Diabetologia

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...

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...

Prediabetes (PD), which includes impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), is a dysfunctional metabolic state that often progresses to type 2 diabetes (T2D). Standard screening tools such as random glucose and hemoglobin A1c frequently miss early or intermittent dysglycemia and cannot distinguish underlying physiological differences relevant for targeted intervention. Although the oral glucose tolerance test (OGTT) detects more PD and T2D and identifies high-risk indiv...

Type 2 diabetes (T2D) affects 11.1% of the global population, underscoring the need for biomarkers that inform treatment response and glycemic outcomes. We evaluated the association between the FTO variant rs9939609-A and glycemic control in a Mexican population. A total of 174 individuals living with T2D from Merida and Sisal, Yucatan, were included, of whom 85% were receiving oral hypoglycemic agents as main treatment. Glycemic control was defined cross-sectionally as good ([&le;]130 mg/dL, n=...

BackgroundGenetic risk scores (GRS) for type 1 diabetes (T1D) have been developed primarily in European populations, limiting their generalisability across ancestries. Indians differ from Europeans in clinical characteristics of T1D and overall genetic architecture, yet systematic evaluation of T1D GRS performance in multi-regional Indian cohorts is lacking. MethodsThe study included 597 T1D patients and 3347 non-diabetic controls from different regions in India. Genotyping, imputation, quality...

Aims/HypothesisUnderstanding heterogeneous patient responses to various glucose-lowering therapies is crucial for advancing personalized treatment approaches and optimizing outcomes for type 2 diabetes mellitus. While average treatment effects are known for many drug classes, patient responses may differ by underlying clinical and demographic factors. We hypothesize that major glucose-lowering drug classes exhibit heterogeneous treatment effects (HTE) across patient subgroups defined by key clin...

Stratifying progression from early-stage type 1 diabetes to clinical disease is essential for optimally timing disease-modifying therapies. We previously developed a progression likelihood score (PLS) that includes quantitative IA-2 autoantibody (IA-2A) measurements. This study aligned IA-2A thresholds used for PLS calculation between the radiobinding assay (RBA) and a commercially available RSR IA-2A ELISA to support broader clinical application. Serum samples from 349 children with stage 1 typ...

Uric acid (UA) is traditionally regarded as a metabolic risk marker; however, its dynamic behavior during glucose-lowering therapy remains incompletely understood. We compared UA responses to a modified traditional Japanese diet (MJDD) and the DPP-4 inhibitor alogliptin in patients with early-stage type 2 diabetes mellitus (T2DM). In this prospective observational study, drug-naive patients received MJDD (n=58) or alogliptin (n=52) monotherapy for 3 months. Changes ({Delta}) in serum UA were ana...

Prediabetes and type 2 diabetes (T2D) are metabolic disorders characterized by insulin resistance and {beta}-cell dysfunction. To understand the molecular mechanisms driving the transition from prediabetes to T2D, we performed a longitudinal proteogenomic analysis on 458 participants from the Prediabetes Lifestyle Intervention Study (PLIS). We identified 185 plasma proteins to be differentially expressed between conditions, 36 of which predict future T2D-onset. Integrating genetic data from 321 ...

BackgroundThe diagnostic accuracy of HbA1C for prediabetes has been questioned due to its discordance with fasting plasma glucose (FPG) and 2 h oral glucose tolerance test (OGTT) glucose in non-white populations. This study aims to estimate concordance in the diagnosis of prediabetes using HbA1C FPG, and OGTT in a Filipino-American cohort. MethodsCross-sectional data from 149 Filipino-Americans without known diabetes living in the San Francisco Bay Area were used to compare prevalence of predia...

Type 2 diabetes (T2D) is a genetically and clinically heterogeneous disorder influenced by metabolic, lifestyle, and cardiometabolic factors. Understanding the shared and distinct genetic architecture underlying T2D and its upstream risk traits is critical for improved risk prediction and stratified intervention. We applied genomic structural equation modeling (SEM) to genome-wide association study (GWAS) summary statistics for eight T2D-related phenotypes: gestational diabetes, hypertension, gl...

BACKGROUNDCardiovascular disease (CVD) is a leading cause of diabetes-related mortality in Mexico. Although diabetes subgroups capture underlying disease heterogeneity, their association and utility for risk prediction for fatal CVD in Mexican adults remain unclear. METHODSWe analyzed 24,943 adults with diabetes from the Mexico City Prospective Study. Participants were classified into mild obesity-related (MOD), severe insulin-deficient (SIDD), severe insulin-resistant (SIRD), and mild age-rela...

Mitochondrial dysfunction has long been associated with insulin resistance, yet the causal relationship in humans remains unresolved. Here, we leveraged individuals carrying the diabetogenic m.3243A>G mtDNA mutation as a human genetic model to probe the causal contribution of mitochondrial defects to insulin resistance and delineate the underlying molecular and bioenergetic mechanisms. In vivo metabolic phenotyping revealed selective skeletal muscle insulin resistance with preserved liver and ad...

BackgroundInter-individual variability in lipid response to statin therapy poses a major challenge in cardiovascular risk reduction, particularly among patients with type 2 diabetes mellitus (T2DM), who exhibit complex dyslipidemia and elevated cardiovascular risk. While randomized trials provide population-level estimates of treatment efficacy, individualized prediction of lipid changes, and corresponding uncertainty, remains limited. Using rich clinical data from the Action to Control Cardiova...

Polygenic risk scores (PRSs) are typically constructed under the assumption of a single, homogeneous disease phenotype. However, many common diseases exhibit considerable clinical heterogeneity and encompass multiple subtypes with distinct etiologies and clinical characteristics. As a result, conventional PRSs often overlook differences in underlying biological pathways among disease subtypes, consequently limiting predictive accuracy and cross-ancestry transferability. To address this challenge...

ObjectiveTo introduce and evaluate the clinical utility of the "adipo-B index" as a novel metric of the adipose tissue-pancreatic beta cell axis. To our knowledge, no prior clinical metric has integrated adipose tissue insulin resistance and pancreatic beta-cell function into a single index applicable across therapeutic classes. MethodsTreatment-naive subjects with T2DM received monotherapy with modified traditional diet for diabetes (MJDD, n=61), canagliflozin (n=67), pioglitazone (n=54), or s...

BackgroundDysbiosis of gut microbiota plays a key role in type 1 diabetes mellitus (T1DM). Fecal microbiota transplantation represents a novel therapeutic avenue. We hypothesize that youth-derived fecal microbiota transplantation (yFMT) can remodel the gut microecosystem and improve clinical outcomes. This study aims to investigate the efficacy and safety of orally administered yFMT capsules in adults with T1DM. Methods and analysisThis single-center, randomized, double-blind, placebo-controlle...

Breastfeeding is associated with metabolic benefits for women with type 2 diabetes and their infants, yet breastfeeding rates in these women are poorly described. Obesity is associated with type 2 diabetes, and lower breastfeeding rates, making it difficult to disentangle type 2 diabetes vs. obesity effects on breastfeeding. AimsThe primary objective was to examine breastfeeding rates in women with type 2 diabetes, compared to normoglycaemic women with either (1) matched body mass index (BMI) o...

1PurposeThe KIND (KINder mit Diabetes) cohort investigates diabetic peripheral neuropathy (DPN) in paediatric type 1 diabetes (T1D). Current guidelines recommend DPN screening at puberty or from 11 years and 2-5 years after T1D diagnosis, yet subclinical neurophysiological changes occur within the first 2 years. The cohort examines: (1) longitudinal associations between glycaemic metrics (HbA1c and continuous glucose monitoring-derived variability metrics) and peripheral nerve function and struc...