Current definitions of type 2 diabetes (T2D) and prediabetes do not capture their pathophysiological heterogeneity. We investigated data-driven subtypes of T2D and prediabetes and evaluated their associations with mortality. We analyzed data from 14,036 South Asian participants from the CArdiometabolic Risk Reduction cohort using unsupervised k-means clustering based on five variables: age, BMI, HbA1c, insulin resistance, and β-cell dysfunction. For each subtype of T2D or prediabetes, we estimated Cox hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality and excess years of life lost compared with normal glucose tolerance. Among 2,639 participants with T2D, three subtypes emerged: severe insulin-deficient diabetes (SIDD; 23.0%), mild insulin-deficient diabetes (MIDD; 54.5%), and severe insulin-resistant diabetes (SIRD; 22.5%). Among 4,992 participants with prediabetes, two subtypes were identified: insulin-deficient prediabetes (IDPD; 66.0%) and insulin-resistant prediabetes (IRPD; 34.0%). Over a median follow-up of 10.6 years, 1,076 deaths occurred (405 due to CVD). Compared with normal glucose tolerance, SIDD had the highest all-cause mortality (HR 3.34; 95% CI 2.39-4.68), followed by MIDD (1.39; 95% CI 1.05-1.84), and SIRD (1.67; 95% CI 1.15-2.41). Among prediabetes subtypes, IDPD was associated with increased all-cause (HR 1.32; 95% CI 1.03-1.68) and CVD mortality (HR 1.53; 95% CI 1.00-2.34), whereas IRPD was not. Excess years of life lost were greatest for SIDD (17.7 years), followed by MIDD (12.8 years) and SIRD (12.0 years). Insulin-deficient subtypes made up a high proportion of individuals with T2D and prediabetes and were associated with higher mortality hazards and excess years of life lost.

HbA1c 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. We analyzed 5,024 autoantibody-positive relatives (3,720 children and 1,304 adults) participating in the TrialNet Pathway to Prevention study. Age-related HbA1c effects were modeled using 6,273 adults from the population-based Exeter 10000 cohort. Progression risk was compared using the standard dysglycemia threshold (HbA1c ≥5.7% [39 mmol/mol]), age-adjusted HbA1c, and an alternative threshold of HbA1c ≥6.0% (42 mmol/mol). Using HbA1c ≥5.7% (39 mmol/mol), children had higher 1-year progression risk than adults among single autoantibody-positive participants (38% [95% CI 28, 47] vs. 13% [7.2, 19]) and multiple autoantibody-positive participants (55% [49, 60] vs. 38% [27, 47]) (both P < 0.001). Age adjustment reduced these differences; progression risk was similar among single autoantibody-positive participants (38% [28, 47] vs. 27% [13, 39]; P = 0.32), with attenuated differences among multiple autoantibody-positive participants. An HbA1c threshold ≥6.0% (42 mmol/mol) yielded comparable progression risk between adults and children across autoantibody subgroups. In post hoc analyses, adults aged <30 years had progression risk similar to children (P = 0.1). Age-related variation in HbA1c influences dysglycemia classification in adults at risk for type 1 diabetes. Age-adjusted HbA1c or a higher HbA1c threshold (≥6.0% [42 mmol/mol]) in adults aged ≥30 years identifies individuals with progression risk comparable to children and may improve age-specific risk stratification in prevention settings.

To evaluate the real-world feasibility and efficacy of low-dose antithymocyte globulin (ATG) by an exploratory modified quantitative response (mQR) of C-peptide in type 1 diabetes. Individuals with stage 2 (n = 6) or stage 3 (n = 33) diabetes were treated clinically with low-dose ATG (2.5 mg/kg) and asked to obtain C-peptide via a commercial laboratory 90 min postconsumption of 6 mL/kg Boost. Thirty individuals (77%) completed 1 year of follow-up, with 22 (73% of those) providing pre-ATG and 1-year-post-ATG C-peptides. Area under the curve C-peptide was estimated from 90-min values to calculate mQR. In the 22 evaluable patients, average mQR at 1 year was 0.072. Average HbA1c decreased from 7.1% (54 mmol/mol) to 6.0% (42 mmol/mol). There were 15 responders (+mQR) and 7 nonresponders (-mQR). There were no unexpected side effects. C-peptide mQR was feasible and produced expected responder frequencies following low-dose ATG in a clinical practice setting.

We assessed whether 1) severe acute respiratory syndrome coronavirus (SARS-CoV-2) vaccination is associated with the risk of type 1 diabetes and 2) SARS-CoV-2 vaccination or infection is associated with disease severity at type 1 diabetes diagnosis. Every Finnish child aged 5-14 years diagnosed with type 1 diabetes (case subjects, n = 433) during a 16-month period (September 2021 to December 2022) were compared with three control subjects matched for age, sex, and municipality. Information on coronavirus disease 2019 (COVID-19) vaccinations was obtained from the National Vaccination Register. SARS-CoV-2 infections were identified based on circulating antibody titer in samples obtained soon after the diagnosis of type 1 diabetes. COVID-19 vaccinations preceding type 1 diabetes diagnosis were not associated with risk of type 1 diabetes (hazard ratio 1.30, 95% CI 0.97-1.72, P = 0.076). Vaccinations were linked to less severe symptoms at the time of diagnosis. Children with protective HLA genotypes were more common among the vaccinated case subjects compared with unvaccinated case subjects. Vaccinations were inversely associated with insulin autoantibody positivity. There was no association between SARS-CoV-2 and type 1 diabetes symptoms or autoantibodies at the time of type 1 diabetes diagnosis. There was no significant association between SARS-CoV-2 vaccination and risk of type 1 diabetes. Neither COVID-19 vaccinations nor SARS-CoV-2 infections explain the more severe symptoms at type 1 diabetes diagnosis observed in Finnish children after the beginning of the COVID-19 pandemic. Parents who vaccinate their children are more likely to seek medical care. This may result in less severe symptoms in their children at diagnosis of diabetes.

Discordance between the glucose management indicator (GMI) and hemoglobin A1c (HbA1c) is frequently observed in diabetes, yet its physiological basis remains unclear. This study investigated how specific glucose excursion patterns captured by continuous glucose monitoring (CGM) contribute to this discordance in individuals with type 1 diabetes. Ninety-day CGM traces from 611 adults with type 1 diabetes were paired with HbA1c results obtained within ±15 days. Glucose excursions were quantified using the glucose rate increase detector (GRID) algorithm with varied peak glucose and time-to-peak thresholds. Discordance was defined using GMI-to-HbA1c and updated GMI (uGMI)-to-HbA1c ratios, and associations with GRID-derived excursion metrics were evaluated alongside conventional CGM-derived variability metrics. Excursions with peak glucose ≥250 mg/dL and time to peak ≥90 min were significantly associated with higher uGMI-to-HbA1c ratios after adjustment for age, sex, eGFR, and HbA1c group, with consistent findings across CGM devices (sensor type 1: β = 0.174, 95% CI 0.147-0.201; sensor type 2: β = 0.102, 95% CI 0.068-0.136; both P < 0.001) and alternative GMI formulations. In restricted cubic spline analyses, adjustment for GRID-derived excursion metrics differentially reshaped the associations of HbA1c, GMI, and uGMI with albuminuria and elevated triglyceride-glucose (TyG) index in an outcome- and context-dependent manner, preferentially enhancing the informativeness of GMI and uGMI-but not HbA1c. Frequent high and prolonged glucose excursions were consistently associated with GMI-HbA1c discordance across devices, HbA1c strata, and analytic conditions. GRID-derived excursion metrics modify the relationship between GMI/uGMI and glycemia-associated risk.

Prediabetes is a precursor of type 2 diabetes mellitus (T2DM), and lifestyle modifications are key preventive strategies. Primary care is central to prevention efforts, including screening, diagnosis, and follow-up. This systematic review and meta-analysis aimed to evaluate the effectiveness of lifestyle interventions delivered in primary care to patients at elevated risk of developing T2DM. We searched Medline and Embase from inception to 28 March 2024. We screened 639 records and included 14 eligible studies of lifestyle-based diabetes prevention programs. Eligible participants had prediabetes or high diabetes risk scores, and interventions were delivered in primary care. Outcomes included diabetes incidence, glycemic and anthropometric indicators, physical activity, and diet. Pooled mean differences (MD) were estimated using inverse variance methods; leave-one-out cross-validation (LOOCV) addressed heterogeneity (>50%). Meta-analysis found no significant effects on diabetes incidence (relative risk 0.82; 95% CI 0.65-1.02), and pooled MD on HbA1c (MD -0.41, 95% CI -0.94 to 0.12), fasting glucose, 2-h glucose, body weight, BMI, waist circumference (MD -1.13, 95% CI -2.40 to 0.13), or systolic and diastolic blood pressure. LOOCV identified one study driving heterogeneity in several outcomes. English-only publications may reduce generalizability. This review found no significant differences in diabetes incidence or other key indicators of T2DM, with certainty of evidence varying from moderate to low. Future studies should test integrated screening, referral, and social support strategies in routine care for high-risk groups.

To examine the associations between cumulative BMI burden from childhood to adulthood and the risk of adult metabolic multimorbidity. This prospective cohort study used data from the Hanzhong Adolescent Hypertension Study (1987-2023). A total of 2,446 participants with at least two BMI measurements in both childhood (6-18 years) and adulthood (19-52 years) were included. Cumulative BMI exposure was quantified using total and incremental area under the curve (AUC). Outcomes included metabolic multimorbidity, defined as the presence of two or more or three or more metabolic diseases, specifically hypertension, diabetes, dyslipidemia, elevated liver enzymes/bilirubin, and kidney damage. Higher total and incremental BMI AUC during childhood, adulthood, and over the life course were consistently associated with an increased risk of adult metabolic multimorbidity (two or more diseases). For total AUC, odds ratios (ORs) ranged from 1.51 to 2.59 (all P < 0.05); for incremental AUC, ORs ranged from 1.94 to 4.33 (all P < 0.05). Compared with total AUC, incremental AUC showed a stronger association with metabolic multimorbidity in childhood (OR 4.33 [95% CI 2.93, 6.40] vs. 1.51 [1.17, 1.95], respectively). Conversely, total AUC exhibited a stronger association in adulthood than in childhood (OR 2.51 [2.08, 3.04] vs. 1.94 [1.62, 2.31]). Furthermore, the associations for adulthood and life course BMI AUC were significantly stronger in males than in females (P for interaction < 0.05). These findings highlight the importance of life stage-specific strategies: curbing rapid BMI gain in childhood and maintaining long-term weight control throughout adulthood.

To examine the relationship between long-term air pollution exposure, including black carbon (BC), fine particulate matter (PM2.5), and nitrogen dioxide (NO2), and total fat mass, visceral fat mass, and lean mass in older adults with overweight or obesity and metabolic syndrome. We included 1,454 older adults (aged 54-75 years; 48% female) from the PREDIMED-Plus trial in Spain who underwent baseline DXA scans at recruitment (2013-2016) and at 1- and 3-year follow-up. Annual air pollution exposure was assigned at participants' baseline residential address at 100 m resolution. We used linear mixed-effect regression models with interaction terms for exposure and time to examine longitudinal associations with body composition, also stratifying by sex, age, and physical activity. At baseline, a 1× 10-5/m increase in BC was associated with 1.01% (95% CI 0.31-1.71) higher body fat percentage, -0.97% (95% CI -1.64 to -0.30) lower lean mass percentage, and -0.74 kg (95% CI -1.37 to -0.12) lower lean mass. PM2.5 and NO2 showed similar relationships with body fat and lean mass percentage at baseline. These associations persisted in years 1 and 3 for BC and PM2.5. In age-stratified analyses, associations with visceral fat mass were observed only in participants younger than 65 years. Associations did not meaningfully differ by sex or physical activity. Long-term air pollution exposure was adversely associated with body composition over 3 years. Results indicate air pollution is associated with fat accumulation and lean mass loss in metabolically vulnerable older adults.