Aims/hypothesis: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European.
Methods: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations.
Results: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development.
Conclusions/interpretation: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations.
Data availability: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub ( https://github.com/Arthur1021/MESA-1K-PWAS ).
Aims/hypothesis: The aim of this study was to investigate how diabetes mellitus affects longer term outcomes in individuals presenting to hospital with non-ST segment elevation myocardial infarction (NSTEMI).
Methods: We analysed data from 456,376 adults hospitalised between January 2005 and March 2019 with NSTEMI from the UK Myocardial Ischaemia National Audit Project (MINAP) registry, linked with Office for National Statistics death reporting. We compared outcomes and quality of care by diabetes status.
Results: Individuals with diabetes were older (median age 74 vs 73 years), were more often of Asian ethnicity (13% vs 4%) and underwent revascularisation (percutaneous coronary intervention or coronary artery bypass graft surgery) (38% vs 40%) less frequently than those without diabetes. The mortality risk for those with diabetes compared with those without was significantly higher at 30 days (HR 1.19, 95% CI 1.15, 1.23), 1 year (HR 1.28, 95% CI 1.26, 1.31), 5 years (HR 1.36, 95% CI 1.34, 1.38) and 10 years (HR 1.39, 95% CI 1.36, 1.42). In individuals with diabetes, higher quality inpatient care, assessed by opportunity-based quality indicator (OBQI) score category ('poor', 'fair', 'good' or 'excellent'), was associated with lower mortality rates compared with poor care (good: HR 0.74, 95% CI 0.73, 0.76; excellent: HR 0.69, 95% CI 0.68, 0.71). In addition, compared with poor care, excellent care in the diabetes group was associated with the lowest mortality rates in the diet-treated and insulin-treated subgroups (diet-treated: HR 0.64, 95% CI 0.61, 0.68; insulin-treated: HR 0.69, CI 0.66, 0.72).
Conclusion/interpretation: Individuals with diabetes experience disparities during inpatient care following NSTEMI. They have a higher risk of long-term mortality than those without diabetes, and higher quality inpatient care may lead to better long-term survival.
Aims/hypothesis: Genome-wide association studies (GWAS) have identified hundreds of type 2 diabetes loci, with the vast majority of signals located in non-coding regions; as a consequence, it remains largely unclear which 'effector' genes these variants influence. Determining these effector genes has been hampered by the relatively challenging cellular settings in which they are hypothesised to confer their effects.
Methods: To implicate such effector genes, we elected to generate and integrate high-resolution promoter-focused Capture-C, assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq datasets to characterise chromatin and expression profiles in multiple cell lines relevant to type 2 diabetes for subsequent functional follow-up analyses: EndoC-BH1 (pancreatic beta cell), HepG2 (hepatocyte) and Simpson-Golabi-Behmel syndrome (SGBS; adipocyte).
Results: The subsequent variant-to-gene analysis implicated 810 candidate effector genes at 370 type 2 diabetes risk loci. Using partitioned linkage disequilibrium score regression, we observed enrichment for type 2 diabetes and fasting glucose GWAS loci in promoter-connected putative cis-regulatory elements in EndoC-BH1 cells as well as fasting insulin GWAS loci in SGBS cells. Moreover, as a proof of principle, when we knocked down expression of the SMCO4 gene in EndoC-BH1 cells, we observed a statistically significant increase in insulin secretion.
Conclusions/interpretation: These results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings.
Data availability: Raw and processed next-generation sequencing data for EndoC-BH1, HepG2, SGBS_undiff and SGBS_diff cells are deposited in GEO under the Superseries accession GSE262484. Promoter-focused Capture-C data are deposited under accession GSE262496. Hi-C data are deposited under accession GSE262481. Bulk ATAC-seq data are deposited under accession GSE262479. Bulk RNA-seq data are deposited under accession GSE262480.
Aims/hypothesis: Homozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6's known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6.
Methods: We examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs).
Results: RFX6 expression was detected in PDX1+ cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets.
Conclusions/interpretation: These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+/NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes.
Data availability: RNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891 ).
Cardiovascular autonomic neuropathy (CAN) is an under-recognised yet highly prevalent microvascular complication of diabetes. CAN affects approximately 20% of people with diabetes, with recent studies highlighting the presence of CAN in prediabetes (impaired glucose tolerance and/or impaired fasting glucose), indicating early involvement of the autonomic nervous system. Understanding of the pathophysiology of CAN continues to evolve, with emerging evidence supporting a potential link between lipid metabolites, mitochondrial dysfunction and genetics. Recent advancements, such as streamlining CAN detection through wearable devices and monitoring of heart rate variability, present simplified and cost-effective approaches for early CAN detection. Further research on the optimal use of the extensive data provided by such devices is required. Despite the lack of specific pharmacological interventions targeting the underlying pathophysiology of autonomic neuropathy, several studies have suggested a favourable impact of newer glucose-lowering agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, where there is a wealth of clinical trial data on the prevention of cardiovascular events. This review delves into recent developments in the area of CAN, with emphasis on practical guidance to recognise and manage this underdiagnosed condition, which significantly increases the risk of cardiovascular events and mortality in diabetes.
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