Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(7), P. 1268 - 1281

Published: June 13, 2024

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes

Language: Английский

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Utility of genetic risk scores in type 1 diabetes

Diabetologia, Journal Year: 2023, Volume and Issue: 66(9), P. 1589 - 1600

Published: July 13, 2023

Iterative advances in understanding of the genetics type 1 diabetes have identified >70 genetic regions associated with risk disease, including strong associations across HLA class II region that account for >50% heritability. The increased availability data combined decreased costs generating these data, facilitated development polygenic scores aggregate variants from loci into a single number: either score (GRS) or (PRS). PRSs incorporate many possibly correlated genome, even if they do not reach genome-wide significance, whereas GRSs estimate cumulative contribution smaller subset significance. Type utility classification, aiding discrimination between diabetes, 2 and MODY. are also being used newborn screening studies to identify infants at future presentation disease. Most early been conducted European ancestry populations, but, develop accurate diverse ancestries, large case-control cohorts non-European populations still needed. current barriers GRS implementation within healthcare mainly related lack guidance knowledge on integration other biomarkers clinical variables. Once limitations addressed, there is huge potential 'test treat' approaches be tailor care individuals diabetes.

Language: Английский

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Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias

European Heart Journal, Journal Year: 2023, Volume and Issue: 45(10), P. 791 - 805

Published: Nov. 11, 2023

Abstract Background and Aims Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion blood cells with preleukemic mutations, is associated atherosclerotic cardiovascular disease heart failure. This study aimed to test association CHIP new-onset arrhythmias. Methods UK Biobank participants without prevalent arrhythmias were included. Co-primary outcomes supraventricular arrhythmias, bradyarrhythmias, ventricular Secondary cardiac arrest, atrial fibrillation, any arrhythmia. Associations [variant allele fraction (VAF) ≥ 2%], large (VAF ≥10%), gene-specific subtypes incident evaluated using multivariable-adjusted Cox regression. myocardial interstitial fibrosis [T1 measured magnetic resonance (CMR)] also tested. Results included 410 702 [CHIP: n = 13 892 (3.4%); CHIP: 9191 (2.2%)]. Any multi-variable-adjusted hazard ratios 1.11 [95% confidence interval (CI) 1.04–1.18; P .001] 1.13 (95% CI 1.05–1.22; .001) for 1.09 1.01–1.19; .031) 1.03–1.25; .011) 1.16 CI, 1.00–1.34; .049) 1.22 1.03–1.45; .021) respectively. independent coronary artery heterogeneous across arrhythmia strongest arrest. Gene-specific analyses revealed an increased risk driver genes other than DNMT3A. Large was 1.31-fold odds 1.07–1.59; .009) being in top quintile by CMR. Conclusions may represent a novel factor indicating target modulation towards prevention treatment.

Language: Английский

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Validation of Register-Based Diabetes Classifiers in Danish Data

Clinical Epidemiology, Journal Year: 2023, Volume and Issue: Volume 15, P. 569 - 581

Published: May 1, 2023

To validate two register-based algorithms classifying type 1 (T1D) and 2 diabetes (T2D) in a general population using Danish register data.After linking data on prescription drug usage, hospital diagnoses, laboratory results diabetes-specific healthcare services from nationwide registers, was defined for all individuals Central Denmark Region age 18-74 years 31 December 2018 according to distinct classifiers: 1) novel classifier incorporating diagnostic hemoglobin-A1C measurements, the Open-Source Diabetes Classifier (OSDC), 2) an existing classifier, Register Selected Chronic Diseases (RSCD). These classifications were validated against self-reported Health survey - overall stratified by at onset of diabetes. The source-code both classifiers made available open-source R package osdc.A total 2633 (9.0%) 29,391 respondents reported having any diabetes, divided across 410 (1.4%) cases T1D 2223 (7.6%) T2D. Among cases, 2421 (91.9%) classified as classifiers. In T1D, sensitivity OSDC-classification 0.773 [95% CI 0.730-0.813] (RSCD: 0.700 [0.653-0.744]) positive predictive value (PPV) 0.943 [0.913-0.966] 0.944 [0.912-0.967]). T2D, [0.933-0.953] 0.905 [0.892-0.917]) PPV 0.875 [0.861-0.888] 0.898 [0.884-0.910]). onset-stratified analyses classifiers, low with after 40 T2D before 40.Both identified valid populations population, but substantially higher OSDC compared RSCD. Register-classified atypical should be interpreted caution. validated, provide robust transparent tools researchers.

Language: Английский

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Exposure to sugar rationing in the first 1000 days of life protected against chronic disease

Science, Journal Year: 2024, Volume and Issue: 386(6725), P. 1043 - 1048

Published: Oct. 31, 2024

We examined the impact of exposure to sugar restrictions within 1000 days after conception on type 2 diabetes and hypertension, leveraging quasi-experimental variation from end United Kingdom’s rationing in September 1953. Rationing restricted intake levels current dietary guidelines, consumption nearly doubled immediately ended. Using an event study design with UK Biobank data comparing adults conceived just before or ended, we found that early-life reduced hypertension risk by about 35 20% delayed disease onset 4 years, respectively. Protection was evident utero increased postnatal restriction, especially 6 months, when eating solid foods likely began. In alone accounted for one-third reduction.

Language: Английский

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The challenges of identifying and studying type 1 diabetes in adults

Diabetologia, Journal Year: 2023, Volume and Issue: 66(12), P. 2200 - 2212

Published: Sept. 20, 2023

Abstract Diagnosing type 1 diabetes in adults is difficult since 2 the predominant type, particularly with an older age of onset (approximately >30 years). Misclassification therefore common and will impact both individual patient management reported features clinically classified cohorts. In this article, we discuss challenges associated correctly identifying adult-onset implications these for clinical practice research. We how many differences characteristics autoimmune/type increasing diagnosis are likely explained by inadvertent study mixed populations without autoimmune aetiology diabetes. show that when defined high-specificity methods, presentation, islet-autoantibody positivity, genetic predisposition progression C-peptide loss remain broadly similar severe at all ages unaffected within adults. Recent guidance recommends routine testing suspected or context rapid to insulin therapy after a moderate high prior-probability setting, positive test usually confirm (type diabetes). argue those apparent should not be routinely undertaken as, low prior-prevalence predictive value single-positive islet antibody modest. When studying diabetes, extremely approaches needed identify adults, optimal approach depending on research question. believe until recommendations widely adopted researchers, true phenotype late-onset largely misunderstood. Graphical

Language: Английский

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Elevated serum IL-2 and Th17/Treg imbalance are associated with gout

Clinical and Experimental Medicine, Journal Year: 2024, Volume and Issue: 24(1)

Published: Jan. 19, 2024

Abstract Gout is considered an auto-inflammatory disorder, and the immunological drivers have not been fully unraveled. This study compared peripheral lymphocyte CD4 + T cell subsets, cytokines in gout healthy controls (HCs) to explore contributions of helper 17 (Th17) cells, regulatory (Treg) cells pathogenesis gout. We enrolled 126 patients (53 early-onset with age first presentation < 40 years, 73 late-onset ≥ years) 77 HCs. Percentage absolute numbers subpopulations each group were detected by flow cytometry. The serum cytokine levels determined cytometric bead array. For circulating Th17/Treg ratio was significantly higher gout, without tophus than HCs; Th17 elevated tophus, while percentage Treg decreased Additionally, had (including IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, TNF-α) IL-2 positively correlated negatively ESR. ROC analysis showed that disease duration, CRP fibrinogen, moderate predictive performances for (the AUCs 0.753, 0.703 0.701, respectively). Our suggests differ imbalance, which due cells. And increased levels, especially may play essential role that. Restoring balance be a crucial way improve prognosis patients.

Language: Английский

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Risk factor associations for severe COVID-19, influenza and pneumonia in people with diabetes to inform future pandemic preparations: UK population-based cohort study

BMJ Open, Journal Year: 2024, Volume and Issue: 14(1), P. e078135 - e078135

Published: Jan. 1, 2024

Objective This study aimed to compare clinical and sociodemographic risk factors for severe COVID-19, influenza pneumonia, in people with diabetes. Design Population-based cohort study. Setting UK primary care records (Clinical Practice Research Datalink) linked mortality hospital records. Participants Individuals type 1 2 diabetes (COVID-19 cohort: n=43 033 n=584 854 diabetes, pneumonia n=42 488 n=585 289 diabetes). Primary secondary outcome measures COVID-19 hospitalisation from February 2020 31 October (pre-COVID-19 vaccination roll-out), September 2016 May 2019 pandemic). Secondary outcomes were mortality. Associations between each assessed using multivariable Cox proportional hazards models. In we explored modifying effects of glycated haemoglobin (HbA1c) body mass index (BMI) by age, sex ethnicity. Results poor glycaemic control obesity consistently associated increased pneumonia. The highest HbA1c BMI-associated relative risks observed aged under 70 years. Sociodemographic-associated differed markedly respiratory infection, particularly Compared white ethnicity, black south Asian groups had a greater hospitalisation, but lesser hospitalisation. Risk factor associations broadly consistent the analysis. Conclusions Clinical high are especially younger people. contrast, infection. emphasises that stratification should be specific individual infections.

Language: Английский

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Treatment outcomes with oral anti‐hyperglycaemic therapies in people with diabetes secondary to a pancreatic condition (type 3c diabetes): A population‐based cohort study

Diabetes Obesity and Metabolism, Journal Year: 2025, Volume and Issue: 27(3), P. 1544 - 1553

Published: Jan. 6, 2025

Abstract Aims To assess outcomes of oral anti‐hyperglycaemic therapies in people with diabetes secondary to a pancreatic condition (type 3c), where specific treatment guidance is limited. Materials and Methods Using hospital‐linked UK primary care records (Clinical Practice Research Datalink; 2004–2020), we identified 7084 (acute pancreatitis, chronic cancer haemochromatosis) preceding diagnosis 3c cohort), initiating glucose‐lowering therapy (metformin, sulphonylureas, SGLT2‐inhibitors, DPP4‐inhibitors or thiazolidinediones), without concurrent insulin treatment. We stratified by exocrine insufficiency [PEI] ( n = 5917 PEI, 1167 PEI) matched 97 227 type 2 (T2D) controls. 12‐month HbA1c response weight change 6‐month discontinuation were compared versus T2D. Results People had substantial mean reduction those PEI (12.2 [95%CI 12.0–12.4] mmol/mol) (9.4 [8.9–10.0] mmol/mol). Compared T2D controls, similar (0.7 [0.4–1.0] mmol/mol difference) odds (Odds ratio [OR] 1.08 [0.98–1.19]). In contrast, lower (3.5 [2.9–4.1] lesser reduction) greater (OR 2.03 [1.73–2.36]) Weight was largely consistent across underlying conditions drug classes. Conclusions Oral are effective could provide an important component glycaemic management. identify requiring closer monitoring response.

Language: Английский

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Investigating misclassification of type 1 diabetes in a population-based cohort of British Pakistanis and Bangladeshis using polygenic risk scores

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 13, 2025

Correct classification of type 1 (T1D) and 2 diabetes (T2D) is challenging due to overlapping clinical features the increasingly early onset T2D, particularly in South Asians. Polygenic risk scores (PRSs) for T1D T2D have been shown work relatively well Asians, despite being derived from largely European-ancestry samples. Here we used PRSs investigate rate potential misclassification amongst British Bangladeshis Pakistanis. Using linked health records Genes & Health cohort (n = 38,344) defined two reference groups meeting stringent diagnostic criteria: 31 cases, 1842 after excluding these, further groups: 839 insulin-treated diabetic individuals with ambiguous 5174 non-diabetic controls. Combining these 307 confirmed cases controls India, calculated ancestry-corrected which estimated proportion within group at ~ 6%, dropping 4.5% subset who had codes their (and are thus most likely misclassified). We saw no significant association between or PRS BMI diagnosis, time insulin, presence suggesting that not helpful aiding diagnosis cases. Our results emphasise robust identification appropriate care may require routine measurement autoantibodies C-peptide.

Language: Английский

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