BCAA) have been reported to be affected by microbiota. The association of plasma TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants are still incompletely described. We evaluated the association between plasma BCAA and TMAO, and the association of TMAO with CV mortality in T2D individuals. We used data of 595 participants (mean age 69.5 years) from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analyzed. Plasma TMAO and BCAA were measured with nuclear magnetic resonance spectroscopy. CV mortality risk was estimated using multivariable-adjusted Cox regression models. Cross-sectionally, TMAO was independently associated with BCAA standardized (Std) β = 0.18 (95% Confidence Interval (CI) 0.09; 0.27), p <0.001. During a median follow-up of 10 years, 113 CV deaths were recorded. In Cox regression analyses, adjusted for multiple clinical and laboratory variables including BCAA, TMAO was independently associated with CV mortality: adjusted hazard ratio (adjHR) 1.93 (95% CI 1.11; 3.34), p = 0.02 (for the highest vs. the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: adjHR 1.32 (95% CI 1.07; 1.63), p = 0.01 (per 1 SD increase). In contrast, BCAAs were not associated with increased CV mortality. In conclusion, higher plasma TMAO but not BCAA concentrations are associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers.
| S-EPMC8197378 | biostudies-literature
Project description:Type 2 diabetes associates with increased risk of mortality, but how kidney disease contributes to this mortality risk among individuals with type 2 diabetes is not completely understood. Here, we examined 10-year cumulative mortality by diabetes and kidney disease status for 15,046 participants in the Third National Health and Nutrition Examination Survey (NHANES III) by linking baseline data from NHANES III with the National Death Index. Kidney disease, defined as urinary albumin/creatinine ratio ?30 mg/g and/or estimated GFR ?60 ml/min per 1.73 m(2), was present in 9.4% and 42.3% of individuals without and with type 2 diabetes, respectively. Among people without diabetes or kidney disease (reference group), 10-year cumulative all-cause mortality was 7.7% (95% confidence interval [95% CI], 7.0%-8.3%), standardized to population age, sex, and race. Among individuals with diabetes but without kidney disease, standardized mortality was 11.5% (95% CI, 7.9%-15.2%), representing an absolute risk difference with the reference group of 3.9% (95% CI, 0.1%-7.7%), adjusted for demographics, and 3.4% (95% CI, -0.3% to 7.0%) when further adjusted for smoking, BP, and cholesterol. Among individuals with both diabetes and kidney disease, standardized mortality was 31.1% (95% CI, 24.7%-37.5%), representing an absolute risk difference with the reference group of 23.4% (95% CI, 17.0%-29.9%), adjusted for demographics, and 23.4% (95% CI, 17.2%-29.6%) when further adjusted. We observed similar patterns for cardiovascular and noncardiovascular mortality. In conclusion, those with kidney disease predominantly account for the increased mortality observed in type 2 diabetes.
| S-EPMC3559486 | biostudies-literature
Project description:Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency rather than hyperglycemia elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we investigated the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic Apoc3 expression in diabetic mice - resulting in lower levels of TRLs - without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and the accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibiting APOC3 might reduce CVD risk in T1DM patients.
| S-EPMC6763229 | biostudies-literature
Project description:BackgroundAn increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation ('WBF-011') in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease.ResultsHere we report targeted and untargeted metabolomic measurements on fasting plasma (n = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation's C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro.ConclusionTo our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies.
| S-EPMC8742391 | biostudies-literature
Project description:Statin is the medication most widely prescribed to reduce plasma cholesterol levels. Yet, how the medication contributes to diabetes risk and impaired glucose metabolism is not clear. This study aims to examine the epigenetic mechanisms of ABCG1 through which statin use associates with risk of type 2 diabetes. We determined the association between the statin use, DNA methylation at ABCG1 and type 2 diabetes/glycemic traits in the Framingham Heart Study Offspring (FHS, n = 2741), with validation in the Women's Health Initiative Study (WHI, n = 2020). The causal effect of statin use on the risk of type 2 diabetes was examined using a two-step Mendelian randomization approach. Next, based on transcriptome analysis, we determined the links between the medication-associated epigenetic status of ABCG1 and biological pathways on the pathogenesis of type 2 diabetes. Our results showed that DNA methylation levels at cg06500161 of ABCG1 were positively associated with the use of statin, type 2 diabetes and related traits (fasting glucose and insulin) in FHS and WHI. Two-step Mendelian randomization suggested a causal effect of statin use on type 2 diabetes and related traits through epigenetic mechanisms, specifically, DNA methylation at cg06500161. Our results highlighted that gene expression of ABCG1, ABCA1 and ACSL3, involved in both cholesterol metabolism and glycemic pathways, was inversely associated with statin use, CpG methylation, and diabetic signatures. We concluded that DNA methylation site cg06500161 at ABCG1 is a mediator of the association between statins and risk of type 2 diabetes.
| S-EPMC7308584 | biostudies-literature
Project description:ObjectivesType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia and metabolic stress, involved in the stepwise development of cardiovascular complications. Fibroblast growth factor 21 (FGF21) is a novel hepatokine involved in regulating glucose and lipid metabolism, and has been linked to the prediction, treatment, and improvement of prognosis in multiple cardiovascular diseases (CVDs). The aim of this study is to explore the relationship between FGF21 levels and vascular diseases (VDs) including carotid atherosclerosis (CAS) and hypertension (HP) in patients with T2DM.MethodsBaseline serum FGF21 was determined in a cross-sectional study of 701 patients with T2DM and 258 healthy control.ResultsThe morbidity of CAS was increased in T2DM patients with HP as compared with those without (p < 0.001). The average serum FGF21 level of healthy was [123.9 (67.2-219.3)]. Baseline FGF21 was significantly higher in those who developed CAS or HP than in those who did not [305.9 (177.2-508.4) vs. 197.2 (129.7-308.3) pg/mL, p < 0.001]. In addition, an elevated serum FGF21 was observed in T2DM patients with HP and CAS than that of T2DM patients with CAS or HP [550.5 (312.6-711.3) vs. 305.9 pg/mL, p < 0.001]. Serum FGF21 levels were positively correlated with body mass index and carotid intima media thicknes (p < 0.05), the association remained significant after adjusting for age and T2DM duration. Furthermore, the multinomial logistic regression showed that serum FGF21 was independently associated with CAS and HP in patients with T2DM after adjustment for demographic and traditional VDs risk factors (p < 0.001).ConclusionsBaseline FGF21 is elevated in VDs during diabetes, changes of serum FGF21 levels were appropriately matched to metabolic stress. FGF21can be used as an independent predictor for diagnosing VDs and predicting prognosis.
| S-EPMC10702049 | biostudies-literature
Project description:ObjectiveObservational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.MethodsWe constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.ResultsWe identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively.InterpretationGenetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.
| S-EPMC7523882 | biostudies-literature
Project description:The relationship between genetic risk variants associated with glucose homeostasis and type 2 diabetes risk has yet to be fully explored in African American populations. We pooled data from 4 prospective studies including 4622 African Americans to assess whether ?-cell dysfunction (BCD) and/or insulin resistance (IR) genetic variants were associated with increased type 2 diabetes risk. The BCD genetic risk score (GRS) and combined BCD/IR GRS were significantly associated with increased type 2 diabetes risk. In cardiometabolic-stratified models, the BCD and IR GRS were associated with increased type 2 diabetes risk among 5 cardiometabolic strata: 3 clinically healthy strata and 2 clinically unhealthy strata. Genetic risk scores related to BCD and IR were associated with increased risk of type 2 diabetes in African Americans. Notably, the GRSs were significant predictors of type 2 diabetes among individuals in clinically normal ranges of cardiometabolic traits.
| S-EPMC5757425 | biostudies-literature