From cause to consequence: Insights into incident diabetes mellitus after hepatic steatosis.
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ABSTRACT:
SUBMITTER: Aggarwal M
PROVIDER: S-EPMC10013334 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
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From cause to consequence: Insights into incident diabetes mellitus after hepatic steatosis.
Aggarwal Manik M Lindenmeyer Christina C CC
Clinical liver disease 20230113 2
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Project description:BackgroundThis study aims to identify early metabolomic biomarkers of gestational diabetes mellitus (GDM) and evaluate their association with hepatic steatosis.MethodsWe compared maternal serum metabolomic profiles between women who developed GDM (n = 118) and matched controls (n = 118) during the first (10-14 gestational weeks) and second (24-28 gestational weeks) trimesters using ultra-performance liquid chromatography coupled with mass spectrometry. Mediation analysis was performed to evaluate the mediating role of metabolic dysfunction-associated steatotic liver disease (MASLD) in the relationship between metabolites and subsequent development of GDM. A refined prediction model was developed to predict GDM using established clinical factors and selected metabolites.ResultsSignificant alterations in circulating metabolites, including amino acids, bile acids, and phospholipids, were observed in the GDM group compared to controls during early pregnancy. Mediation analysis revealed that several metabolites, including glycocholic acid (proportion mediated (PM) = 31.9%), butanoyl carnitine (PM = 25.7%), and uric acid (PM = 22.4%), had significant indirect effects on GDM incidence mediated by hepatic steatosis. The refined prediction model composed of clinical factors and selected metabolites in the first trimester demonstrated higher performance in predicting GDM development than the established prediction model composed solely of clinical factors (AUC, 0.85 vs. 0.63, p < 0.001).ConclusionsWomen who developed GDM exhibited altered metabolomic profiles from early pregnancy, which showed a significant correlation with GDM, with MASLD as a mediator. Selected metabolomic biomarkers may serve as predictive markers and potential targets for early risk assessment and intervention in GDM.Research insightsWHAT IS CURRENTLY KNOWN ABOUT THIS TOPIC?: Gestational diabetes mellitus (GDM) is a common pregnancy complication with significant health risks. Early identification of women at high risk for GDM is crucial for timely intervention and improved outcomes. WHAT IS THE KEY RESEARCH QUESTION?: What alterations in circulating metabolites during early pregnancy are associated with subsequent GDM development? Does metabolic dysfunction-associated steatotic liver disease (MASLD) mediate the association between specific metabolites and GDM risk? WHAT IS NEW?: Significant alterations in bile acids, amino acids, phosphatidylethanolamines, and phosphatidylinositols were observed in early pregnancy sera of women who later developed GDM. MASLD significantly mediated the effects of several metabolites on GDM risk, with mediation proportions ranging from 9.7 to 31.9%. A refined prediction model composed of clinical factors and metabolites significantly improved the performance in predicting GDM development. HOW MIGHT THIS STUDY INFLUENCE CLINICAL PRACTICE?: These results provide new insights into early metabolic alterations associated with GDM development and highlight the potential mediating role of MASLD. This comprehensive metabolomic approach may contribute to the development of improved risk prediction models and targeted interventions for GDM prevention.
| S-EPMC11927189 | biostudies-literature
Project description:PurposeIn the Chinese population, we looked at the relationship between the hepatic steatosis index (HSI) and the risk of type 2 diabetes mellitus (T2DM).MethodsTo evaluate the association between HSI and the risk of T2DM, Cox regression models were employed. Hazard ratios (HR) and 95 percent confidence intervals (CI) were computed. A stratified analysis with interaction testing was also carried out. Additionally, we evaluated the incremental predictive value of the HSI over the established risk factors using the C-statistic, the IDI, and the NRI.ResultsDuring a median follow-up period of 2.97 years, 433 (1.97%) participants developed new-onset T2DM. The smoothing curve fit plot showed a positive correlation between HSI and the risk of T2DM. After adjusting for all noncollinear variables, the risk of T2DM increased by 62% for every 1 standard deviation (SD) increase in HSI. Subgroup analysis indicated that higher HSI levels were associated with a higher risk of T2DM in those aged < 40 years. The addition of HSI enhanced the reclassification and discrimination of established risk factors, with an IDI of 0.027 and an NRI of 0.348 (both P < 0.001).ConclusionOur findings suggest that an elevated HSI is substantially associated with a greater risk of T2DM in the Chinese population. HSI has the potential to be an available and supplementary monitoring method for the management of T2DM risk stratification in the Chinese population.
| S-EPMC9365599 | biostudies-literature
Project description:Aims/hypothesisHepatic steatosis is strongly associated with hepatic and whole-body insulin resistance. It has proved difficult to determine whether hepatic steatosis itself is a direct cause of insulin resistance. In patients with familial hypobetalipoproteinaemia (FHBL), hepatic steatosis is a direct consequence of impaired hepatic VLDL excretion, independently of metabolic derangements. Thus, patients with FHBL provide a unique opportunity to investigate the relation between increased liver fat and insulin sensitivity.MethodsWe included seven male participants with FHBL and seven healthy matched controls. Intrahepatic triacylglycerol content and intramyocellular lipid content were measured using localised proton magnetic resonance spectroscopy (¹H-MRS). A two-step hyperinsulinaemic-euglycaemic clamp, using stable isotopes, was assessed to determine hepatic and peripheral insulin sensitivity.Results¹H-MRS showed moderate to severe hepatic steatosis in patients with FHBL. Basal endogenous glucose production (EGP) and glucose levels did not differ between the two groups, whereas insulin levels tended to be higher in patients compared with controls. Insulin-mediated suppression of EGP during lower dose insulin infusion and insulin-mediated peripheral glucose uptake during higher dose insulin infusion were comparable between FHBL participants and controls. Baseline fatty acids and lipolysis (glycerol turnover) at baseline and during the clamp did not differ between groups.Conclusions/interpretationIn spite of moderate to severe hepatic steatosis, people with FHBL do not display a reduction in hepatic or peripheral insulin sensitivity compared with healthy matched controls. These results indicate that hepatic steatosis per se is not a causal factor leading to insulin resistance.Trial registrationISRCTN35161775.
| S-EPMC3131507 | biostudies-literature
Project description:The occurrence of diabetes mellitus (DM) in pancreatitis is being increasingly recognized lately. Diabetes can develop not only with chronic pancreatitis but even after the first episode of acute pancreatitis (AP). The incidence of diabetes after AP varies from 18% to 23% in 3 years and reaches up to 40% over 5 years. The exact pathogenesis of diabetes after AP is poorly understood and various mechanisms proposed include loss of islet cell mass, AP-induced autoimmunity, and alterations in the insulin incretin axis. Risk factors associated with increased risk of diabetes includes male sex, recurrent attacks of pancreatitis, presence of pancreatic exocrine insufficiency and level of pancreatitic necrosis. Diagnosis of post-pancreatitis DM (PPDM) is often excluded. Treatment includes a trial of oral antidiabetic drugs in mild diabetes. Often, insulin is required in uncontrolled diabetes. Given the lack of awareness of this metabolic disorder after AP, this review will evaluate current information on epidemiology, risk factors, diagnosis and management of PPDM and identify the knowledge gaps.
| S-EPMC10473947 | biostudies-literature
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice
2014-04-01 | E-GEOD-48815 | biostudies-arrayexpress
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM.
2014-04-01 | GSE48815 | GEO
Project description:BackgroundDiabetes mellitus (DM) is common in patients hospitalized with an acute myocardial infarction (AMI), representing in some cases the first opportunity to recognize and treat DM. We report the incidence of new DM and its recognition among patients with AMI.Methods and resultsPatients in a 24-site US AMI registry (2005-08) had glycosylated hemoglobin assessed at a core laboratory, with results blinded to clinicians and local clinical measurements left to the discretion of the treating providers. Among 2854 AMI patients without known DM on admission, 287 patients (10%) met criteria for previously unknown DM, defined by a core laboratory glycosylated hemoglobin of ≥6.5%. Among these, 186 (65%) were unrecognized by treating clinicians, receiving neither DM education, glucose-lowering medications at discharge, nor documentation of DM in the chart (median glycosylated hemoglobin of unrecognized patients, 6.7%; range, 6.5-12.3%). Six months after discharge, only 5% of those not recognized as having DM during hospitalization had been initiated on glucose-lowering medications versus 66% of those recognized (P<0.001).ConclusionsUnderlying DM that has not been previously diagnosed is common among AMI patients, affecting 1 in 10 patients, yet is recognized by the care team only one third of the time. Given its frequency and therapeutic implications, including but extending beyond the initiation of glucose-lowering treatment, consideration should be given to screening all AMI patients for DM during hospitalization. Inexpensive, ubiquitous, and endorsed as an acceptable screen for DM, glycosylated hemoglobin testing should be considered for this purpose.
| S-EPMC4439264 | biostudies-literature
Project description:Aims/hypothesisSleep duration is a risk factor for incident diabetes mellitus and CHD. The primary aim of the present study was to investigate, in sex-specific analyses, the role of incident diabetes as the possible biological mechanism for the reported association between short/long sleep duration and incident CHD. Considering that diabetes is a major risk factor for CHD, we hypothesised that any association with sleep duration would not hold for cases of incident CHD occurring before incident diabetes ('non-diabetes CHD') but would hold true for cases of incident CHD following incident diabetes ('diabetes-CHD').MethodsA total of 6966 men and 9378 women aged 45-73 years from the Malmö Diet Cancer Study, a population-based, prospective cohort, who had answered questions on habitual sleep duration and did not have a history of prevalent diabetes or CHD were included in the analyses. Incident cases of diabetes and CHD were identified using national registers. Sex-specific Cox proportional hazards regression models were stratified by BMI and adjusted for known covariates of diabetes and CHD.ResultsMean follow-up times for incident diabetes (n = 1137/1016 [men/women]), incident CHD (n = 1170/578), non-diabetes CHD (n = 1016/501) and diabetes-CHD (n = 154/77) were 14.2-15.2 years for men, and 15.8-16.5 years for women. In men, short sleep duration (< 6 h) was associated with incident diabetes (HR 1.35, 95% CI 1.01, 1.80), CHD (HR 1.41, 95% CI 1.06, 1.89) and diabetes-CHD (HR 2.34, 95% CI 1.20, 4.55). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.35, 95% CI 0.98, 1.87). Long sleep duration (≥ 9 h) was associated with incident diabetes (HR 1.37, 95% CI 1.03, 1.83), CHD (HR 1.33, 95% CI 1.01, 1.75) and diabetes-CHD (HR 2.10, 95% CI 1.11, 4.00). Long sleep duration was not associated with incident non-diabetes CHD (HR 1.33, 95% CI 0.98, 1.80). In women, short sleep duration was associated with incident diabetes (HR 1.53, 95% CI 1.16, 2.01), CHD (HR 1.46, 95% CI 1.03, 2.07) and diabetes-CHD (HR 2.88, 95% CI 1.37, 6.08). Short sleep duration was not associated with incident non-diabetes CHD (HR 1.29, 95% CI 0.86, 1.93).Conclusions/interpretationThe associations between sleep duration and incident CHD directly reflect the associations between sleep duration and incident diabetes. Incident diabetes may thus be the explanatory mechanism for the association between short and long sleep duration and incident CHD.
| S-EPMC6448951 | biostudies-literature
Project description:Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance. Causation was confirmed by CRISPR/Cas9 gene targeting to recapitulate the original ENU allele, specifying Arg74Cys (R74C). The CRISPR/Cas9-targeted (Arnt2R74C/R74C) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases.
| S-EPMC6307907 | biostudies-literature
Project description:BackgroundWe assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM).MethodsWe conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or < 1.3). We calculated the Steno type 1 risk engine and the atherosclerotic CVD (ASCVD) risk score to estimate the 10-year risk of developing a first fatal or nonfatal CVD event.ResultsUsing the Steno type 1 risk engine, a significantly greater proportion of patients with hepatic steatosis and significant fibrosis (n = 91) had a high 10-year estimated CVD risk compared to those with hepatic steatosis alone (n = 509) or without steatosis (n = 654) (75.8% vs. 23.2% vs. 24.9%, p < 0.001). After adjustment for sex, BMI, diabetes duration, hemoglobin A1c, chronic kidney disease, and lipid-lowering medication use, patients with hepatic steatosis and significant fibrosis had an increased 10-year estimated risk of developing a first fatal or nonfatal CVD event (adjusted-odds ratio 11.4, 95% confidence interval 3.54-36.9) than those without steatosis. We observed almost identical results using the ASCVD risk calculator.ConclusionsThe 10-year estimated CVD risk is remarkably greater in T1DM adults with hepatic steatosis and significant fibrosis than in their counterparts with hepatic steatosis alone or without steatosis.
| S-EPMC10416459 | biostudies-literature