Diabetologia

BackgroundType 2 diabetes (T2D) is a multi-organ disease defined by hyperglycemia resulting from different disease mechanisms. Using clinical parameters measured at diagnosis (age, BMI, HbA1c, HOMA2-B, HOMA2-IR and GAD autoantibodies) adult patients with diabetes have been reproducibly clustered into five subtypes, that differed clinically with respect to disease progression and outcomes.1 In this study we use genetic information to investigate if these subtypes have distinct underlying genetic ...

This study aimed to investigate the modifying effects of rare genetic variants on the risk of type 2 diabetes in the context of common genetic and lifestyle factors. We conducted a comprehensive analysis of genetic and lifestyle factors associated with type 2 diabetes in a cohort of 146,284 Korean individuals. Among them, 4,603 individuals developed type 2 diabetes during the follow-up period of up to 18 years. We calculated a polygenic risk score (PRS) for type 2 diabetes and identified carrier...

ContextIndividuals with youth-onset type 2 diabetes mellitus (T2DM) display substantial, but unexplained, heterogeneity in their clinical presentations and risk of complications such as diabetic neuropathy. Data-driven clustering may be useful in characterizing this heterogeneity. ObjectiveTo identify data-driven subphenotypes of newly diagnosed youth-onset T2DM and study their association with distal symmetric polyneuropathy (DSPN) at time of diagnosis. DesignCross-sectional SettingUSA Part...

Identifying individuals at risk of early onset type 1 diabetes (diagnosed <2 years) would be highly beneficial in reducing risk of severe diabetic ketoacidosis (DKA) for those with extreme autoimmunity. We aimed to investigate whether genetic variation contributes to heterogeneity in age of type 1 diabetes onset, focusing on those diagnosed <2 years and ages previously defined by histological differences. We carried out association testing on 6773 individuals with type 1 diabetes and tested for ...

The detection of monogenic diabetes illustrates the potential of precision medicine, with treatments tailored to specific genes and diagnosis involving targeted genetic testing. Current detection criteria are derived from White populations. We investigated detection of monogenic diabetes in an unselected multiethnic cohort comprising 1,706 participants diagnosed with diabetes before the age of 30-years. Using broad biomarker criteria (triple pancreatic antibody negative and detectable C-peptide...

BackgroundAlthough statistical models for predicting type 1 diabetes risk have been developed, approaches that reveal clinically meaningful clusters in the at-risk population and allow for non-linear relationships between predictors are lacking. We aimed to identify and characterize clusters of islet autoantibody-positive individuals that share similar characteristics and type 1 diabetes risk. MethodsWe tested a novel outcome-guided clustering method in initially non-diabetic autoantibody-posit...

IntroductionNumerous observational investigations have hinted at a possible link between Graves disease (GD) and the susceptibility to Type 2 diabetes (T2D). The primary objective of this study was to explore the potential underlying causal connection between GD and T2D through the application of bidirectional Mendelian randomization (MR) analysis. Materials and MethodsMR analysis was conducted with summary-level data from genome-wide association studies (GWAS) for GD and T2D. Single-nucleotide...

AbstractA variable number of tandem repeats (VNTR) located in the insulin gene (INS) control region may be involved in the development of type 2 diabetes (T2D). The TH01 microsatellite is located close to INS and has previously been suggested to be involved its regulation. Therefore, this observational study investigated whether the TH01 microsatellite and INS VNTR, as assessed via the surrogate marker single nucleotide polymorphism (SNP) rs689, are associated with T2D in the Mexican population....

Maturity Onset Diabetes of the Young (MODY) can present after the age of 40yrs, but its prevalence, clinical characteristics, and the utility of simple clinical features for selecting cases in this age group remain poorly defined. We analysed whole-exome and clinical data from 51,619 individuals with diabetes diagnosed after 40 years of age from two large cohorts: the UK Biobank (n = 25,012) and the US health system MyCode cohort (n = 26,607). The prevalence of MODY due to pathogenic variants in...

ObjectivesThe high heritability of type 1 diabetes has enabled the development of polygenic risk scores (PRS) as disease risk screening tools. PRS can identify individuals at the highest genetic risk in a population, who can benefit from autoantibody and metabolic surveillance, to avoid ketoacidosis at diagnosis and access preventive therapies. However, PRS for type 1 diabetes developed from European data perform less well in non-European ancestries. We aimed to develop a PRS with comparable per...

Identifying genetic determinants for longitudinal changes in albumin excretion in individuals with type 1 diabetes may help identify those that are predisposed to renal, retinal and cardiovascular complications. Most studies have focussed on genetic predisposition to diabetic kidney disease and used cross-sectional measurements of urinary albumin excretion, but with limited success. Here, we utilise the wealth of longitudinal data and bio-samples collected from cohorts of childhood-onset type 1 ...

ObjectivePolygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we developed a multi-ancestry polygenic score to accurately predict type 1 diabetes risk across diverse populations. Research Design and MethodsWe used recent multi-ancestry genome-wide association studies to create a type 1 diabetes multi-ancestry polygenic score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individua...

PurposeTo investigate the effect of sex and age on the timing of a type 2 diabetes (T2D) diagnosis and the influence T2D-related genes, parental history of T2D, and obesity on T2D development. MethodsIn this case-control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, [&le;]45 years; late, [&ge;]46 years). Seventy T2D-associated SNPs were explored and the percentage con...

ContextDiagnosing Maturity-Onset Diabetes of the Young (MODY) is clinically important for treatment and prognosis. However, phenotype-based studies of MODY are prone to ascertainment bias, limiting accurate estimates of its population prevalence and phenotypic spectrum. ObjectiveTo apply a genotype-first approach to determine the population prevalence, penetrance, and all-cause mortality associated with MODY. MethodsWe analysed exome sequencing and clinical data from 454,275 UK Biobank partici...

BackgroundIndia, characterised as the "diabetes capital" of the world, faces a rapidly increasing diabetes crisis with over 65 million cases diagnosed. Despite the growing prevalence, the genetic underpinnings of insulin resistance (IR) among Indians with normal BMI remain understudied. This research aims to fill the knowledge gap by investigating the association of specific gene variants (RNF138, ABCA1, and ESRRG-GPATCH2) with IR risk in this demographic. MethodsA total of 191 participants (90...

BackgroundIndividuals with monogenic diabetes are at risk for diabetes-related complications; however, overall prognosis and whether prognosis is similar to other diabetes forms is poorly understood. AimTo assess diabetes-related microvascular and macrovascular complications in the common forms of monogenic diabetes. MethodsSystematic review with data sources from Pubmed, Medline and Embase was performed to assess diabetes-related complications in KCNJ11-neonatal diabetes, ABBC8-neontal diabet...

IntroductionType 2 diabetes (T2D) is associated with severe complications, including chronic kidney disease (CKD), cardiovascular disease, heart failure and premature death. By the time T2D is diagnosed, many patients already have emerging complications. Therefore, early treatment has the potential for prevention or even early reversal of serious complications. However, until recently, it was not well-defined which patients were most at risk of developing complications in the stage of prediabete...

BackgroundTo evaluate the association between Glucagon-like peptide-1 receptor agonists (GLP-1RA) use and the risk of acute diabetes complications among adults with type 1 diabetes (T1D) who were eligible for anti-obesity medication (AOM) treatment. MethodsWe employed a target trial emulation using EHR data from the OneFlorida+ network (2014-2024) to investigate the association between GLP-1RA initiation and acute diabetes complications among adults with T1D. Eligible participants were adults w...

ObjectiveWith the high prevalence of pediatric obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D). MethodsWe studied 2,966 youth with diabetes in the prospective SEARCH study (diagnosis age [&le;]19 years) to develo...

ObjectiveHbA1c thresholds used to define dysglycemia in autoantibody-positive individuals at risk for type 1 diabetes do not account for age-related increases in HbA1c and may overestimate progression risk in adults. We evaluated whether age-adjusted HbA1c or a higher HbA1c threshold improves risk stratification across age groups. Research Design and MethodsWe analyzed 5,024 autoantibody-positive relatives (3,720 children and 1,304 adults) participating in the TrialNet Pathway to Prevention stu...