Diabetologia最新文献

{"title":"HLA-focused type 1 diabetes genetic risk prediction in populations of diverse ancestry.","authors":"Dominika A Michalek, Courtney Tern, Catherine C Robertson, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich","doi":"10.1007/s00125-025-06563-8","DOIUrl":"10.1007/s00125-025-06563-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Type 1 diabetes is characterised by the destruction of pancreatic beta cells. Genetic factors account for approximately 50% of the total risk, with variants in the HLA region contributing to half of this genetic risk. Research has historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRS_HLA) using SNPs or HLA alleles from four ancestry groups (admixed African [AFR; T1D GRS_HLA-AFR], admixed American [AMR; T1D GRS_HLA-AMR], European [EUR; T1D GRS_HLA-EUR] and Finnish [FIN; T1D GRS_HLA-FIN]). We also developed an across-ancestry GRS (ALL; T1D GRS_HLA-ALL). We assessed the performance of the GRS in each population to determine the transferability of constructed scores.</p><p><strong>Methods: </strong>A total of 41,689 samples and 13,695 SNPs in the HLA region were genotyped, with HLA alleles imputed using the HLA-TAPAS multi-ethnic reference panel. Conditionally independent SNPs and HLA alleles associated with type 1 diabetes were identified in each population group to construct T1D GRS_HLA models. Generated T1D GRS_HLA models were used to predict HLA-focused type 1 diabetes genetic risk across four ancestry groups. The performance of each T1D GRS_HLA model was assessed using receiver operating characteristic (ROC) AUCs, and compared statistically.</p><p><strong>Results: </strong>Each T1D GRS_HLA model included a different number of conditionally independent HLA-region SNPs (AFR, n=5; AMR, n=3; EUR, n=38; FIN, n=6; ALL, n=36) and HLA alleles (AFR, n=6; AMR, n=5; EUR, n=40; FIN, n=8; ALL, n=41). The ROC AUC values for the T1D GRS_HLA from SNPs or HLA alleles were similar, and ranged from 0.73 (T1D GRS_{HLA-allele-AMR} applied to FIN) to 0.88 (T1D GRS_{HLA-allele-EUR} applied to EUR). The ROC AUC using the combined set of conditionally independent SNPs (T1D GRS_HLA-SNP-ALL) or HLA alleles (T1D GRS_{HLA-allele-ALL}) performed uniformly well across all ancestry groups, with values ranging from 0.82 to 0.88 for SNPs and 0.80 to 0.87 for HLA alleles.</p><p><strong>Conclusions/interpretation: </strong>T1D GRS_HLA models derived from SNPs performed equivalently to those derived from HLA alleles across ancestries. In addition, T1D GRS_HLA-SNP-ALL and GRS_{HLA-allele-ALL} models had consistently high ROC AUC values when applied across ancestry groups. Larger studies in more diverse populations are needed to better assess the transferability of T1D GRS_HLA across ancestries.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of youth type 2 diabetes in global Indigenous populations: a systematic review.","authors":"Emily R Papadimos,Courtney Claussen,Dianna J Magliano,Cheri Hotu,Alex Brown,Odette Pearson,Donald Warne,Louise Maple-Brown,Baiju R Shah,Hiliary Monteith,Louise A Baur,Andrew Cotterill,Anthony J Hanley,Elizabeth L M Barr","doi":"10.1007/s00125-025-06556-7","DOIUrl":"https://doi.org/10.1007/s00125-025-06556-7","url":null,"abstract":"AIMS/HYPOTHESISWe aimed to synthesise global prevalence estimates of type 2 diabetes among Indigenous youth aged under 25 years, and examine age- and gender-specific differences and secular trends.METHODSWe searched MEDLINE, Embase, CINAHL and Cochrane, and bibliographies of included studies, from 1 January 1980 to 14 September 2024. We included cross-sectional observational studies that reported diabetes point prevalence estimates (per 1000) and prevalence trends in Indigenous youth aged under 25 years from all regions. Age- and gender-specific analysis and secular trends were reported. Study quality was assessed using a modified Newcastle-Ottawa Scale adapted for Indigenous health research.RESULTSFrom 2342 records and 27 additional references, 49 studies were retained for data extraction. Total type 2 diabetes prevalence, reported in 33 of 49 studies from 36 distinct populations across six countries and two self-governing states, varied widely (0-44 per 1000), with 75% (27/36) of the populations reporting a prevalence of over 1 per 1000. Age-specific data, available in 44 studies, showed increased prevalence with age: 0-4 per 1000 at age <10 years; 0-44 per 1000 at age 10-19 years; and 0-64 per 1000 at age 15-25 years. Of 22 studies with gender-specific data, 77% showed a female predominance. Secular trends, examined in 12 studies since 1981, showed a rising prevalence in young adults (aged 15-25 years) in eight of ten studies, and in youth aged under 15 years in six of nine studies. Heterogeneity in study design, diagnostic criteria, and incomplete age- and gender disaggregation precluded meta-analysis.CONCLUSIONS/INTERPRETATIONYouth type 2 diabetes prevalence in Indigenous populations is very high, particularly in young adulthood, and among the female sex. Prevalence has increased over time. Future research should stratify data by age and pubertal status, and identify both protective and risk factors to inform targeted prevention strategies. Indigenous-led, community-specific approaches that actively engage youth are critical in the development and implementation of diabetes surveillance, prevention and management programmes.TRIAL REGISTRATIONPROSPERO registration no. CRD42021278418.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"76 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Up Front.","authors":"","doi":"10.1007/s00125-025-06570-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06570-9","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D electron microscopy reveals novel ultrastructural changes in the diabetic retinal neurovascular unit.","authors":"Mona J Albargothy,Evan P Troendle,Ross Laws,Peter Barabas,David H W Steel,Michael J Taggart,Tim M Curtis","doi":"10.1007/s00125-025-06554-9","DOIUrl":"https://doi.org/10.1007/s00125-025-06554-9","url":null,"abstract":"AIMS/HYPOTHESISThis study used serial block-face scanning electron microscopy (SBF-SEM), a nanoscale imaging technique in x-y-z planes, to investigate 3D ultrastructural changes in the retinal neurovascular unit (NVU) associated with diabetes. We hypothesised that this approach would reveal previously uncharacterised pathological alterations that contribute to the development of diabetic retinal disease (DRD).METHODSRetinas from male diabetic and non-diabetic mice, as well as from human male donors with and without diabetes, were prepared for SBF-SEM imaging. Retinal tissue was microdissected, fixed and embedded for serial sectioning and 3D reconstruction. Ultrastructural analysis of the NVU was performed in capillary regions exclusively within the superficial vascular plexus of both mouse and human retinas. Image stacks were processed using Microscopy Image Browser for contrast normalisation and segmentation, with 3D visualisation performed in Amira software. Quantitative analyses were conducted on pericyte-endothelial cell peg-and-socket formations, cell-basement membrane (BM) interactions, endothelial tubule formation and vascular BM thickness.RESULTSSBF-SEM revealed novel 3D ultrastructural changes in the retinal NVU of diabetic mice and humans, including: (1) partial detachment and reduced frequency of pericyte-endothelium peg-and-socket formations (p<0.05-0.001); (2) localised detachment of endothelial cells and pericytes from the vascular BM (p<0.05-0.01), along with macroglial cell retraction from the outer vascular BM; and (3) increased formation of endothelial tubules (p<0.01-0.001). These changes were observed in the absence of any obvious vascular BM thickening, as no significant differences in mean or maximum BM thickness were found between diabetic and non-diabetic retinal capillaries analysed in this study.CONCLUSIONS/INTERPRETATIONThis study provides new insights into the early ultrastructural changes in the retinal NVU in DRD, offering a basis for a better understanding of the pathological processes that contribute to the development of this disease.DATA AVAILABILITYLinks to all raw image stacks analysed in this article are available at https://doi.org/10.5281/zenodo.15210333 . The MATLAB vascular BM thickness measurement script is available at the GitHub link https://github.com/Curtis-WWIEM/BM_thickness .","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"19 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of maternal overweight and gestational diabetes mellitus with offspring adiposity trajectory: from birth to early adolescence.","authors":"Yuzhi Deng, Claudia H T Tam, Aimin Yang, Mai Shi, Lai Yuk Yuen, Noel Y H Ng, Atta Y T Tsang, Kit Ying Tsoi, Risa Ozaki, Albert M Li, Elaine Chow, Lai Ling Hui, Juliana C N Chan, Chi Chiu Wang, Wing Hung Tam, Ronald C W Ma","doi":"10.1007/s00125-025-06468-6","DOIUrl":"10.1007/s00125-025-06468-6","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>We aimed to examine offspring adiposity trajectories from birth to age 9-14 years and to assess the joint associations of maternal overweight and gestational diabetes mellitus (GDM) with these trajectories.</p><p><strong>Methods: </strong>This is a prospective cohort study with 564 mother-child dyads from the Hyperglycemia and Adverse Pregnancy Outcome study Hong Kong field centre. Assessments and anthropometric measurements were taken during pregnancy, at delivery and at median ages of 7 and 10 years postpartum. Offspring adiposity was primarily assessed using sum of skinfold thickness. We used linear mixed-effect models to evaluate the independent and joint associations of maternal overweight and GDM with the offspring adiposity trajectories, and applied group-based trajectory modelling to identify distinct patterns of adiposity development based on both statistical indices and clinical interpretability.</p><p><strong>Results: </strong>Offspring skinfold thickness trajectories varied significantly based on maternal overweight and GDM (p<0.05). Group-based trajectory modelling identified two trajectory groups for skinfold thickness: 52.1% with slow increase and 47.9% with rapid increase. Combined maternal overweight and GDM was associated with 6.90-fold increased risk (95% CI 1.89, 33.32; p=0.006) of the rapidly increasing trajectory. Linear mixed-effect model analysis showed greater increases in skinfold thickness among offspring of mothers with either condition, with the highest trajectory observed in offspring of mothers with both conditions (β 1.62; 95% CI 0.69, 2.54; p=0.001).</p><p><strong>Conclusions/interpretation: </strong>Maternal overweight and GDM are independently and jointly associated with rapidly increasing adiposity trajectories from birth to early adolescence. The findings underscore the importance of considering both maternal metabolic conditions when evaluating offspring adiposity risk.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2194-2204"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12423264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-autoimmune diabetes in young people from Assam, India: the PHENOEINDY-2 study.","authors":"Anupam Dutta, Pranjal K Dutta, Sreemanta M Baruah, Prasanta Dihingia, Arpita Ray, Dattatrey S Bhat, Sonali W Patki, Pradeep Tiwari, Madhura Deshmukh, Rucha Wagh, Rubina Mulchandani, Tanica Lyngdoh, Sanjeeb Kakati, Chittaranjan S Yajnik","doi":"10.1007/s00125-025-06500-9","DOIUrl":"10.1007/s00125-025-06500-9","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>In the Western world, non-autoimmune diabetes in the young is believed to be driven by overweight/obesity and insulin resistance. However, it is increasingly being reported in undernourished people in low- and middle-income countries, including India. We hypothesised that these patients would show markers of chronic undernutrition and a 'thin-fat' phenotype and be predominantly beta cell-deficient.</p><p><strong>Methods: </strong>We studied young patients (clinically diagnosed with type 2 diabetes at <40 years) who attended the outpatient department of Assam Medical College and Hospital, Dibrugarh (in North-East India). We measured weight, height, waist and hip circumference, haemoglobin, fasting glucose, HbA_1c, lipid, GADA and C-peptide levels, and body fat percentage (adiposity, assessed using dual-energy x-ray absorptiometry), and calculated BMI (kg/m²), body roundness index and HOMA indices. Volunteers from similar socioeconomic background with normal glucose tolerance (measured by 75 g OGTT) were assessed as control participants. We also compared the anthropometric characteristics and body composition of our participants with those of non-Hispanic white Americans from the NHANES study.</p><p><strong>Results: </strong>The study included 252 control participants (136 male participants, median age 30 years, BMI 23.0 kg/m²) and 240 GADA-negative young patients with diabetes (155 male participants, age 36 years, BMI 23.0 kg/m²). The majority of study participants came from a relatively impoverished population of tea garden workers ('tribal' workers). Of the patients with diabetes, 28% had stunted growth (male <161.2 cm, female <149.8 cm), 27% were anaemic, 68% were lean (BMI <25 kg/m², including 14% who were underweight [BMI <18.5 kg/m²]) and 32% were overweight/obese (BMI ≥25 kg/m²). When assessed using dual-energy x-ray absorptiometry, 61% of control participants and 53% of patients had adiposity (body fat percentage >25% in male participants or >35% in female participants). Compared with a contemporary non-Hispanic white American population, Assamese control participants and diabetic patients had higher WHR, body roundness index, and total and truncal adiposity (assessed using dual-energy x-ray absorptiometry) across the range of BMI, thus conforming to the description of the 'thin-fat' phenotype. The diabetic patients were severely beta cell-deficient (median HOMA-B 25.7) and only moderately insulin-resistant (median HOMA-S 103) with higher triacylglycerol and lower HDL-cholesterol concentrations than control participants. Underweight patients (<18.5 kg/m²) were the most hyperglycaemic (based on fasting plasma glucose and HbA_1c), and were severely beta cell-deficient but insulin-sensitive. As previously reported, two-thirds of these patients belonged to the severely insulin-deficient diabetes (SIDD) cluster a","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2179-2193"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recognising, quantifying and accounting for classification uncertainty in type 2 diabetes subtypes.","authors":"Tim Mori, Oana P Zaharia, Klaus Straßburger, John M Dennis, Knut Mai, Stefan Kabisch, Stefan Bornstein, Julia Szendroedi, Matthias Blüher, Svenja Meyhöfer, Jochen Seissler, Andreas Birkenfeld, Norbert Stefan, Michael Roden, Robert Wagner, Oliver Kuß","doi":"10.1007/s00125-025-06486-4","DOIUrl":"10.1007/s00125-025-06486-4","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Despite continued interest in precision diagnostics and type 2 diabetes subtypes, the challenge of uncertainty in the classification of individuals into subtypes remains. This study introduces a novel method for quantifying and accounting for classification uncertainty in type 2 diabetes subtypes.</p><p><strong>Methods: </strong>Building on recommendations from the ADA/EASD Precision Medicine in Diabetes Initiative, we quantified classification uncertainty using the normalised relative entropy (NRE), computed from distances to cluster centroids. A lower NRE value indicates greater uncertainty in an individual's cluster assignment. We examined the NRE in a cohort of 859 individuals with recent-onset type 2 diabetes from the prospective, observational German Diabetes Study (GDS) and compared it across previously identified diabetes subtypes, defined by age, BMI, HbA_1c, HOMA-IR and HOMA-B. Predicted 10 year CVD risk (SCORE2-Diabetes) of the subtypes was evaluated with and without accounting for classification uncertainty.</p><p><strong>Results: </strong>Individuals with mild age-related diabetes (n=395) and mild obesity-related diabetes (n=316) had a median NRE of 0.155 (95% CI 0.142, 0.177) and 0.119 (95% CI 0.107, 0.131), respectively. By contrast, individuals with severe insulin-resistant diabetes (n=130) and severe insulin-deficient diabetes (n=18) had a lower median NRE of 0.086 (95% CI 0.075, 0.108) and 0.082 (95% CI 0.071, 0.109), respectively. After weighting individuals by classification certainty, the proportion of variation in SCORE2-Diabetes explained by the subtypes (R²) increased from 17.4% (95% CI 12.8, 23.0) to 31.5% (95% CI 26.4, 37.1). The predicted 10 year CVD risk of the mild age-related diabetes subtype increased from 10.3% (95% CI 9.8, 10.7) to 11.6% (95% CI 11.2, 12.0).</p><p><strong>Conclusions/interpretation: </strong>The NRE provides a means to quantify and compare individual classification uncertainty in type 2 diabetes subtypes. Classification uncertainty varied between subtypes and individuals with type 2 diabetes, and accounting for it improved the ability of the subtypes to predict 10 year CVD risk.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2139-2150"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12423224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steatotic liver disease interacts with a polygenic risk score for triglyceride clearance to impact the risk of hypertriglyceridaemia: The Maastricht Study.","authors":"Zhewen Ren, Anke Wesselius, M Eline Kooi, Marleen van Greevenbroek, Pieter Dagnelie, Tos T J M Berendschot, Abraham A Kroon, Alfons J H M Houben, Coen D A Stehouwer, Martijn C G J Brouwers","doi":"10.1007/s00125-025-06479-3","DOIUrl":"10.1007/s00125-025-06479-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The pathogenesis of hypertriglyceridaemia is explained by a complex interplay between genetic and environmental factors. We hypothesised that intrahepatic lipid (IHL) content, which drives the production of triacylglycerol-rich VLDL particles, interacts with a polygenic risk score (PRS) for triglyceride clearance to impact the risk of hypertriglyceridaemia.</p><p><strong>Methods: </strong>We used data from The Maastricht Study, a population-based prospective cohort study (n=3810; age: 60 years, 48% women, 10% hypertriglyceridaemia, 26% steatotic liver disease). We performed multivariable linear regression analyses to assess the impact of the cross-sectional interaction between IHL content (quantified by MRI) and a PRS for triglyceride clearance (based on nine SNPs) on fasting serum triglycerides, after adjustment for sociodemographic, lifestyle and cardiovascular risk factors. We subsequently explored whether a similar longitudinal interaction affects incident CVD during a 10 year follow-up.</p><p><strong>Results: </strong>There was an impact of interaction between IHL content and the PRS for triglyceride clearance on serum triglycerides (p=0.005). The strength of the association between a high PRS and risk of hypertriglyceridaemia was larger in individuals with steatotic liver disease (OR 6.196; 95% CI 3.966, 9.768) than in those without (OR 1.618; 95% CI 1.110, 2.380). A similar trend was observed for incident CVD risk (p=0.078).</p><p><strong>Conclusions/interpretation: </strong>Genetically predisposed individuals have a substantially higher risk of hypertriglyceridaemia when they also have steatotic liver disease. This gene-environment interaction might contribute to more personalised treatment approaches, which require further exploration in future studies.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2217-2226"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12423141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time to approve glucagon-like peptide-1 receptor agonists for MASLD: a rational step based on robust evidence.","authors":"Abdelilah Arredouani","doi":"10.1007/s00125-025-06527-y","DOIUrl":"10.1007/s00125-025-06527-y","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":"2296-2298"},"PeriodicalIF":10.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function.","authors":"Lindsey B Lamarche, Christopher Koch, Shareef Khalid, Maleeha Zaman Khan, Richard Zessis, Matthew E Clement, Daniel P Denning, Allison B Goldfine, Igor Splawski, Ali Abbasi, Jennifer L Harrow, Christina Underwood, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Juan L Rodriguez-Flores, Alan R Shuldiner, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Usman Abdulsalam, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, Allan M Gurtan, John E Dominy, Danish Saleheen","doi":"10.1007/s00125-025-06530-3","DOIUrl":"https://doi.org/10.1007/s00125-025-06530-3","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Genetic association studies have demonstrated that partial loss of SLC30A8 Function protects against type 2 diabetes in humans. We investigated the impact of complete loss of SLC30A8 Function on type 2 diabetes risk and related phenotypes in humans.</p><p><strong>Methods: </strong>The Pakistan Genome Resource (PGR), a biobank comprising whole-exome and whole-genome sequences of 145,037 participants, was analysed for phenotypic associations with SLC30A8 loss-of-function (LoF) variants. To follow up on the observations in the PGR, we conducted recall-by-genotype analyses of SLC30A8 LoF heterozygotes and homozygotes, as well as their participating family members, using OGTTs.</p><p><strong>Results: </strong>We identified 18 SLC30A8 knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter), and 1024 heterozygotes for LoF variants. Type 2 diabetes risk was lower in SLC30A8 LoF heterozygotes and homozygotes relative to non-carriers, and the protective effect strengthens in a gene dose-dependent manner (OR_additive=0.62; 95% CI 0.53, 0.72; p=1.1×10^-9; OR_recessive=0.34; 95% CI 0.12, 0.93; p=0.04). OGTTs in recall-by-genotype studies showed a gene dose-dependent reduction in glucose levels, coupled with elevated insulin.</p><p><strong>Conclusions/interpretation: </strong>The corrected insulin response, disposition index and insulin sensitivity index in LoF heterozygotes and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function that was independent of BMI. These data suggest that therapeutic inhibition of SLC30A8, up to and including complete knockout, may treat type 2 diabetes safely and effectively.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}