Introduction Pre-diabetes is becoming increasingly prevalent in adolescent populations. We recently reported a high prevalence of pre-diabetes among rural adolescent girls from the DERVAN cohort study established in the predominantly undernourished KONKAN region of India. We aimed to investigate the heterogeneity of pre-diabetes by identification of distinct subtypes. Research design and methods Anthropometry (body mass index (BMI) and waist circumference) and body composition (adiposity), as well as glycemic parameters (glucose, insulin, and glycated hemoglobin), were measured at the recruitment stage. Indices for insulin resistance (homeostatic model assessment (HOMA)-IR), β-cell function (HOMA-β), insulin sensitivity (HOMA-S), and compensatory β-cell response for prevailing insulin insensitivity were calculated using the homeostasis model. Pre-diabetes was diagnosed using the American Diabetes Association criteria. Unsupervised K-means clustering and a subgrouping algorithm were applied to characterize pre-diabetes. We used BMI, waist circumference, and adiposity for characterization. Glycemic parameters and HOMA indices were compared between clusters, as well as subgroups. Results Among 1382 girls, 809 (58.5%) were thin and 550 (39.8%) were pre-diabetic. We identified five clusters based on phenotypic characteristics: Cluster 1: young lean (YL), Cluster 2: old lean (OL), Cluster 3: low BMI-high waist, Cluster 4: normal BMI-low waist, and Cluster 5: obese. The cluster frequencies were 145 (26.4%), 131 (23.8%), 146 (26.5%), 74 (13.5%), and 54 (9.8%). Clusters YL and OL had the lowest fasting insulin concentrations, HOMA-IR, and HOMA-β but high HOMA-S and a compensatory β cell response for prevailing insulin insensitivity. Subgroup analysis further revealed a distinct lean pre-diabetic phenotype (n=314) with the lowest BMI (<18.5 kg/m 2 ), no central obesity and adiposity, and the lowest fasting insulin concentration, HOMA-IR, and HOMA-β compared with remaining subgroups. Conclusions We demonstrated the existence of a distinct lean pre-diabetic phenotype in adolescent girls whose characteristics seem to mirror those of adult type 5 diabetes, which has been recently recognized as a distinct entity. This suggests a need for precise strategies for primordial prevention.
Aims The association between reproductive lifespan (RLS) and diabetes and metabolic syndrome in menopausal women remains unclear. We investigated whether a short RLS is associated with diabetes and metabolic syndrome using nationally representative US data.Methods We conducted a cross-sectional analysis of menopausal women using data from the US National Health and Nutrition Examination Survey from 2007 to 2018. Weighted logistic regression models accounting for the complex survey design were used to estimate ORs and 95% CIs for diabetes and metabolic syndrome across quartiles of RLS.Results A total of 868 postmenopausal women with a mean age of 54.1 years were included. The mean ages at menarche and menopause were 12.7 and 51.2 years, respectively. The mean RLS was 38.5 years and was categorized into quartiles (11–35, 36–39, 40–42 (reference group), and 43–50 years). Compared with the reference group, women in the second quartile had higher odds of diabetes (OR 2.23; 95% CI 1.05 to 4.73) after adjustment for age, demographic characteristics, behavioral factors, age at menarche, and family history of diabetes. In contrast, women in the shortest RLS quartile were not at increased odds of diabetes, and no significant linear trend was observed across RLS categories. No robust association was observed between RLS and metabolic syndrome. These findings were consistent in sensitivity analyses that additionally included women with surgical menopause and that further adjusted for dietary factors.Conclusion A relatively short RLS may be associated with higher odds of diabetes, although this association did not follow a clear dose-response pattern. These findings suggest that reduced lifetime estrogen exposure may contribute to cardiometabolic risk. Given the cross-sectional design, longitudinal studies are needed to support these findings.
INTRODUCTION:Sub-Saharan Africa is undergoing rapid demographic, sociocultural, and economic transitions that are contributing to rising rates of overweight/obesity, which in turn may drive cardiometabolic sequelae such as diabetes and hypertension. However, the extent to which excess adiposity may contribute to the prevalence of such sequelae in sub-Saharan Africa remains uncertain. We thus sought to systematically evaluate body composition by dual-energy X-ray absorptiometry (DEXA) and its associations with glycemia and blood pressure (BP) in young women in Soweto, South Africa. RESEARCH DESIGN AND METHODS:This study was performed in 7735 women (median age of 22.4 years) undergoing assessment for a clinical trial. Whole-body DEXA scan yielded 12 measures of body composition (reflecting whole-body fat, central adiposity, peripheral adiposity, and lean mass/soft tissue) that were assessed as predictors of A1c, systolic BP, and diastolic BP, respectively. RESULTS:The study population had high rates of overweight/obesity (49.6%), pre-diabetes/diabetes (10.9%), and hypertension (11.9%). While specific adiposity measures (fat mass (FM), visceral adipose tissue, subcutaneous adipose tissue (SAT), android fat) were significantly associated with A1c, these associations were exceedingly modest, with these measures additionally explaining only 0.14% to 0.37% of the variance in A1c. In contrast, all 12 body composition measures showed significant associations with systolic BP and diastolic BP. Indices of lean mass/soft tissue (lean mass index, lean mass, fat-free soft tissue mass) explained 5.8% to 6.3% of the variance in systolic BP, while measures of adiposity (android fat, SAT, FM) reconciled 4.6% to 4.8% of the variance in diastolic BP, reflecting much stronger associations with BP than with A1c. CONCLUSION:In this young adult population with high rates of overweight/obesity and pre-diabetes/diabetes, DEXA-derived adiposity exhibits modest associations with glycemia, underscoring the atypical nature of diabetes in sub-Saharan Africa. TRIAL REGISTRATION NUMBER:PACTR201903750173871.
BACKGROUND:Stress hyperglycemia is common during percutaneous coronary intervention (PCI) and is associated with worse outcomes. The stress hyperglycemia ratio (SHR), which standardizes acute glucose levels to chronic glycemic status, may provide superior prognostic information compared with admission glucose alone. OBJECTIVE:To systematically evaluate the association between SHR and clinical outcomes in PCI patients and to quantify the exposure-response relationship. DATA SOURCES:PubMed, Embase, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov were searched from inception to August 5, 2025. STUDY SELECTION:Observational studies reporting SHR prior to PCI and subsequent clinical outcomes were included. DATA EXTRACTION:Two investigators independently extracted study characteristics, SHR definitions, and adjusted effect estimates. Risk of bias was assessed using ROBINS-I (Risk Of Bias In Non-randomized Studies of Interventions), and certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation framework. DATA SYNTHESIS:Thirteen studies comprising 41 096 PCI patients were included. Elevated SHR was associated with increased risks of all-cause mortality, major adverse cardiac and cerebrovascular events (MACCE), cardiovascular mortality, recurrent myocardial infarction, and stroke, but not with repeat revascularization. Sensitivity analyses yielded consistent results. The dose-response analysis suggested an approximately linear dose-response pattern between SHR and MACCE. LIMITATIONS:Most studies were observational, SHR definitions varied, and residual confounding cannot be excluded. The limited number of studies restricted the interpretability of dose-response analyses. CONCLUSIONS:Elevated SHR was associated with an increased risk of adverse outcomes after PCI. The dose-response analysis suggested an approximately linear dose-response pattern between SHR and MACCE. However, these findings should be interpreted cautiously given the observational nature of the evidence and the limited number of studies for certain analyses. PROSPERO REGISTRATION NUMBER:CRD420251045853.
We aimed to estimate the cardiovascular (CV) benefit of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) without a history of CV disease (CVD) (primary CVD prevention). We searched MEDLINE and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) and Epistemonikos for systematic reviews (up to July 4, 2025). We included RCTs of patients with T2D comparing a GLP-1 RA to placebo using a CV or renal primary outcome. 11 drug manufacturer-funded trials (77 419 participants) were included. We used version 1 of the Cochrane risk of bias tool. Our primary analysis was the pooled estimate of the treatment effect in primary CVD prevention. Outcomes of interest were major adverse cardiovascular events (MACE, primary outcome), all-cause mortality, CV mortality, myocardial infarction, stroke, and serious adverse events (secondary outcomes). Only 26% of participants were primary CVD prevention patients. The pooled estimates of treatment effect for primary CVD prevention were not significant for the primary outcome, MACE (pooled HR 0.88, 95% CI 0.74 to 1.05, based on eight trials, n=16 672), and all secondary outcomes. The certainty of the evidence was rated as low due to trials’ risk of bias and imprecision. Our review was limited to subgroup analyses of aggregated data from studies not powered for primary prevention alone. Current evidence is insufficient to establish CV benefits of GLP-1 RAs in T2D without a history of CVD, and dedicated primary prevention trials are needed.
Introduction Randomized controlled trials and real-world studies have demonstrated that automated insulin delivery (AID) systems enhance glycemic control and mitigate hypoglycemia risk in individuals with type 1 diabetes. This study evaluated the safety, effectiveness, and usability of the twiist AID System on glycemic outcomes in adults with type 1 diabetes. Research design and methods This 8-week, prospective, single-center, single-arm study included 20 adults with type 1 diabetes. The primary outcome measures were the percent of time spent in established continuous glucose monitoring (CGM) glycemic target ranges at 8 weeks. The primary efficacy outcome was percent time in range (%TIR; 70–180 mg/dL) at 8 weeks. Secondary outcomes were the change in glucose pre-occlusion detection; the effects of total daily insulin delivery (TDD) on glucose pre- and post-occlusion detection; the effect of Max basal ratio on %TIR; the effect of users’ correction range on %TIR; and change in glycated haemoglobin (HbA1c). Changes in TDD and body weight were also assessed. Results 19 participants completed the study. At 8 weeks, the mean %TIR was 70.3±15.5%. Participants achieved or maintained glycemic targets for all CGM metrics except time above >250 mg/dL. A total of 67 occlusion events occurred in 15 participants. These events were detected within 30 min of rising glucose. Higher max basal ratio settings were associated with higher %TIR. The %TIR for participants with a correction range <100 mg/dL was 79.2±13.4% vs 67.2±15.0% for those with a correction range >100 mg/dL. HbA1c levels decreased (−0.4%±0.5%) in participants with baseline HbA1c >7%. A slight increase in TDD (1.3±16.2 U) and a decrease in body weight (−0.09±2.9 kg) were observed. No serious adverse events were reported. Conclusions Eight-week use of twiist enabled participants to achieve or maintain established glycemic targets and suggests the system’s ability to detect occlusions before clinically significant glucose rise regardless of TDD. Larger and longer term studies are needed.
Introduction Increasing evidence suggests that liver fibrosis is an independent risk factor for cardiovascular disease. However, the mechanisms underlying this increased risk are still unsettled. The aim of this study was to explore the relationship between myocardial glucose metabolism and the severity of liver fibrosis.Research design and methods We evaluated insulin-stimulated myocardial glucose metabolic rate (MrGlu) using cardiac dynamic positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) combined with a euglycemic-hyperinsulinemic clamp and liver fibrosis severity, estimated by the fibrosis-4 (FIB-4) index, in 57 individuals with varying degrees of glucose tolerance. According to the FIB-4 index, subjects were stratified into three groups: low risk of fibrosis (<1.3; n=37), intermediate risk of fibrosis (≥1.3 to <2.67; n=16), and high risk of fibrosis (≥2.67; n=4).Results Subjects with a high risk of advanced fibrosis exhibited an age-adjusted decrease of myocardial MrGlu compared with both individuals with a low FIB-4 index category (4.6±4.3 µmol/min/100 g vs 21.7±11.2 µmol/min/100 g; p=0.009) and intermediate FIB-4 index category (20.±11.03 µmol/min/100 g; p=0.01, respectively). No significant differences in glycemic and anthropometric parameters, whole-body insulin sensitivity, or blood pressure were found between groups.In a multivariable regression analysis, the only variable significantly associated with advanced liver fibrosis risk was myocardial MrGlu (β=−0.286; p=0.003), explaining 28.6% of the variation.Conclusions These data suggest that impairment of insulin-stimulated myocardial glucose metabolism is associated with a high risk of advanced liver fibrosis in individuals with varying degrees of glucose tolerance.
Introduction Long-term trends in diabetes care use and socioeconomic inequalities are not well described in Japan. Research design and methods We analyzed nationally representative data from the Comprehensive Survey of Living Conditions (1986–2022). Diabetes care use was defined as self-reported current medical facility attendance for diabetes. Age-standardized prevalence was calculated as the proportion of adults currently receiving outpatient diabetes care; undiagnosed cases and diagnosed individuals not currently in treatment were therefore not captured. In the 2022 survey, a survey-weighted Poisson regression model was used to estimate prevalence ratios (PRs) of factors associated with current diabetes care use, including educational level and occupational class. Results Age-standardized self-reported current diabetes care use increased from 1986 to 2022, rising from 2.2% to 8.3% in men and from 1.7% to 4.4% in women, with a significant widening of the sex inequalities over the study period. Educational differences were evident, particularly among working-age adults. In 2022, compared with the high-education group, PRs were 1.17 (95% CI 1.13 to 1.22) for the middle-education group and 1.22 (95% CI 1.13 to 1.32) for the low-education group for both sexes. Occupational differences were more modest. Compared with upper non-manual workers, lower non-manual workers had a lower PR=0.92 (95% CI 0.86 to 0.98), while non-employed individuals had a higher PR=1.10 (95% CI 1.01 to 1.21); manual workers, self-employed individuals, and farmers did not differ significantly from the reference group. Older age, men, hypertension, depression, and current smoking were also associated with higher current diabetes care use. Conclusions Self-reported diabetes care use increased from 1986 to 2022 in Japan, with lower educational level associated with higher current diabetes care use, particularly among working-age adults. These findings help inform continued monitoring of socioeconomic inequalities in diabetes care.
Introduction This study examined how insulin resistance and impaired insulin secretion are associated with hyperglucagonemia during oral glucose tolerance tests (OGTT) in type 2 diabetes mellitus (T2DM).Research design and methods A retrospective analysis included 247 patients with T2DM treated at Tianjin Medical University General Hospital from October 2022 to March 2025. All underwent a 75 g OGTT, with blood samples collected at 0, 0.5, 1, 2, and 3 hours for glucose, insulin, C-peptide, and glucagon measurement. Insulin resistance was assessed via homeostasis model assessment of insulin resistance (HomaIR) and C-peptide immunoreactivity insulin resistance (CPRIR), while insulin secretion was evaluated using C-peptide area under the curve (AUCcp), homeostasis model assessment of beta cell function (HomaB), first-phase and second-phase insulin secretion during OGTT (first PH and second PH). Generalized linear models and mediation analyses examined associations between glucagon levels and above indices. Model fitness and robustness were evaluated via residual diagnostics, Cook's distance, and bootstrapped CIs.Results Glucagon levels during the OGTT were significantly elevated in patients with severe insulin resistance (HomaIR Q3 and CPRIR Q1), even after adjusting for confounders. In contrast, groups with the poorest insulin secretion (AUCcp Q1, HomaB Q1, first PH Q1, and second PH Q1) did not show elevated glucagon levels compared with those with better secretion. Mediation analysis confirmed that neither AUCcp nor HomaB mediated the relationship between insulin resistance and glucagon levels. Residual diagnostics demonstrated a satisfactory model fit. Furthermore, sensitivity analyses, both by excluding influential points identified via Cook's distance and by applying bootstrapped CIs, yielded consistent results, thereby affirming the robustness of the model.Conclusions In T2DM, impaired glucagon suppression during OGTT is associated with insulin resistance closely, highlighting insulin resistance as a key factor in alpha-cell dysfunction.
Current knowledge of hyperosmolar hyperglycaemic state (HHS) is drawn from case series and small observational cohorts, limiting applicability to broader clinical practice. There is a lack of robust, large-scale studies exploring triggers of HHS and associated mortality. This absence of reliable data impedes prevention strategies, tailored clinical guidelines, and equitable resource allocation. We conducted this systematic review to aggregate all relevant HHS cases, explore precipitating factors and outcomes, and how these vary by region. Searches across Ovid, PubMed, EMBASE, MEDLINE, Scopus, Web of Science, and Cochrane Library followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies reporting HHS cases from database inception to February 2025 were selected. Data on demographics, biochemical results, precipitants, outcomes, and complications were collected. 27 studies with a total of 63 935 cases were included. The median age was 63.8 years (IQR: 56.1–72.0). Common precipitants were non-infective illness (49.5%), infection (44.0%), and new diabetes diagnosis (31.7%). Intensive treatment unit admission was 40.8%, with the highest rate in North America (70.0%). Median hospital stay was 7.5 days, longest in Asia (17.5 days) and shortest in North and South America (4.0 days). Overall mortality was 21.1%, highest in Africa (40.0%), followed by Asia (18.2%), and lowest in North America (4.8%). Complications were acute kidney injury (7.6%), pulmonary oedema (4.8%), and acute coronary syndrome (3.9%). HHS presents with similar biochemistry globally, but outcomes vary significantly. Reducing mortality requires better diabetes diagnosis, harmonised protocols, and resource-adapted management to reduce gaps and inform prevention guidelines. PROSPERO registration number CRD42025625923.
Introduction Type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) frequently coexist in the same individual. Dyslipidemia plays a central role in the pathogenesis of MASLD. Remnant cholesterol (RC) is the cholesterol content carried in triglyceride-rich lipoproteins. We aimed to examine the association of RC, its discordance with low-density lipoprotein cholesterol (LDL-C) in terms of MASLD risk in patients with T2DM. Research design and methods A total of 26 302 T2DM patients who were hospitalized were cross-sectionally assessed. Logistic regression models were employed to assess the associations. We used three approaches to assess the effects of the discordance between RC and LDL-C on MASLD risk: clinical cut-off points, differences of >10 percentile points and residuals. Results The median age was 62.0 years, and 48.3% had MASLD. RC was more closely associated with MASLD than LDL-C. Furthermore, discordantly high RC was associated with higher MASLD risk than discordantly high LDL-C, regardless of which method of discordance analysis is used. For example, for the residual approach, in a regression model including LDL-C and RC residual, the latter, representing the portion of RC not explained by LDL-C, was more associated with MASLD risk than LDL-C (OR=1.26, 95% CI 1.22 to 1.30 for RC residual and OR=1.04, 95% CI 1.01 to 1.07 for LDL-C); in a regression model including RC and LDL-C residual, the latter representing the portion of LDL-C not explained by RC, RC was more associated with MASLD risk than LDL-C residual (OR=1.24, 95% CI 1.20 to 1.29 for RC and OR=1.09, 95% CI 1.06 to 1.12 for LDL-C residual). Conclusions Discordantly high RC was associated with higher MASLD risk than discordantly high LDL-C. Our findings suggest that RC may serve as a potential target for prevention and intervention for MASLD.
BACKGROUND:Despite the high prevalence of diabetes in Qatar, Ramadan-related glycemic events remain inadequately characterized. This study examined sociodemographic, clinical and behavioral factors independently associated with hypoglycemic or hyperglycemic events among patients with diabetes during Ramadan in Qatar. METHODS:A retrospective analysis was conducted using routinely collected data from the Qatar Diabetes Association (QDA) Ramadan support program covering three Ramadan seasons (2022-2024). Patients with type 1 or type 2 diabetes who attended QDA diabetes education or dietetic clinics were included, regardless of fasting intention. Those with pre-diabetes or gestational diabetes were excluded. Assessments began 6-8 weeks before Ramadan, with structured follow-up throughout the month. Primary outcomes-based on patient-recorded blood glucose readings-were defined to capture the overall risk of glycemic instability during Ramadan and included (1) any hypoglycemic (<70 mg/dL) or hyperglycemic (>250 mg/dL) event and (2) any such events during fasting hours. Generalized estimating equation logistic regression models identified factors associated with hypoglycemic or hyperglycemic outcomes. Missing data were <5% and handled by complete-case analysis. Statistical significance was defined as 95% CIs excluding 1. RESULTS:The study included 374 patients; 95.5% of observations were from patients with type 2 diabetes and 43.3% reflected longer diabetes duration. Adjusted ORs indicated higher odds of hypoglycemia or hyperglycemia at any time among patients with a longer diabetes duration, a high International Diabetes Federation-Diabetes and Ramadan risk score, those who discussed a fasting plan with a physician, those who used medications known to increase hypoglycemia risk, and those who used continuous glucose-monitoring devices. During fasting hours, higher odds were observed among patients with type 1 diabetes and those with a higher daily number of recorded blood glucose readings. CONCLUSIONS:The findings underscore the importance of structured pre-Ramadan risk assessment, patient-centered education, close and rigorous follow-up and individualized treatment adjustment-particularly for high-risk groups-to optimize safety and enhance the overall Ramadan experience among persons with diabetes.
Introduction Orexins, hypothalamic neuropeptides, play a critical role in promoting wakefulness. Suvorexant, a dual orexin receptor antagonist, which is primarily indicated for the treatment of insomnia, also lowers blood glucose. Similarly, in rodent studies, suvorexant has shown beneficial effects on overall glucose homeostasis. Using an animal model of type 2 diabetes (T2D) db/db mice, we hypothesized that suvorexant treatment could improve the ocular complications of T2D.Reseach design and methods Male db/db mice were treated daily with suvorexant (30 mg/kg, intraperitoneal) or vehicle at Zeitgeber time 0–2 for 12 weeks. The following visual assessments were performed to study the effects of suvorexant: electroretinogram, optomotor response test, and fluorescein angiography. Glucose and insulin tolerance tests were performed to assess the impact on glycemic control. After euthanasia, retinas were isolated, and qPCR and immunofluorescence staining were performed.Results Suvorexant treatment improved visual acuity and vascular parameters, including reduced avascular and increased vascular areas. There was a decrease in scotopic a-wave and b-wave amplitudes in suvorexant-treated mice, along with increased b-wave implicit time. Suvorexant downregulated mRNA of phospholipase C γ1 and protein kinase C beta, as well as inflammatory markers tumor necrosis factor-α (Tnf-a) and interleukin 1β (Il-1b). Consistent with changes in mRNA levels, suvorexant reduced protein expression of PKCβ and CD45 in immunofluorescence studies of retinal transverse sections. Furthermore, suvorexant-treated mice demonstrated improved glucose tolerance compared with vehicle-treated mice.Conclusions We found that suvorexant improved visual acuity and retinal vascular insufficiency by reducing retinal inflammation and improving glucose homeostasis in db/db mice. Our findings suggest that orexin receptor inhibition, with suvorexant, may be a potential treatment for ocular complications associated with T2D.
Obesity is a heterogeneous chronic disease in which excess adiposity increases the risk of morbidity and mortality. The Obesity Association, a division of the American Diabetes Association (ADA), developed comprehensive, evidence-based guidelines on screening, diagnosis, evaluation, and staging of overweight and obesity in adults. Monitoring for consistent increases in weight over time may facilitate early intervention to prevent obesity and its complications, and screening for excess adiposity should be performed at least annually using BMI. The recommended diagnostic criteria for overweight and obesity include race- and ethnicity-specific BMI thresholds supplemented with waist circumference-based measures for certain individuals to reduce the risk of underdiagnosis. healthcare professionals should perform a comprehensive clinical evaluation, including risk stratification and staging, of all adults diagnosed with overweight or obesity, which will inform the management plan and follow-up care. The ADA's Obesity Association encourages healthcare professionals to adopt these guidelines for evaluating obesity in adults.
Introduction Type 2 diabetes mellitus (T2D) accelerates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to hepatic fibrosis, and a subset of MASLD subjects has T2D. Identification of molecular mediators linking T2D and MASLD progression remains unmet. Studies revealed patients with steatohepatitis have lower hepatic Mitogen inducible gene-6 (Mig-6) expression, and Mig-6 gene silencing causes hyperglycemia in a preclinical study. However, the relationship between Mig-6 and dysglycemia in MASLD, including its association with pancreatic β-cell dysfunction, is unknown. We assessed serum Mig-6 level in MASLD with or without dysglycemia, and its association with Homeostasis Model Assessment of β-cell function (HOMA-β).Methods Fibrosis 4 Index (FIB-4) score was calculated in 479 MASLD patients; those scoring 1.3–2.67 underwent liver vibration-controlled transient elastography for fibrosis assessment. F2 and F3 fibrosis subjects (119) were classified as normal glucose tolerance (NGT) (35), impaired glucose tolerance (44), and treatment-naïve T2D (40), as per American Diabetes Association criteria. Serum Mig-6 levels were measured by ELISA. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and HOMA-β were computed using serum C peptide.Results Metabolic syndrome was present in 68% and 27% of participants with FIB-4>1.3 and <1.3, respectively. Reduced serum Mig-6 level was observed in the FIB-4 score >1.3 group. Participants with dysglycemia had lower (p<0.05) serum Mig-6 levels compared with NGT. Mig-6 showed a negative correlation with fasting plasma glucose, hemoglobin A1C and HOMA-IR and a positive correlation with HOMA-β. A cut-off value of serum Mig-6 level <97.49 pg/mL predicted dysglycemia in metabolic dysfunction-associated steatohepatitis (sensitivity 77.50%, specificity 73.08%, receiver operating characteristic analysis curve). 74.2% of the treatment-naïve T2D subjects had a low serum Mig-6, compared with 22% of subjects with NGT. HOMA-β was lower in the group having Mig-6 below the cut-off level (97.49 pg/mL). Positive predictive and negative predictive values of Mig-6 in identifying pancreatic β-cell dysfunction were 79.41% and 85.17%, respectively. For patients having HOMA-IR>1.6, corresponding values were 80% and 86.67%, respectively.Conclusion Serum Mig-6 levels may identify MASLD patients at an increased risk of dysglycemia and positively correlate with pancreatic β-cell dysfunction.
Objective This pilot project served as a proof of concept to assess the operational feasibility of integrating presymptomatic type 1 diabetes screening and monitoring, using islet autoantibody (AAB) testing, into routine clinical care at two pediatric T1D Exchange Quality Improvement Collaborative (T1DX-QI) centers. Additionally, it identified care team perceptions of operational challenges and surveyed healthcare teams’ readiness in the T1DX-QI.Research design and methods Over an 18-month period, this initiative focused on developing and optimizing workflows, provider and patient education, technological integration, and health equity, utilizing quality improvement methodologies. Focus groups were conducted to identify care team perceptions of operational challenges via Zoom. Prior to project start, a cross-sectional survey was administered among T1DX-QI centers to assess screening and monitoring readiness.Results Workflows for screening and monitoring were tested over time at the two centers, both developing process maps. A total of 147 individuals were screened during 12 months of active screening. No episodes of diabetes-related ketoacidosis were reported among those screened with confirmed positive results. Key facilitators of implementation identified during focus groups included enhanced interdisciplinary communication, streamlined insurance processes, and improvements to electronic health record systems. Challenges included limited clinical resources, variable patient engagement, and inconsistent insurance coverage. Readiness survey results highlighted that pediatric centers were twice as likely to conduct screening and reported greater access to results from research screening programs.Conclusions Findings from this pilot offer critical insights into the practical implementation of presymptomatic type 1 diabetes screening and monitoring programs in diverse clinical environments. Despite identified barriers, continuous quality improvement efforts, along with identified facilitators to success, led to an increase in the number of individuals screened and monitored. Future work will focus on expanding these efforts across diverse care settings, with strategies to support sustainability beyond pilot phases.
BACKGROUND AND HYPOTHESIS:Chronic kidney disease (CKD) is a global health and economic burden, particularly among individuals with type 2 diabetes (T2D). According to Kidney Disease: Improving Global Outcomes guidelines, key CKD indicators include urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Although independent genetic loci for these traits have been reported, their shared genetic architecture remains insufficiently understood. We hypothesized that there are shared genetic markers of kidney function (eGFR) and albuminuria generally, but also specific to the T2D population. METHODS:We conducted a cross-sectional observational study including 432 451 UK Biobank participants of primarily European descent (94%), with a subgroup of 16 265 with T2D after data quality control. We examined whether 423 single-nucleotide polymorphisms previously associated with eGFR in a large genome-wide association study meta-analysis were associated with (a) eGFR estimated using the 2021 race-free CKD-Epidemiology Collaboration creatinine equation (eGFR2021) and (b) UACR. Multiple linear regression models were adjusted for systolic blood pressure, age, sex, and the first 10 genetic principal components to account for population stratification. Analyses were performed using Python and R. Bonferroni correction (BC) was performed. For the T2D subgroup, the models were additionally adjusted for body mass index and glycated hemoglobin. RESULTS:In the overall population, 422 loci were nominally associated with eGFR2021, of which 75 were nominally associated with UACR (p≤0.05); 12 remained significant after BC (Pb ≤ [Formula: see text]). In the T2D subgroup, 76 loci nominally associated with eGFR2021, six also associated nominally with UACR (p≤0.05), and one remained significant after BC (Pb ≤ [Formula: see text]). Two pleiotropic loci (GSTA2, USP2-AS1) suggested diabetes-specific effects. CONCLUSION:This study identifies several shared genetic loci underlying eGFR and UACR in both general and T2D European populations. These findings highlight common pathobiological pathways between albuminuria and reduced kidney function and provide a genetic map that may inform future CKD risk stratification and towards the development of therapeutic targets.
INTRODUCTION:Renal involvement in type 2 diabetes (T2DM) can be due to diabetes (diabetic kidney disease, DKD) or other causes (non-DKD, NDKD) or both (mixed kidney disease). Available clinical and laboratory parameters have limitations in predicting a diagnosis (gold standard renal biopsy). Long non-coding RNAs (lncRNAs) evaluated in preclinical models but unexplored in biopsy-proven kidney disease in T2DM. We aimed to determine whether there is differential expression of lncRNAs in DKD (compared with NDKD). RESEARCH DESIGN AND METHODS:lncRNAs preselected through database search for evaluation in humans.Discovery cohort: Preselected lncRNAs () evaluated in three components of urine (urinary cell, urinary exosome, and cell-free urine) from biopsy-proven DKD, NDKD, T2DM without kidney disease and healthy subjects (n=40/group). lncRNAs found consistently significant in all components were checked in kidney tissue. Receiver operating characteristic curves were performed to evaluate diagnostic performance.Validation cohort: Best performing lncRNA (in discovery cohort) evaluated in independent cohort. CLINICAL UTILITY:The utility of identified lncRNAs was further assessed for clinical decision-making. RESULTS:Discovery cohort: Level of MALAT1 and PVT1 differed in all urinary components of DKD and elevated in kidney biopsy tissue. MALAT1 showed the most consistent results. Urinary cell-derived MALAT1 showed the most consistent results (ΔCt <8.3, sensitivity 90%, specificity 89.6% OR 53.9, p<0.0001) to differentiate DKD from NDKDValidation cohort: Urinary cell-derived MALAT1 showed sensitivity (90%) and specificity (88.5%). CLINICAL UTILITY:Addition of MALAT1 to currently existing clinical/biochemical discriminators of DKD from NDKD helps improve clinical decision making, with a net reclassification improvement (NRI) of 0.53, 64% of DKD cases were correctly reclassified to a higher probability of disease (NRI+ = 0.280), and 62.5% of NDKD controls were correctly reclassified to a lower probability of disease (NRI- = 0.250). CONCLUSIONS:Urinary cell-derived MALAT1 improves the ability to differentiate DKD from NDKD over and above currently used clinical and biochemical parameters.
INTRODUCTION:Seroconversion (SV) marks islet autoimmunity (IA) onset and preclinical type 1 diabetes (T1D), yet the contributions beyond T and B lymphocytes remain unclear. We evaluated DNA methylation (DNAm)-derived immune cell ratios between T1D cases and controls around SV. RESEARCH DESIGN AND METHODS:High-resolution immune cell-type deconvolution of peripheral blood DNAm from nested case-control samples in the Diabetes Autoimmunity Study in the Young (DAISY; n=151) and the Environmental Determinants of Diabetes in the Young (TEDDY; n=166) estimated immune cell proportions at pre-SV (the latest visit before SV) and at SV (the first visit with persistent detected autoantibodies) to construct immune cell ratios, such as the neutrophil-to-lymphocyte ratio (NLR). Linear models compared T1D cases to matched T1D controls (IA negative) at pre-SV, SV, and the change across time points. RESULTS:From pre-SV to SV, controls showed expected developmental increases in B-memory/naive, B-CD4T-CD8T memory/naive, and NLR, while cases failed to follow these patterns, with attenuated trajectories of 35%, 38%, and 21%, respectively. Pre-SV, cases had 15% higher NLR and 9% lower CD4T/CD8T. At SV, the combined B-CD4T-CD8T memory/naive ratio was 26% reduced in cases. CONCLUSIONS:These patterns may reflect increased neutrophil activation or pancreatic infiltration, altered CD4 and CD8 T cell balance, and delayed or disrupted immune maturation with the persistence or expansion of naive B and T cells or impaired transition to memory B and T subsets following antigen exposure. Our findings highlight early shifts in innate and adaptive immune cell dynamics during T1D pathogenesis and support methylation-derived immune cell ratios as potential biomarkers for risk stratification and mechanistic insight.
