Diabetes最新文献

{"title":"Comment on Lin et al. Reconsidering Adipose Tissue Lipolysis Dysfunction: Evidence for a Distal Machinery Defect Beyond Insulin Resistance.","authors":"Giovanni Ragozzino, Maria Teresa Cantelli, Elisabetta Fulgione, Edi Mattera","doi":"10.2337/db26-0284","DOIUrl":"10.2337/db26-0284","url":null,"abstract":"","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 6","pages":"e19-e20"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Different Metabolic Responses to Long-term Weight Loss After Lifestyle Intervention Among Type 2 Diabetes Risk Clusters: Results From the TULIP Study.","authors":"Caroline Z Meier, Robert Wagner, Marlene Ganslmeier, Konstantinos Kantartzis, Martin Heni, Andreas Peter, Reiner Jumpertz-von Schwartzenberg, Jürgen Machann, Fritz Schick, Andreas L Birkenfeld, Hans-Ulrich Häring, Andreas Fritsche, Norbert Stefan","doi":"10.2337/db25-0757","DOIUrl":"10.2337/db25-0757","url":null,"abstract":"<p><p>We previously identified six clusters of people at different risks of type 2 diabetes and/or comorbidities, of which cluster 3 (β-cell deficient) and 5 (older age, higher BMI, severe insulin resistance) had a high risk of progression to diabetes. We have now investigated whether cluster 3 and 5 individuals differed from those of the other clusters in changes in insulin sensitivity, insulin secretion, and the development of type 2 diabetes during a long-term reduction of body weight. A total of 190 participants completed a 24-month lifestyle intervention in the Tübingen Lifestyle Intervention Program (TULIP) and were followed up for 8.7 ± 1.6 years. Sixty participants had a weight loss ≥3% (mean reduction of 8%) at the long-term follow-up. Of them, cluster 5 participants (n = 17) had a larger increase of adjusted fasting glycemia compared with the cluster group 1,2,4,6 (n = 33) and cluster 3 (n = 10) and a larger increase of adjusted 2-h glucose levels compared with cluster 3 (all P < 0.05). In cluster 5, a larger decrease of adjusted insulin secretion compared with cluster 3 (P = 0.01) and cluster group 1,2,4,6 (P = 0.05) was observed. Forty-one percent of cluster 5 participants (0% in cluster group 1,2,4,6 and 10% in cluster 3) developed type 2 diabetes. In conclusion, despite a sustained and large amount of weight loss, diabetes risk cluster 5 participants had deterioration of glycemia and insulin secretion and a high risk of type 2 diabetes. If this result can be replicated in a prospective study, people of this cluster would need targeted prevention strategies.</p><p><strong>Article highlights: </strong>There may be heterogeneity in the response to a lifestyle intervention to prevent type 2 diabetes. This study investigated whether participants of Tübingen Lifestyle Intervention Program (TULIP) type 2 diabetes risk clusters 3 and 5, who have a very high risk of diabetes, benefit from long-term weight loss following a 2-year lifestyle intervention. Diabetes risk cluster 5 participants had an impaired response regarding improvement of glycemia and insulin secretion and a high risk of developing type 2 diabetes, despite a long-term (9-year) mean weight loss of 8%. Alternative or intensified interventions should be considered for people in Tübingen type 2 diabetes risk cluster 5.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"965-973"},"PeriodicalIF":0.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13191407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Combined Genetic and Lifestyle Risks With Incident Type 2 Diabetes in the UK Biobank.","authors":"Chi Zhao, Konstantinos Hatzikotoulas, Raji Balasubramanian, Elizabeth Bertone-Johnson, Na Cai, Lianyun Huang, Alicia Huerta-Chagoya, Margaret Janiczek, Chaoran Ma, Ravi Mandla, Amanda Paluch, Nigel W Rayner, Lorraine Southam, Susan R Sturgeon, Ken Suzuki, Henry J Taylor, Nicole Vankim, Xianyong Yin, Chi Hyun Lee, Francis Collins, Cassandra N Spracklen","doi":"10.2337/db25-0672","DOIUrl":"10.2337/db25-0672","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) results from the interplay of genetic susceptibility and an unhealthy lifestyle, but their combined effects are not well studied. We examined whether unhealthy modifiable behaviors were associated with similar increases in the risk of incident T2D in individuals with different levels of genetic risk. Among 332,251 UK Biobank participants without diabetes, we constructed a multiancestry genetic risk score (GRS) based on 783 T2D-associated variants, categorized into tertiles. Lifestyle was classified as healthy, intermediate, or unhealthy based on baseline self-reported smoking status, BMI, physical activity level, and diet quality. Cox proportional hazards regression models were used to generate adjusted hazard ratios (HRs) for T2D and associated 95% CIs. During follow-up (median 13.6 years), 13,128 (4.0%) participants developed T2D. GRS (P < 0.001) and lifestyle classification (P < 0.001) were independently associated with increased risk of T2D. Compared with a healthy lifestyle, an unhealthy lifestyle was associated with increased risk in all genetic risk strata, with adjusted HRs ranging from 7.11 to 16.33. High genetic risk and an unhealthy lifestyle were the most significant contributors to T2D development. Individuals at all levels of genetic risk can substantially mitigate their T2D risk through lifestyle modifications.</p><p><strong>Article highlights: </strong>Both genetic susceptibility and an unhealthy lifestyle are known to be associated with elevated type 2 diabetes (T2D) risk. However, their combined effects on T2D risk are not well studied. In this large prospective cohort study of more than 332,000 individuals, unhealthy lifestyle factors were associated with risk of incident T2D within and across different levels of genetic risk. These findings suggest individuals at all levels of genetic risk can greatly mitigate their risk of T2D by adhering to a healthy lifestyle.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 5","pages":"860-866"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple Mechanisms Contribute to Robust Type 1 Diabetes Protection in Nfkbid- Overexpressing NOD Mice.","authors":"Jennifer R Dwyer, Jeremy J Racine, Harold D Chapman, Amy Bell, Anna Quinlan, Grace A Stafford, David V Serreze","doi":"10.2337/db25-0956","DOIUrl":"10.2337/db25-0956","url":null,"abstract":"<p><p>We previously reported that transgenic overexpression of Nfkbid in NOD mice led to robust type 1 diabetes protection associated with enhanced negative selection of autoreactive T cells and expansion of regulatory T cells (Tregs) with increased suppressive capacity. The goal of this study was to further identify cellular and molecular mechanisms underlying strong protection from type 1 diabetes imbued by overexpressing Nfkbid. Transcript analysis of Tregs from Nfkbid-overexpressing NOD mice show enrichment of cellular replication pathways. Effector T cells from Nfkbid-overexpressing NOD mice have increased indicators of activation-induced exhaustion in pancreatic lymph nodes and islets. This trait is intrinsic to Nfkbid-overexpressing T cells, as ex vivo anti-CD3 stimulation of splenic-derived T cells can reproduce this phenotype. Anti-PD-1 administration breaks the diabetes protective effect. Furthermore, we found that Nfkbid-overexpressing dendritic cells, but not B cells, have an enhanced capacity to stimulate proliferation of diabetogenic AI4 CD8+ T cells (with wild-type levels of Nfkbid). Conversely, B cells, but not dendritic cells, drive enhanced de novo conversion of regulatory T cells from effector T cells. Together, this study documents additional mechanisms that likely synergize to contribute to the diabetes-protective effects of Nfkbid overexpression. Understanding the mechanisms underlying protection from Nfkbid overexpression may lead to novel therapeutic avenues.</p><p><strong>Article highlights: </strong></p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"816-824"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis.","authors":"Katherine C Perez, Justin Alexander, Md Mostafizur Rahman, Haifa Alsharif, Yanping Liu, Jeong-A Kim, Chad S Hunter, Thanh Nguyen, Sushant Bhatnagar","doi":"10.2337/db25-0644","DOIUrl":"10.2337/db25-0644","url":null,"abstract":"<p><p>The transition from a proliferative to a functionally mature state is a critical phase in postnatal pancreatic β-cell development, yet the molecular mechanisms coordinating this shift remain poorly understood. Here, we identify tomosyn-2 as a key regulator that restrains β-cell maturation and insulin secretory capacity. Tomosyn-2 expression progressively declines in mouse islets with age, coinciding with enhanced biphasic glucose-stimulated insulin secretion and reduced β-cell proliferation. Mice lacking tomosyn-2 exhibit improved glucose clearance, elevated plasma insulin levels, and enhanced insulin secretion from isolated islets without changes in insulin action. Mechanistically, tomosyn-2 interacts with syntaxin-1A to inhibit insulin granule exocytosis by limiting SNARE complex assembly. Transcriptomic and network analyses reveal that loss of tomosyn-2 is associated with coordinated changes in insulin secretion and cell-cycle regulation, reducing β-cell proliferation and mass expansion by downregulating Akt1 signaling and cell-cycle mediators, while promoting β-cell identity and functional maturation accompanied by altered islet cytoarchitecture. These findings identify tomosyn-2 as a molecular brake that balances proliferation and insulin secretion to achieve a threshold of functionally mature β-cell mass during postnatal development. Targeting tomosyn-2 or its downstream pathways may enhance β-cell functional competence and offer new strategies to restore insulin secretion in diabetes.</p><p><strong>Article highlights: </strong>The mechanisms governing the postnatal transition of pancreatic β-cells from a proliferative, immature state to a functionally mature, glucose-responsive state remain poorly understood. We investigate the role of tomosyn-2 in modulating β-cell proliferation and insulin secretion during postnatal maturation. Tomosyn-2 inhibits SNARE complex formation and insulin secretion, and its loss is associated with enhanced β-cell maturation, increased biphasic insulin secretion, reduced β-cell proliferation, and suppressed Akt1-cyclinD1 signaling. Tomosyn-2 functions as a physiological brake on insulin secretion, coordinating the balance between β-cell maturation and proliferation, with implications for diabetes pathogenesis and β-cell regenerative strategies.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 5","pages":"799-815"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative β-Cell Mass Imaging Redefines Disease Staging and Glycemic Control in Type 1 Diabetes.","authors":"Kentaro Sakaki, Takaaki Murakami, Hayao Yoshida, Daisuke Otani, Kanae Kawai Miyake, Yoichi Shimizu, Hiroyuki Fujimoto, Daisuke Yabe, Yuji Nakamoto, Nobuya Inagaki","doi":"10.2337/db25-1127","DOIUrl":"10.2337/db25-1127","url":null,"abstract":"<p><p>Noninvasive measurement of pancreatic β-cell mass remains an important unmet need in type 1 diabetes because conventional surrogate markers, such as C-peptide, often lack sensitivity in advanced disease. This study evaluated the glucagon-like peptide 1 receptor-targeted positron emission tomography tracer, 18F-labeled exendin-4-based probe conjugated with polyethylene glycol, [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), to determine its ability to visualize pancreatic β-cell mass. Positron emission tomography/computed tomography performed at 60 and 120 min after tracer injection in individuals with type 1 diabetes was compared with data from healthy control participants. No serious adverse events occurred. Pancreatic uptake was consistently lower in individuals with type 1 diabetes and showed clear separation between individuals with insulin-dependent diabetes and healthy control participants at 120 min. Pancreatic uptake at 120 min correlated with fasting C-peptide index and inversely with hemoglobin A1c and daily insulin dose per body weight. These findings support [18F]FB(ePEG12)12-exendin-4 positron emission tomography/computed tomography as a noninvasive approach for assessing β-cell mass and disease status.</p><p><strong>Article highlights: </strong>We undertook this study to address the persistent need for noninvasive assessment of β-cell mass in type 1 diabetes. We aimed to determine whether 18F-exendin positron emission tomography/computed tomography can reliably visualize residual β-cell mass and distinguish stages of disease. We found that pancreatic tracer uptake was consistently reduced in type 1 diabetes, differentiated insulin-dependent patients from control participants, and aligned with markers of β-cell function and glycemic status. Our findings suggest that 18F-exendin imaging may offer fundamental platform for disease staging, therapeutic monitoring, and individualized care.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"787-798"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic Pathogenic Variants in IL2RA Cause Neonatal-Onset Monogenic Autoimmune Diabetes.","authors":"Georgia Bonfield, James Russ-Silsby, Suraj Ramchand, Amber M Luckett, Matthew N Wakeling, Abhishek Kulkarni, V Sri Nagesh, Asma Deeb, K G Ravikumar, Phuong T K Nguyen, Andrew T Hattersley, Richard A Oram, Sarah E Flanagan, Elisa De Franco, Matthew B Johnson","doi":"10.2337/db25-0885","DOIUrl":"10.2337/db25-0885","url":null,"abstract":"<p><p>Autoimmune diabetes presenting in infancy or with additional autoimmune disorders can be the result of highly penetrant variants in key immune homeostasis genes. An example of this is observed with biallelic pathogenic variants in IL2RA (CD25), which causes immunodeficiency 41 (IMD41). IL2RA encodes the α-chain of the interleukin-2 receptor, which helps regulate the growth and activity of T cells. The diabetes phenotype in IMD41 has not been systematically described. We sequenced IL2RA in 290 individuals with diabetes diagnosed <6 months and in 64 individuals diagnosed <10 years who had additional autoimmunity. We also reviewed all previously reported IMD41 cases. We identified five new unrelated individuals with biallelic pathogenic IL2RA variants. Four presented with diabetes in the first month of life with very low/absent C-peptide, and all were GAD antibody-positive. Of 17 previously reported cases, 9 had diabetes, yielding a total of 14 of 22 (64%) with early-onset diabetes. No relationship between variant location/type and diabetes development was observed. Autoimmune diabetes is therefore a common and early feature of IMD41. IL2RA should be included in genetic testing panels for neonatal and monogenic autoimmune diabetes. These findings highlight the important role of IL2RA in immune tolerance and β-cell protection.</p><p><strong>Article highlights: </strong>We report five new cases of neonatal or early childhood-onset diabetes caused by biallelic pathogenic variants in IL2RA. Autoimmune diabetes was the presenting feature in most individuals and occurs in 64% of all reported cases of immunodeficiency 41. Patients typically presented in infancy with diabetic ketoacidosis, low C-peptide, and GAD antibody positivity, highlighting an autoimmune etiology. The diabetes phenotype was consistent across cases but not linked to variant type or location. IL2RA should be included in genetic testing for neonatal diabetes and considered in children with diabetes plus immune dysregulation.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"867-875"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147319057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IDH3A Deficiency Compromises Adaptive Thermogenesis and Exacerbates Obesity-Induced Metabolic Dysfunction via Impaired BCKDHA-Dependent BCAA Catabolism.","authors":"Xuhong Lu, Ningning Bai, Jialu Lyu, Jingjing Sun, Yingying Su, Yafen Ye, Tingting Hu, Tianwen Liu, Wenfei Li, Xiaoya Li, Xiaojing Ma, Ying Yang, Yuqian Bao","doi":"10.2337/db25-0789","DOIUrl":"10.2337/db25-0789","url":null,"abstract":"<p><p>Adaptive thermogenesis in beige adipocytes is essential for maintaining energy homeostasis and preventing obesity. Emerging evidence suggests that human visceral adipose tissue harbors adipocytes with beige-like thermogenic features, enabling analysis of thermogenic gene regulation in humans. Isocitrate dehydrogenase 3A (IDH3A) is a rate-limiting enzyme of the tricarboxylic acid cycle, yet its function in adipocytes remains poorly defined. In this study, we examined IDH3A expression in human visceral adipose tissue and generated adipocyte-specific IDH3A knockout mice to investigate its role in beige adipocyte thermogenesis and metabolic regulation. IDH3A expression in human visceral fat was inversely associated with adiposity and adverse metabolic traits. Moreover, IDH3A expression was induced in human and mouse adipocytes following thermogenic stimulation. Adipocyte-specific IDH3A deletion in mice impaired beige fat thermogenic capacity, led to cold intolerance, and exacerbated diet-induced metabolic dysfunction. Mechanistically, IDH3A deficiency increased DNA methylation at the Bckdha promoter, resulting in the repression of this key branched-chain amino acid (BCAA) catabolic gene and impaired BCAA catabolism. Notably, restoring BCKDHA in IDH3A-deficient adipocytes rescued respiration and thermogenic function. Together, in addition to its canonical enzymatic role, our findings identify IDH3A as a critical regulator of BCAA catabolism that facilitates adaptive thermogenesis under metabolic stress conditions.</p><p><strong>Article highlights: </strong>IDH3A expression in human visceral fat exhibits a negative correlation with metabolic dysfunction indicators. IDH3A is induced during thermogenic activation, yet its role in adipose tissue is not well characterized. Adipocyte-specific deletion of IDH3A impairs adaptive thermogenesis and metabolic homeostasis by disrupting BCKDHA-mediated BCAA catabolism. Overexpression of BCKDHA restores the thermogenic program in IDH3A-deficient beige adipocytes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":"75 5","pages":"772-786"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolite Erythritol in 24-Hour Urine Is Associated With Higher Intrahepatic Lipid Content: The Maastricht Study.","authors":"Amée M Buziau, Anke Wesselius, Evan Yi-Wen Yu, Irene M L W Körver-Keularts, Dennis Visser, Laura K M Steinbusch, Pomme I H G Simons, Marleen M J van Greevenbroek, Pieter C Dagnelie, M Eline Kooi, Simone J P M Eussen, Ilja C W Arts, Carla J H van der Kallen, Casper G Schalkwijk, Martijn C G J Brouwers","doi":"10.2337/db25-0881","DOIUrl":"10.2337/db25-0881","url":null,"abstract":"<p><p>The pentose phosphate pathway (PPP) furnishes NADPH for hepatic de novo lipogenesis, driving intrahepatic lipid (IHL) accumulation. The aim of the current study was to examine the association between the PPP, proxied by 24-h urinary erythritol, and IHL content at the population level. We used cross-sectional data from the Maastricht Study, a population-based cohort study (N = 1,494; mean ± SD age 59 ± 8 years; 49% women). We first assessed the relationship between 24-h urinary erythritol and IHL content (quantified with 3T Dixon MRI), with adjustment for age, sex, type 2 diabetes, proxies of socioeconomic status/lifestyle, MRI lag time, BMI, and intake of erythritol-containing food items. Second, we performed a genome-wide association study (GWAS) for 24-h urinary erythritol (N = 2,000) and Mendelian randomization (MR) study using common variants in genes associated with erythritol in relation to IHL content. In the fully adjusted model, 24-h urinary erythritol levels were associated with higher (10log) IHL content. The GWAS identified one genome-wide significant locus (rs72686491; TESK2) and replicated two previously reported genetic variants at nominal significance. MR analysis, using these three genetic instruments, did not reveal a statistically significant association between genetically predicted erythritol levels and IHL content. The findings of this population-based study show that higher PPP flux is associated with higher IHL content, a well-established risk factor for type 2 diabetes. An active role for erythritol per se was excluded by MR analysis.</p><p><strong>Article highlights: </strong>The role of the pentose phosphate pathway (PPP) in the pathogenesis of intrahepatic lipid (IHL) accumulation has not been studied before in humans. Is the PPP, proxied by 24-h urinary erythritol, associated with IHL content at the population level? In the fully adjusted model, 24-h urinary erythritol levels were associated with higher IHL content. Furthermore, genetically predicted erythritol levels were not associated with liver fat, suggesting that erythritol per se is not responsible for the former observation. Findings of the current study suggest that 1) the PPP is associated with IHL content at the population level, and 2) erythritol could potentially serve as a urinary biomarker for IHL content.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"762-771"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal Stem Cell and Secretome Treatments Inhibit the mTOR-NOX4 Pathway in Diabetic Kidney Disease.","authors":"Rachel Njeim, Sahar Alkhansa, Sarah Almoussawi, Amani Slika, Sarah Hamade, Ghaith Al Danaf, Batoul Dia, Leonard Lawandos, Ali H Eid, Hala Kfoury Kassouf, Frederic Harb, Antoine Abou Fayad, Fuad N Ziyadeh, Fadlo R Khuri, Assaad A Eid","doi":"10.2337/db25-1036","DOIUrl":"10.2337/db25-1036","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a major complication of diabetes characterized by progressive renal dysfunction driven by oxidative stress and inflammation involving mammalian target of rapamycin (mTOR) and NADPH oxidase (NOX) pathways. Mesenchymal stem cells (MSCs) have gained attention for their regenerative and immunomodulatory properties in attenuating DKD, but the mechanisms behind their protective effects are still being explored. Moreover, concerns regarding tumorigenic risks hinder their direct clinical use. In this study, we compared MSCs and their conditioned media (MSCs-CM; secretome) in a type 1 diabetic rodent model, demonstrating that both treatments attenuated glomerular injury, preserved podocyte integrity, reduced NOX4 expression and activity, and tempered inflammation, by inhibiting mTORC1 and mTORC2 signaling. Importantly, MSCs-CM replicated the renoprotective effects of MSCs, indicating that soluble factors mediate these benefits. To our knowledge, this is the first study to directly compare MSCs and their conditioned media (MSCs-CM) in DKD, revealing that MSCs-CM delivers equivalent therapeutic efficacy while circumventing the safety concerns inherent to cell-based therapies. These findings identify the mTOR/NOX axis as a therapeutic target and support MSCs-CM as a promising, safer, cell-free alternative for DKD treatment, potentially advancing regenerative strategies to mitigate diabetic renal injury.</p><p><strong>Article highlights: </strong>Despite advances in diabetes management, diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease. We investigated whether mesenchymal stem cells (MSCs) and their conditioned medium, containing the MSC-derived secretome, protect against DKD by modulating the mammalian target of rapamycin (mTOR)/NADPH oxidase (NOX) pathway. MSCs and MSCs-conditioned medium both reduced kidney injury, podocyte structural integrity, oxidative stress, and inflammation by inhibiting mTORC1/mTORC2 and NOX4. MSCs-conditioned medium offers a safe, secretome-based, cell-free approach for DKD therapy.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"840-851"},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147438445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}