Daily Endocrinology Research Analysis
Analyzed 43 papers and selected 3 impactful papers.
Summary
Three high-impact endocrinology studies span mechanistic epigenetics and population-level interventions. A Nature Metabolism study maps age- and disease-related DNA methylation remodeling in human pancreatic beta cells, a Diabetologia Mendelian randomization identifies causal CpG sites for type 2 diabetes in West Africans, and a large Diabetic Medicine cohort links multidisciplinary care to fewer major amputations in diabetic foot ulcers.
Research Themes
- Epigenetic regulation of pancreatic beta cells in aging and type 2 diabetes
- Causal epigenetic biomarkers for type 2 diabetes in underrepresented populations
- Health services interventions to reduce complications in diabetic foot ulcers
Selected Articles
1. Epigenetic adaptation of beta cells across lifespan and disease.
Using cell-type-specific human pancreatic methylomes, the authors show progressive age-related demethylation at cis-regulatory elements of beta cell identity/function genes, opposite trends in alpha cells, and further demethylation in T2D beta cells. Findings indicate a compensatory epigenomic remodeling in beta cells that accelerates in T2D but ultimately fails under chronic insulin resistance.
Impact: Provides a high-resolution, cell-type-specific map linking age and T2D to epigenomic remodeling in human beta cells, advancing mechanistic understanding of beta cell adaptation and failure.
Clinical Implications: While not immediately practice-changing, the work supports development of epigenetic biomarkers of beta cell stress and potential therapeutic strategies targeting chromatin remodeling to preserve beta cell function.
Key Findings
- In healthy donors, beta cells exhibit progressive age-related demethylation enriched at cis-regulatory elements of identity and function genes.
- Alpha cells display the opposite trajectory with subtle age-related hypermethylation.
- T2D beta cells show further demethylation beyond healthy controls, consistent with an accelerated compensatory epigenomic response.
Methodological Strengths
- Cell-type-specific methylome profiling from the Human Pancreas Analysis Program
- Genome-wide analysis with direct comparison between beta and alpha cells across age and disease states
Limitations
- Observational epigenomic mapping cannot establish causality between methylation changes and functional outcomes.
- Sample sizes and donor diversity are not specified; generalizability across ancestries and disease stages remains uncertain.
Future Directions: Longitudinal human studies and perturbation experiments to test whether modifying specific methylation programs preserves beta cell function; development of epigenetic biomarkers for early beta cell stress in T2D risk.
Although the prevalence of type 2 diabetes (T2D) increases with age, most adults maintain normoglycaemia despite rising insulin resistance owing to the adaptive capacity of pancreatic beta cells to meet increased metabolic demand. However, persistent insulin resistance can lead to beta cell dysfunction and T2D onset. Here we show the mapping of genome-wide DNA methylation (DNAm) patterns and the epigenomic basis of beta cell adaptations by leveraging cell-type-specific methylome data from the Human Pancreas Analysis Program. In healthy donors, we identify progressive age-related demethylation enriched in cis-regulatory elements at beta cell identity and function genes. By contrast, alpha cells show the opposite trajectory, with subtle, age-related hypermethylation. In T2D beta cells, but not alpha cells, we observed further demethylation compared to healthy controls, underscoring a unique capacity of beta cells to respond to changes in metabolic demand. Together, our findings suggest that DNAm remodelling in healthy beta cells reflects a long-term adaptation to metabolic demand, which, in T2D, is accelerated as part of a compensatory response that ultimately fails under sustained insulin resistance.
2. Causal relationship between epigenetic markers and type 2 diabetes in West African populations: a Mendelian randomisation analysis.
In two West African cohorts (RODAM and AADM; n=879 and n=332), MR leveraging blood DNA methylation identified two CpG sites with evidence of causal effects on type 2 diabetes. The study also catalogued dozens of CpGs associated with T2D and glycaemic traits, addressing critical gaps in underrepresented populations.
Impact: Demonstrates causal epigenetic markers for T2D in West Africans using MR, improving mechanistic inference and prioritizing biomarkers/targets in an under-studied high-burden population.
Clinical Implications: The identified causal CpGs could inform early-risk stratification and guide development of epigenetic biomarkers or therapies tailored for African populations with rising T2D burden.
Key Findings
- Two CpG sites showed Mendelian randomization evidence supporting a causal role in type 2 diabetes among West Africans.
- Across cohorts, 28 CpGs were associated with T2D and 26 with glycaemic traits (HbA-related) in EWAS follow-up analyses.
- Participants were not on glucose-lowering therapy, reducing treatment confounding; DNA methylation profiled using Illumina EPIC array.
Methodological Strengths
- Mendelian randomization framework to mitigate confounding and reverse causation
- Inclusion of two independent West African cohorts with longitudinal data and standardized EPIC array profiling
Limitations
- Blood-derived methylation may not reflect disease-relevant tissues; identified CpGs and effect sizes are not detailed in the abstract.
- Moderate sample sizes (879 and 332) and potential heterogeneity between cohorts limit precision.
Future Directions: Validate causal CpGs in larger, multi-ancestry cohorts and in disease-relevant tissues; integrate methylation with gene expression and chromatin assays; develop blood-based risk scores for early T2D.
AIMS/HYPOTHESIS: Evidence for a causal role of DNA methylation sites (CpGs) in type 2 diabetes and glycaemic traits is limited due to the cross-sectional nature of many epigenome-wide association studies (EWAS). In addition, epigenetic studies in West African populations are particularly sparse, despite the high and rising burden of type 2 diabetes in these populations. Hence, we aimed to identify CpGs causally associated with type 2 diabetes among West Africans by leveraging Mendelian randomisation (MR) analysis and longitudinal data. METHODS: We used the Illumina EPIC DNA methylation array to profile the methylation of DNA extracted from white blood cells collected from 879 Ghanaian individuals (the Research on Obesity and Diabetes among African Migrants [RODAM] study) and 332 Nigerian individuals (the Africa America Diabetes Mellitus [AADM] study) who were not on glucose-lowering medication. We carried forwards CpGs identified in EWAS for type 2 diabetes and meta-analysed EWAS for HbA RESULTS: We identified 28 CpGs associated with type 2 diabetes, 26 with HbA CONCLUSIONS/INTERPRETATION: Our study identified two epigenetic markers as likely to be causal for type 2 diabetes in West African populations. In addition to enhancing our understanding of disease mechanisms, these CpGs with evidence of causal associations could be prioritised as potential biomarkers for early detection of disease or as drug development targets.
3. The burden of diabetic foot ulcers in a multi-ethnic Asian cohort.
In a 22,830-patient retrospective registry, 11.1% had DFU and these patients had higher comorbidity burden. After adjustment, DFU independently associated with higher mortality and longer hospitalization. Referral to a multidisciplinary rapid-access clinic (DREAM) was independently associated with lower risk of major, but not minor, lower extremity amputation.
Impact: Demonstrates, at scale, that multidisciplinary rapid-access management of DFU is associated with fewer major amputations, directly informing health system design in diabetes care.
Clinical Implications: Supports early referral to multidisciplinary DFU services to reduce major amputations and hospital burden; reinforces risk stratification in patients with longer diabetes duration and multiple comorbidities.
Key Findings
- Among 22,830 adults with diabetes, 11.1% had DFU; DFU patients were older with longer diabetes duration and more cardiometabolic comorbidities (p<0.001).
- After multivariable adjustment, DFU independently associated with increased mortality and prolonged hospitalization.
- Within the DFU cohort, referral to the multidisciplinary DREAM clinic independently associated with reduced risk of major lower extremity amputation, but not minor amputation.
Methodological Strengths
- Very large health system registry with 22,830 participants and comprehensive clinical data
- Multivariable adjustment and prespecified subgroup analysis of multidisciplinary care pathway (DREAM)
Limitations
- Retrospective observational design with potential residual confounding and selection bias.
- Single healthcare system limits generalizability; specific amputation criteria and adherence measures not detailed.
Future Directions: Prospective evaluation of multidisciplinary DFU pathways with standardized outcome definitions; cost-effectiveness analyses and implementation studies across diverse health systems.
AIMS: Diabetic foot ulcers (DFUs) are a major source of morbidity among individuals with diabetes mellitus (DM), imposing a substantial burden on healthcare systems. Our institution established a multidisciplinary service aiming to facilitate early specialist intervention for DFU management. This study examined demographic and cardiovascular risk profiles associated with DFU, the clinical burden of DFU in a large population, and the impact of our multidisciplinary specialist care on clinical outcomes. METHODS: We conducted a retrospective cohort study using the SingHealth Diabetes Registry on patients aged ≥18 years with DM from a tertiary centre between August 2018 and December 2023. There were 22,830 individuals with DM analysed; 2527 (11.1%) were diagnosed with DFU. Baseline demographics and clinical characteristics data were collected. Subgroup analyses were performed among patients attending the Diabetic Rapid Evaluation and lower limb Amputation Management (DREAM) clinic to evaluate differences in outcomes. RESULTS: Individuals with DFU were older, had a longer duration of DM, and had a significantly higher prevalence of cardiovascular and metabolic comorbidities compared with those without (p < 0.001). After multivariable adjustment, DFU was independently associated with increased mortality and prolonged hospitalization. Within the DFU cohort, referral to the multidisciplinary DREAM clinic in our institution was independently associated with a significantly reduced risk of major LEA, but not minor LEA, after multivariable adjustment. CONCLUSIONS: DFU represent a substantial clinical burden in Singapore and are independently associated with adverse outcomes. Beyond preventive screening, early multidisciplinary, multi-specialty management is critical to reduce amputations, hospitalization, and hence mortality.