Ameth N. Garrido, Song-Yang Zhang, Kyla Bruce, Charmaine S.H. Lai, Zeyu Yang, Melissa T. Wang, Tony K.T. Lam
Growth differentiation factor 15 (GDF15) is an anorectic and weight-loss–inducing hormone that responds to stimuli such as endoplasmic reticulum stress, exercise, metformin, and more recently, dietary lipids. Given its potential as an antiobesogenic agent, we examined how endogenous GDF15 responds to an Intralipid infusion in different organs to regulate food intake in vivo. We found that an acute Intralipid infusion into the upper small intestine (USI) inhibited food intake and increased plasma GDF15, as well as kidney and hepatic Gdf15 expression in chow-fed but not high-fat (HF)–induced hyperphagic male rats. Kidney Gdf15 knockdown blunted Intralipid-induced increases in kidney and plasma GDF15 levels as well as its feeding-lowering effects, while hepatic Gdf15 expression remained unaffected. Lastly, we knocked down GDNF family receptor α-like (Gfral) in the area postrema, which negated the feeding-lowering effect of Intralipid despite a rise in plasma GDF15 levels in chow rats. In summary, we report that kidney GDF15 is necessary for USI intralipid sensing to trigger an area postrema axis to inhibit food intake. We propose that HF feeding impairs acute lipid sensing to lower feeding by negating the lipid-regulatory effect on kidney GDF15. ARTICLE HIGHLIGHTS Upper small intestine lipid infusion increases kidney, hepatic, and plasma growth differentiation factor 15 (GDF15) levels in chow but not high-fat rats. Upper small intestine lipid infusion lowers food intake in chow but not high-fat rats. Knockdown of kidney Gdf15 negates lipids to increase plasma GDF15 and lower feeding. Knockdown of GDNF family receptor α-like (Gfral) in the area postrema negates lipid anorectic effect.
{"title":"Lipids Engage a Kidney-Brain GDF15 Axis to Suppress Food Intake","authors":"Ameth N. Garrido, Song-Yang Zhang, Kyla Bruce, Charmaine S.H. Lai, Zeyu Yang, Melissa T. Wang, Tony K.T. Lam","doi":"10.2337/db25-0174","DOIUrl":"https://doi.org/10.2337/db25-0174","url":null,"abstract":"Growth differentiation factor 15 (GDF15) is an anorectic and weight-loss–inducing hormone that responds to stimuli such as endoplasmic reticulum stress, exercise, metformin, and more recently, dietary lipids. Given its potential as an antiobesogenic agent, we examined how endogenous GDF15 responds to an Intralipid infusion in different organs to regulate food intake in vivo. We found that an acute Intralipid infusion into the upper small intestine (USI) inhibited food intake and increased plasma GDF15, as well as kidney and hepatic Gdf15 expression in chow-fed but not high-fat (HF)–induced hyperphagic male rats. Kidney Gdf15 knockdown blunted Intralipid-induced increases in kidney and plasma GDF15 levels as well as its feeding-lowering effects, while hepatic Gdf15 expression remained unaffected. Lastly, we knocked down GDNF family receptor α-like (Gfral) in the area postrema, which negated the feeding-lowering effect of Intralipid despite a rise in plasma GDF15 levels in chow rats. In summary, we report that kidney GDF15 is necessary for USI intralipid sensing to trigger an area postrema axis to inhibit food intake. We propose that HF feeding impairs acute lipid sensing to lower feeding by negating the lipid-regulatory effect on kidney GDF15. ARTICLE HIGHLIGHTS Upper small intestine lipid infusion increases kidney, hepatic, and plasma growth differentiation factor 15 (GDF15) levels in chow but not high-fat rats. Upper small intestine lipid infusion lowers food intake in chow but not high-fat rats. Knockdown of kidney Gdf15 negates lipids to increase plasma GDF15 and lower feeding. Knockdown of GDNF family receptor α-like (Gfral) in the area postrema negates lipid anorectic effect.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915547","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}
Despite the increasing prevalence of type 2 diabetes in youth, its causal associations with circulating biomarkers remain elusive. We first aimed to identify circulating metabolites causally linked to youth-onset type 2 diabetes using Mendelian randomization (MR). By analyzing 675 metabolites from large metabolomic European genome-wide association studies (GWAS) and data on youth type 2 diabetes from the multiancestry Progress in Diabetes Genetics in Youth (ProDiGY) consortium, we identified 34 candidate metabolites. Among these, phosphatidylcholine (pc) ae C42:3 and propionylcarnitine provided the strongest evidence of association with youth-onset type 2 diabetes, based also on positive genetic colocalization and sensitivity analyses accounting for adiposity. Among the 34 candidate metabolites, 23 were retained following colocalization and a replication MR using independent metabolomic GWAS and testing effects on adult type 2 diabetes. Furthermore, we validated associations of six of these metabolites with glucose metabolism–related traits in an observational study in the Avon Longitudinal Study of Parents and Children (ALSPAC). Notably, pc ae C42:3 levels at age 7 years were linked to dysglycemia and insulin resistance in adolescence. These findings underscore the dynamic role of metabolites in glucose metabolism in childhood, offering insights for future screening and treatment strategies. ARTICLE HIGHLIGHTS Metabolism is key in the pathogenesis of type 2 diabetes in both children and adults, and large-scale metabolomic studies offer a unique source for discovery of biomarkers for these conditions. Leveraging human genetics, we explored whether altered levels of circulating metabolites in the blood are causally linked to type 2 diabetes in youth across different ancestries. Our Mendelian randomization analysis identified causal associations for 34 metabolites, and, among these, Mendelian randomization replication and colocalization prioritized 23 metabolites. Observational evidence from the Avon Longitudinal Study of Parents and Children (ALSPAC) study validated effects on glucose homeostasis for six of these metabolites, among which phosphatidylcholine ae C42:3 emerged as the most promising biomarker. These findings highlight the role of metabolism in glucose homeostasis pathophysiology in youth.
{"title":"Metabolome-Wide Mendelian Randomization and Observational Study Reveal Causal Links Between Circulating Metabolites and Youth-Onset Type 2 Diabetes","authors":"Kaossarath Fagbemi, Raphael Avocegamou, Nahid Yazdanpanah, Mojgan Yazdanpanah, Basile Jumentier, Isabel Gamache, Despoina Manousaki","doi":"10.2337/db25-0093","DOIUrl":"https://doi.org/10.2337/db25-0093","url":null,"abstract":"Despite the increasing prevalence of type 2 diabetes in youth, its causal associations with circulating biomarkers remain elusive. We first aimed to identify circulating metabolites causally linked to youth-onset type 2 diabetes using Mendelian randomization (MR). By analyzing 675 metabolites from large metabolomic European genome-wide association studies (GWAS) and data on youth type 2 diabetes from the multiancestry Progress in Diabetes Genetics in Youth (ProDiGY) consortium, we identified 34 candidate metabolites. Among these, phosphatidylcholine (pc) ae C42:3 and propionylcarnitine provided the strongest evidence of association with youth-onset type 2 diabetes, based also on positive genetic colocalization and sensitivity analyses accounting for adiposity. Among the 34 candidate metabolites, 23 were retained following colocalization and a replication MR using independent metabolomic GWAS and testing effects on adult type 2 diabetes. Furthermore, we validated associations of six of these metabolites with glucose metabolism–related traits in an observational study in the Avon Longitudinal Study of Parents and Children (ALSPAC). Notably, pc ae C42:3 levels at age 7 years were linked to dysglycemia and insulin resistance in adolescence. These findings underscore the dynamic role of metabolites in glucose metabolism in childhood, offering insights for future screening and treatment strategies. ARTICLE HIGHLIGHTS Metabolism is key in the pathogenesis of type 2 diabetes in both children and adults, and large-scale metabolomic studies offer a unique source for discovery of biomarkers for these conditions. Leveraging human genetics, we explored whether altered levels of circulating metabolites in the blood are causally linked to type 2 diabetes in youth across different ancestries. Our Mendelian randomization analysis identified causal associations for 34 metabolites, and, among these, Mendelian randomization replication and colocalization prioritized 23 metabolites. Observational evidence from the Avon Longitudinal Study of Parents and Children (ALSPAC) study validated effects on glucose homeostasis for six of these metabolites, among which phosphatidylcholine ae C42:3 emerged as the most promising biomarker. These findings highlight the role of metabolism in glucose homeostasis pathophysiology in youth.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"23 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144911210","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}
Tessa M. Cacciottolo, Katherine Lawler, Kevin M. Méndez-Acevedo, Edson Mendes de Oliveira, Adam Syanda, Elana Henning, Julia M. Keogh, Rebecca Bounds, Miriam Smith, Daniyal Ashraf, David Harman, Adam Duckworth, Edmund M. Godfrey, Laura Watson, Matthew Hoare, Ben Jones, Alastair Baker, Tamir Rashid, I. Sadaf Farooqi
In mice, glucagon regulates lipid metabolism by activating receptors in the liver; however, its role in human lipid metabolism is incompletely understood. Here we describe three normal-weight individuals from a consanguineous family with early-onset hepatic steatosis and/or cirrhosis. Using exome sequencing, we found they were homozygous for two missense variants in the glucagon receptor gene (GCGR). In cells, the double GCGR mutation reduced cell membrane expression and signaling, resulting in an almost complete loss of function. Carriers of pathogenic GCGR mutations had substantially elevated circulating glucagon and amino acid levels and increased adiposity. Introducing the double GCGR mutation into human-induced pluripotent stem cell–derived hepatocytes using clustered regularly interspaced short palindromic repeats ([CRISPR]/CRISPR-associated protein 9) caused increased lipid accumulation. Our results provide an explanation for increased liver fat seen in clinical trials of GCGR antagonists and reduced liver fat in people with obesity and steatotic liver disease treated with GCGR agonists. ARTICLE HIGHLIGHTS In this study, we investigated a consanguineous family in whom normal-weight individuals had hepatic steatosis and cirrhosis. Using whole-exome sequencing we found two rare homozygous variants in the glucagon receptor (GCGR) gene that cosegregated with the phenotype. In cells, the GCGR mutations result in a loss of function and increased lipid accumulation. These results highlight the potential risks associated with GCGR antagonists and the benefits of GCGR agonists, currently in clinical trials.
{"title":"Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis","authors":"Tessa M. Cacciottolo, Katherine Lawler, Kevin M. Méndez-Acevedo, Edson Mendes de Oliveira, Adam Syanda, Elana Henning, Julia M. Keogh, Rebecca Bounds, Miriam Smith, Daniyal Ashraf, David Harman, Adam Duckworth, Edmund M. Godfrey, Laura Watson, Matthew Hoare, Ben Jones, Alastair Baker, Tamir Rashid, I. Sadaf Farooqi","doi":"10.2337/db25-0209","DOIUrl":"https://doi.org/10.2337/db25-0209","url":null,"abstract":"In mice, glucagon regulates lipid metabolism by activating receptors in the liver; however, its role in human lipid metabolism is incompletely understood. Here we describe three normal-weight individuals from a consanguineous family with early-onset hepatic steatosis and/or cirrhosis. Using exome sequencing, we found they were homozygous for two missense variants in the glucagon receptor gene (GCGR). In cells, the double GCGR mutation reduced cell membrane expression and signaling, resulting in an almost complete loss of function. Carriers of pathogenic GCGR mutations had substantially elevated circulating glucagon and amino acid levels and increased adiposity. Introducing the double GCGR mutation into human-induced pluripotent stem cell–derived hepatocytes using clustered regularly interspaced short palindromic repeats ([CRISPR]/CRISPR-associated protein 9) caused increased lipid accumulation. Our results provide an explanation for increased liver fat seen in clinical trials of GCGR antagonists and reduced liver fat in people with obesity and steatotic liver disease treated with GCGR agonists. ARTICLE HIGHLIGHTS In this study, we investigated a consanguineous family in whom normal-weight individuals had hepatic steatosis and cirrhosis. Using whole-exome sequencing we found two rare homozygous variants in the glucagon receptor (GCGR) gene that cosegregated with the phenotype. In cells, the GCGR mutations result in a loss of function and increased lipid accumulation. These results highlight the potential risks associated with GCGR antagonists and the benefits of GCGR agonists, currently in clinical trials.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"178 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898102","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}
Jimin Park, Sandali D. Lokuge, Menghao Huang, Shen Wang, Sheng Liu, Jingru Liang, Ramkumar Katturajan, Corinn Marakovits, Zhihong Yang, Jun Wan, X. Charlie Dong
Pancreatic β-cells undergo senescence and loss during aging; however, the underlying mechanisms remain incompletely understood. This study aimed to investigate what sirtuin 6 (SIRT6) does during β-cell aging. Pancreatic β-cell–specific Sirt6 transgenic (TgSIRT6) mice were generated for this study. DNA damage, cell death, and cell proliferation were analyzed in cell and mouse models. SIRT6 protein levels were decreased in pancreatic β-cells during aging. TgSIRT6 mice exhibited less DNA damage and cell death, including apoptosis, necroptosis, and pyroptosis, in β-cells than control mice. TgSIRT6 mice had increased total islet area and mass in pancreas compared with control mice. As a result, TgSIRT6 mice showed better glucose tolerance and glucose-stimulated insulin secretion than control mice. RRAD and GEM-like GTPase 2 (REM2), an endogenouse inhibitor of high-voltage–activated calcium channels, was negatively regulated by SIRT6. Knockdown of Rem2 in INS-1 cells partially rescued the SIRT6 deficiency– and palmitic acid–induced DNA damage, lipid peroxidation, and cell death. Rem2 β-cell–specific knockout mice had less DNA damage and cell death in β-cells than control mice. Our data suggest that SIRT6 is a critical antiaging factor in pancreatic β-cells and is a potential therapeutic target. ARTICLE HIGHLIGHTS Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells. Our findings suggest that improving Sirt6 gene expression and function may slow down β-cell decline in older patients.
{"title":"SIRT6 Is a Key Regulator of Pancreatic β-Cell Survival and Function During Aging","authors":"Jimin Park, Sandali D. Lokuge, Menghao Huang, Shen Wang, Sheng Liu, Jingru Liang, Ramkumar Katturajan, Corinn Marakovits, Zhihong Yang, Jun Wan, X. Charlie Dong","doi":"10.2337/db25-0116","DOIUrl":"https://doi.org/10.2337/db25-0116","url":null,"abstract":"Pancreatic β-cells undergo senescence and loss during aging; however, the underlying mechanisms remain incompletely understood. This study aimed to investigate what sirtuin 6 (SIRT6) does during β-cell aging. Pancreatic β-cell–specific Sirt6 transgenic (TgSIRT6) mice were generated for this study. DNA damage, cell death, and cell proliferation were analyzed in cell and mouse models. SIRT6 protein levels were decreased in pancreatic β-cells during aging. TgSIRT6 mice exhibited less DNA damage and cell death, including apoptosis, necroptosis, and pyroptosis, in β-cells than control mice. TgSIRT6 mice had increased total islet area and mass in pancreas compared with control mice. As a result, TgSIRT6 mice showed better glucose tolerance and glucose-stimulated insulin secretion than control mice. RRAD and GEM-like GTPase 2 (REM2), an endogenouse inhibitor of high-voltage–activated calcium channels, was negatively regulated by SIRT6. Knockdown of Rem2 in INS-1 cells partially rescued the SIRT6 deficiency– and palmitic acid–induced DNA damage, lipid peroxidation, and cell death. Rem2 β-cell–specific knockout mice had less DNA damage and cell death in β-cells than control mice. Our data suggest that SIRT6 is a critical antiaging factor in pancreatic β-cells and is a potential therapeutic target. ARTICLE HIGHLIGHTS Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells. Our findings suggest that improving Sirt6 gene expression and function may slow down β-cell decline in older patients.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"17 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901562","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}
Madison E. Weiss, Milin J. Patel, Brandon H. Watts, Paola E. Parrales, Oscar Alcazar, Isabella M. Pizza, Nicholas Karapelou, Abigail S. Hackam, Midhat H. Abdulreda
Diabetic retinopathy (DR) is characterized by microvascular damage and increased vascular permeability in the retina. The investigation of visual outcomes in late-stage DR is limited by challenges of maintaining chronically hyperglycemic mice, and most reports are restricted to early-stage DR. In this study, we used carefully managed diabetic mice to longitudinally investigate associations between vascular leakage and visual acuity during early- and late-stage DR. Diabetes was induced in C57BL/6J mice with streptozotocin, and fluorescence angiography with dual fluorescence (FA-DF) was used to assess retinal vascular leakage dynamics in chronically hyperglycemic mice for 12 months. Retinal vascular leakage was evident 180 days after diabetes induction and before reduced visual acuity, measured using the optokinetic response, and vascular leakage continued to increase during DR progression. Mice were also treated with intravitreal injections of antiangiogenic aflibercept at late-stage DR, and reduced leakage was reliably measured using FA-DF and was associated with improved visual acuity. Inflammatory and vascular phenotypes were assessed using immunostaining, which revealed significantly lower retinal macrophage and vascular densities and reduced capillary diameter in association with anti-VEGF treatment compared with age-matched diabetic controls. In conclusion, this is the first longitudinal quantification of retinal vascular leakage in early, intermediate, and late stages of DR in the same cohort of mice in a minimally invasive fashion to demonstrate the associated effect of antiangiogenic therapy in vivo. Our findings also further confirmed the sensitivity of FA-DF in assessing retinal vascular leakage in conjunction with other functional measures in longitudinal studies in the same animals. ARTICLE HIGHLIGHTS We use the newly developed fluorescence angiography with dual fluorescence imaging method to longitudinally investigate associations between vascular leakage and visual acuity during early-, intermediate-, and late-stage diabetic retinopathy (DR) in diabetic mice. We demonstrate the onset and progression of vascular leakage, association of leakage with reduced visual acuity, and alteration of macrophage and vascular densities in late-stage DR. We confirm the sensitivity of fluorescence angiography with dual fluorescence in assessing retinal vascular leakage in conjunction with other functional measures in longitudinal studies in the same animals and demonstrate inflammatory changes in late-stage DR.
{"title":"Investigating Late-Stage Diabetic Retinopathy: A Long-term Analysis of Vascular Changes in the Streptozotocin-Induced Mouse Model","authors":"Madison E. Weiss, Milin J. Patel, Brandon H. Watts, Paola E. Parrales, Oscar Alcazar, Isabella M. Pizza, Nicholas Karapelou, Abigail S. Hackam, Midhat H. Abdulreda","doi":"10.2337/db25-0434","DOIUrl":"https://doi.org/10.2337/db25-0434","url":null,"abstract":"Diabetic retinopathy (DR) is characterized by microvascular damage and increased vascular permeability in the retina. The investigation of visual outcomes in late-stage DR is limited by challenges of maintaining chronically hyperglycemic mice, and most reports are restricted to early-stage DR. In this study, we used carefully managed diabetic mice to longitudinally investigate associations between vascular leakage and visual acuity during early- and late-stage DR. Diabetes was induced in C57BL/6J mice with streptozotocin, and fluorescence angiography with dual fluorescence (FA-DF) was used to assess retinal vascular leakage dynamics in chronically hyperglycemic mice for 12 months. Retinal vascular leakage was evident 180 days after diabetes induction and before reduced visual acuity, measured using the optokinetic response, and vascular leakage continued to increase during DR progression. Mice were also treated with intravitreal injections of antiangiogenic aflibercept at late-stage DR, and reduced leakage was reliably measured using FA-DF and was associated with improved visual acuity. Inflammatory and vascular phenotypes were assessed using immunostaining, which revealed significantly lower retinal macrophage and vascular densities and reduced capillary diameter in association with anti-VEGF treatment compared with age-matched diabetic controls. In conclusion, this is the first longitudinal quantification of retinal vascular leakage in early, intermediate, and late stages of DR in the same cohort of mice in a minimally invasive fashion to demonstrate the associated effect of antiangiogenic therapy in vivo. Our findings also further confirmed the sensitivity of FA-DF in assessing retinal vascular leakage in conjunction with other functional measures in longitudinal studies in the same animals. ARTICLE HIGHLIGHTS We use the newly developed fluorescence angiography with dual fluorescence imaging method to longitudinally investigate associations between vascular leakage and visual acuity during early-, intermediate-, and late-stage diabetic retinopathy (DR) in diabetic mice. We demonstrate the onset and progression of vascular leakage, association of leakage with reduced visual acuity, and alteration of macrophage and vascular densities in late-stage DR. We confirm the sensitivity of fluorescence angiography with dual fluorescence in assessing retinal vascular leakage in conjunction with other functional measures in longitudinal studies in the same animals and demonstrate inflammatory changes in late-stage DR.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"41 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898107","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}
Johnny Assaf, Ishant Khurana, Ram Abou Zaki, Claudia H.T. Tam, Ilana Correa, Scott Maxwell, Julie Kinnberg, Malou Christiansen, Caroline Frørup, Heung Man Lee, Harikrishnan Kaipananickal, Jun Okabe, Safiya Naina Marikar, Kwun Kiu Wong, Cadmon K.P. Lim, Lai Yuk Yuen, Xilin Yang, Chi Chiu Wang, Juliana C.N. Chan, Kevin Y.L. Yip, William L. Lowe, Wing Hung Tam, Ronald C.W. Ma, Assam El-Osta
Gestational diabetes mellitus affects almost 18 million pregnancies worldwide, increasing by >70% in the past 20 years. DNA methylation has been associated with maternal hyperglycemia and type 2 diabetes risk in offspring. This study hypothesized that hyperglycemia during pregnancy influences DNA methylation changes at birth that mediate metabolic risk in offspring. Cord blood samples (n = 112) were obtained from women with normal (n = 43), impaired (n = 31), and low (n = 38) glucose tolerance enrolled in the Hong Kong field center of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Differentially methylated regions (DMRs) were identified using methylation sequencing and evaluated for their association with offspring metabolic dysfunction. Receiver operating characteristic curve analysis assessed the predictive value of DMRs for the classification of maternal glycemic status. These DMRs were assessed in human β-cells and pancreatic ductal epithelial cells in response to hyperglycemic stimuli. Methylation sequencing identified 19 methylation biomarkers in cord blood associated with maternal hyperglycemia, which correlated with offspring metabolic abnormalities. Incorporating the 19 DMRs improved the prediction of offspring β-cell dysfunction at 7, 11, and 18 years of age from area under the curve (AUC) scores ranging from 0.53 to 0.68 using clinical factors alone to AUC scores ranging from 0.71 to 0.95. Validation in human cell models confirmed that hyperglycemia influences methylation-dependent gene expression. This study demonstrates that DNA methylation biomarkers in cord blood predict offspring metabolic dysfunction, highlighting their potential as early indicators of diabetes risk. The findings align with methylation-mediated regulation in human pancreatic cells. ARTICLE HIGHLIGHTS Maternal hyperglycemia is linked to 19 cord blood DNA methylation biomarkers that predict offspring metabolic dysfunction. These methylation changes, associated with maternal glycemic status, improved the prediction of β-cell dysfunction at 7, 11, and 18 years of age compared with clinical factors alone. Validation in human β-cells and pancreatic ductal epithelial cells confirmed that hyperglycemia influences methylation-dependent gene expression. These findings highlight the role of epigenetic modifications at birth as early indicators of diabetes risk, suggesting that in utero hyperglycemic exposure may mediate long-term metabolic outcomes in offspring.
{"title":"DNA Methylation Biomarkers Predict Offspring Metabolic Risk From Mothers With Hyperglycemia in Pregnancy","authors":"Johnny Assaf, Ishant Khurana, Ram Abou Zaki, Claudia H.T. Tam, Ilana Correa, Scott Maxwell, Julie Kinnberg, Malou Christiansen, Caroline Frørup, Heung Man Lee, Harikrishnan Kaipananickal, Jun Okabe, Safiya Naina Marikar, Kwun Kiu Wong, Cadmon K.P. Lim, Lai Yuk Yuen, Xilin Yang, Chi Chiu Wang, Juliana C.N. Chan, Kevin Y.L. Yip, William L. Lowe, Wing Hung Tam, Ronald C.W. Ma, Assam El-Osta","doi":"10.2337/db25-0105","DOIUrl":"https://doi.org/10.2337/db25-0105","url":null,"abstract":"Gestational diabetes mellitus affects almost 18 million pregnancies worldwide, increasing by >70% in the past 20 years. DNA methylation has been associated with maternal hyperglycemia and type 2 diabetes risk in offspring. This study hypothesized that hyperglycemia during pregnancy influences DNA methylation changes at birth that mediate metabolic risk in offspring. Cord blood samples (n = 112) were obtained from women with normal (n = 43), impaired (n = 31), and low (n = 38) glucose tolerance enrolled in the Hong Kong field center of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Differentially methylated regions (DMRs) were identified using methylation sequencing and evaluated for their association with offspring metabolic dysfunction. Receiver operating characteristic curve analysis assessed the predictive value of DMRs for the classification of maternal glycemic status. These DMRs were assessed in human β-cells and pancreatic ductal epithelial cells in response to hyperglycemic stimuli. Methylation sequencing identified 19 methylation biomarkers in cord blood associated with maternal hyperglycemia, which correlated with offspring metabolic abnormalities. Incorporating the 19 DMRs improved the prediction of offspring β-cell dysfunction at 7, 11, and 18 years of age from area under the curve (AUC) scores ranging from 0.53 to 0.68 using clinical factors alone to AUC scores ranging from 0.71 to 0.95. Validation in human cell models confirmed that hyperglycemia influences methylation-dependent gene expression. This study demonstrates that DNA methylation biomarkers in cord blood predict offspring metabolic dysfunction, highlighting their potential as early indicators of diabetes risk. The findings align with methylation-mediated regulation in human pancreatic cells. ARTICLE HIGHLIGHTS Maternal hyperglycemia is linked to 19 cord blood DNA methylation biomarkers that predict offspring metabolic dysfunction. These methylation changes, associated with maternal glycemic status, improved the prediction of β-cell dysfunction at 7, 11, and 18 years of age compared with clinical factors alone. Validation in human β-cells and pancreatic ductal epithelial cells confirmed that hyperglycemia influences methylation-dependent gene expression. These findings highlight the role of epigenetic modifications at birth as early indicators of diabetes risk, suggesting that in utero hyperglycemic exposure may mediate long-term metabolic outcomes in offspring.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"70 1","pages":"1695-1707"},"PeriodicalIF":7.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898112","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}
In the article cited above, TG was incorrectly introduced as transforming secretory granules in the main text. The correct term is thapsigargin. The editors apologize for the error. The online version of the article (https://doi.org/10.2337/db24-0720) has been updated to correct the error.
{"title":"Erratum. Liraglutide Treatment Reverses Unconventional Cellular Defects in Induced Pluripotent Stem Cell–Derived β-Cells Harboring a Partially Functional WFS1 Variant. Diabetes 2025;74:1273–1288","authors":"Silvia Torchio, Gabriel Siracusano, Federica Cuozzo, Valentina Zamarian, Silvia Pellegrini, Fabio Manenti, Riccardo Bonfanti, Giulio Frontino, Valeria Sordi, Raniero Chimienti, Lorenzo Piemonti","doi":"10.2337/db25-er10a","DOIUrl":"https://doi.org/10.2337/db25-er10a","url":null,"abstract":"In the article cited above, TG was incorrectly introduced as transforming secretory granules in the main text. The correct term is thapsigargin. The editors apologize for the error. The online version of the article (https://doi.org/10.2337/db24-0720) has been updated to correct the error.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"29 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786535","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}
Khang Nguyen, Jialing Tang, Damian Gatica, Ryan C. Russell, Hye Kyoung Sung, Gary Sweeney
Iron overload (IO) is a common contributing factor to aspects of the metabolic syndrome (MetS), including insulin resistance. Mechanisms of IO-induced insulin resistance include elevated oxidative stress, endoplasmic reticulum (ER) stress and impaired autophagy. Using an Akt biosensor L6 skeletal muscle cell line, we found that the adiponectin receptor agonist ALY688 prevented impaired insulin signaling in response to IO. Mechanistically, ALY688 counteracted IO-dependent effects on ER stress, the unfolded protein response (UPR), and autophagic flux. Importantly, we found that ALY688 induced FAM134B-dependent ER-phagy (reticulophagy) to ameliorate ER stress. The beneficial effects of ALY688 were attenuated in cells lacking Atg7 or FAM134B, highlighting the importance of selective autophagy of the ER by FAM134B in mitigating IO-induced impaired insulin signaling. These findings translated to a mouse model of IO in which ALY688 improved glucose tolerance, insulin sensitivity, UPR activation, FAM134B expression, and autophagy flux. Collectively, our results demonstrate that ALY688 effectively attenuated IO-induced ER stress and insulin resistance in both mice and cellular skeletal muscle models via stimulation of the UPR and ER-phagy. Article Highlights This study adds mechanistic insight to the association between excess iron and insulin resistance and identifies an effective intervention strategy. Using a cellular skeletal muscle cell model and a preclinical animal model, we show that iron elicits endoplasmic reticulum (ER) stress and impairs insulin signaling. The adiponectin receptor agonist peptide ALY688 counteracts iron-induced ER stress and maintains insulin sensitivity. Loss-of-function approaches indicated that ALY688 acts via an autophagy-dependent, and specifically ER-phagy–dependent, mechanism.
{"title":"ALY688 Attenuates Iron-Induced ER Stress and Insulin Resistance via Activation of ER-Phagy","authors":"Khang Nguyen, Jialing Tang, Damian Gatica, Ryan C. Russell, Hye Kyoung Sung, Gary Sweeney","doi":"10.2337/db25-0405","DOIUrl":"https://doi.org/10.2337/db25-0405","url":null,"abstract":"Iron overload (IO) is a common contributing factor to aspects of the metabolic syndrome (MetS), including insulin resistance. Mechanisms of IO-induced insulin resistance include elevated oxidative stress, endoplasmic reticulum (ER) stress and impaired autophagy. Using an Akt biosensor L6 skeletal muscle cell line, we found that the adiponectin receptor agonist ALY688 prevented impaired insulin signaling in response to IO. Mechanistically, ALY688 counteracted IO-dependent effects on ER stress, the unfolded protein response (UPR), and autophagic flux. Importantly, we found that ALY688 induced FAM134B-dependent ER-phagy (reticulophagy) to ameliorate ER stress. The beneficial effects of ALY688 were attenuated in cells lacking Atg7 or FAM134B, highlighting the importance of selective autophagy of the ER by FAM134B in mitigating IO-induced impaired insulin signaling. These findings translated to a mouse model of IO in which ALY688 improved glucose tolerance, insulin sensitivity, UPR activation, FAM134B expression, and autophagy flux. Collectively, our results demonstrate that ALY688 effectively attenuated IO-induced ER stress and insulin resistance in both mice and cellular skeletal muscle models via stimulation of the UPR and ER-phagy. Article Highlights This study adds mechanistic insight to the association between excess iron and insulin resistance and identifies an effective intervention strategy. Using a cellular skeletal muscle cell model and a preclinical animal model, we show that iron elicits endoplasmic reticulum (ER) stress and impairs insulin signaling. The adiponectin receptor agonist peptide ALY688 counteracts iron-induced ER stress and maintains insulin sensitivity. Loss-of-function approaches indicated that ALY688 acts via an autophagy-dependent, and specifically ER-phagy–dependent, mechanism.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"12 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778512","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}
Tanya H. Pierre, Maigen M. Bethea, Kristen Coutinho, Yanping Liu, Jin-Hua Liu, Min Guo, Sahil Chada, Sylvia M. Evans, Wei Li, Sushant Bhatnagar, Roland W. Stein, Chad S. Hunter
Diabetes is characterized by a loss of functional β-cell mass; therefore, identifying factors involved in establishing and preserving β-cells is critical to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of coregulators facilitating gene expression is limited. Previously, we demonstrated that the islet-1 (Isl1) transcription factor forms complexes with ubiquitin ligases ring finger 20 (Rnf20) and Rnf40 to regulate β-cells in vitro. Here, we investigated whether Rnf20-mediated complexes are required for β-cell function in adult islets by characterizing a novel β-cell–enriched Rnf20 knockout mouse model. Tamoxifen induction of Rnf20 recombination prompted a robust loss of histone 2B monoubiquitination, imparted severe hyperglycemia and glucose intolerance, and elicited an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose-stimulated insulin secretion and β-cell identity were also dysregulated in Rnf20Δβ-cell mice. Comparative analyses of the loss of either Rnf20 or Isl1 yielded similar changes in the β-cell regulome, supporting that Isl1::Rnf20 complexes are critical regulators of β-cell identity and function. Isl1::Rnf20 complexes are maintained in human tissues wherein they regulate insulin expression, secretion, and content. These findings increase our understanding of key players in β-cell maintenance, which is crucial for the advancement of β-cell derivation diabetes therapeutics. Article Highlights Transcription factor Islet-1 (Isl1) and ubiquitin ligase Ring Finger 20 (Rnf20) complexes regulate insulin secretion and β-cell gene expression in vitro. Loss of Rnf20 in adult β-cells disrupts β-cell identity and insulin processing, production, and secretion. In complex with Isl1, Rnf20 influences the β-cell regulome and supports proper glucose homeostasis.
{"title":"The Islet-1 Interaction Partner Rnf20 Regulates Glucose Homeostasis and Pancreatic β-Cell Identity","authors":"Tanya H. Pierre, Maigen M. Bethea, Kristen Coutinho, Yanping Liu, Jin-Hua Liu, Min Guo, Sahil Chada, Sylvia M. Evans, Wei Li, Sushant Bhatnagar, Roland W. Stein, Chad S. Hunter","doi":"10.2337/db25-0167","DOIUrl":"https://doi.org/10.2337/db25-0167","url":null,"abstract":"Diabetes is characterized by a loss of functional β-cell mass; therefore, identifying factors involved in establishing and preserving β-cells is critical to combat rising diabetes incidence. While transcription factors are crucial β-cell regulators, knowledge of coregulators facilitating gene expression is limited. Previously, we demonstrated that the islet-1 (Isl1) transcription factor forms complexes with ubiquitin ligases ring finger 20 (Rnf20) and Rnf40 to regulate β-cells in vitro. Here, we investigated whether Rnf20-mediated complexes are required for β-cell function in adult islets by characterizing a novel β-cell–enriched Rnf20 knockout mouse model. Tamoxifen induction of Rnf20 recombination prompted a robust loss of histone 2B monoubiquitination, imparted severe hyperglycemia and glucose intolerance, and elicited an overall reduction in insulin content. Expression of mRNAs and proteins involved in glucose-stimulated insulin secretion and β-cell identity were also dysregulated in Rnf20Δβ-cell mice. Comparative analyses of the loss of either Rnf20 or Isl1 yielded similar changes in the β-cell regulome, supporting that Isl1::Rnf20 complexes are critical regulators of β-cell identity and function. Isl1::Rnf20 complexes are maintained in human tissues wherein they regulate insulin expression, secretion, and content. These findings increase our understanding of key players in β-cell maintenance, which is crucial for the advancement of β-cell derivation diabetes therapeutics. Article Highlights Transcription factor Islet-1 (Isl1) and ubiquitin ligase Ring Finger 20 (Rnf20) complexes regulate insulin secretion and β-cell gene expression in vitro. Loss of Rnf20 in adult β-cells disrupts β-cell identity and insulin processing, production, and secretion. In complex with Isl1, Rnf20 influences the β-cell regulome and supports proper glucose homeostasis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755838","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}
Siham Abdelgani, Ahmed Khattab, John M. Adams, Fahd Al-Mulla, Mohamed Abu-Farha, Gozde Baskoy, Jehad Abubaker, Aurora Merovci, Ralph A. DeFronzo, Renata Belfort De Aguiar, Muhammad Abdul-Ghani
The current study examined the effect of empagliflozin on hepatic glucose production (HGP) and total-body norepinephrine (NE) turnover in individuals with and without type 2 diabetes (T2D). The study randomized 36 individuals with T2D and 36 individuals without T2D to receive in a double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. HGP and NE turnover were measured with [3-3H]glucose and [3H]NE infusion, respectively, at baseline and at day 1 and 12 weeks after starting therapy with empagliflozin or placebo. Empagliflozin increased HGP by 22% in individuals with T2D and by 19% in those without T2D, and the increase in HGP persisted at week 12. Total-body NE turnover significantly decreased in both groups at 1 day after empagliflozin administration, and the decrease in NE turnover persisted for 12 weeks. The decrease in NE turnover strongly and inversely correlated with the increase in HGP at week 12 (r = 0.64, P < 0.001), but not with the increase in HGP on day 1 of empagliflozin administration (r = 0.09, P = ns). These results demonstrate that empagliflozin causes a long-term reduction in NE turnover and that the decrease in NE turnover was strongly correlated with the increase in HGP. Regulation of sympathetic activity by sodium–glucose cotransporter 2 inhibitors (SGLT2i) can explain some of the systemic actions of SGLT2i, but cannot explain the long-term SGLT2i-induced rise in HGP. ARTICLE HIGHLIGHTS Sodium–glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 hours) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate. Empagliflozin caused a decrease in total-body NE turnover at 1 day and at 12 weeks after starting therapy, despite an increase in glucose production, and the magnitude of decrease in NE turnover inversely correlated with the increase in HGP caused by empagliflozin.
目前的研究检测了恩格列净对2型糖尿病（T2D）患者和非2型糖尿病患者肝葡萄糖生成（HGP）和全身去甲肾上腺素（NE）转化的影响。该研究随机选择36名T2D患者和36名非T2D患者，以双盲方式接受恩帕列净或匹配的安慰剂（2:1比例），为期12周。在基线和开始使用恩格列净或安慰剂治疗后第1天和第12周，分别用[3-3H]葡萄糖和[3H]NE输注来测量HGP和NE的转换。恩帕列净使T2D患者的HGP升高22%，无T2D患者的HGP升高19%，并且HGP升高持续到第12周。在给予恩格列净1天后，两组的全身NE周转率均显著下降，且NE周转率持续下降12周。NE周转率的降低与第12周HGP的升高呈显著负相关(r = 0.64, P <；0.001)，但与给药第1天HGP升高无关（r = 0.09, P = ns）。这些结果表明，恩格列净导致NE周转的长期减少，并且NE周转的减少与HGP的增加密切相关。钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）对交感神经活动的调节可以解释SGLT2i的一些全身作用，但不能解释SGLT2i诱导的长期HGP升高。钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）导致肝糖生成（HGP）增加。我们之前的研究表明，SGLT2i导致全身去甲肾上腺素（NE）周转率迅速（在4小时内）增加，这可以解释HGP的增加。由于SGLT2i引起的HGP增加是持久的，因此我们研究了SGLT2i对NE周转率的长期影响。在开始治疗后的第1天和第12周，尽管葡萄糖产量增加，但恩帕列净引起的全身NE周转量下降，NE周转量下降的幅度与恩帕列净引起的HGP升高呈负相关。
{"title":"Empagliflozin Enhances Hepatic Glucose Production and Reduces Total-Body Norepinephrine Turnover Rate: A Randomized Trial","authors":"Siham Abdelgani, Ahmed Khattab, John M. Adams, Fahd Al-Mulla, Mohamed Abu-Farha, Gozde Baskoy, Jehad Abubaker, Aurora Merovci, Ralph A. DeFronzo, Renata Belfort De Aguiar, Muhammad Abdul-Ghani","doi":"10.2337/db25-0210","DOIUrl":"https://doi.org/10.2337/db25-0210","url":null,"abstract":"The current study examined the effect of empagliflozin on hepatic glucose production (HGP) and total-body norepinephrine (NE) turnover in individuals with and without type 2 diabetes (T2D). The study randomized 36 individuals with T2D and 36 individuals without T2D to receive in a double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. HGP and NE turnover were measured with [3-3H]glucose and [3H]NE infusion, respectively, at baseline and at day 1 and 12 weeks after starting therapy with empagliflozin or placebo. Empagliflozin increased HGP by 22% in individuals with T2D and by 19% in those without T2D, and the increase in HGP persisted at week 12. Total-body NE turnover significantly decreased in both groups at 1 day after empagliflozin administration, and the decrease in NE turnover persisted for 12 weeks. The decrease in NE turnover strongly and inversely correlated with the increase in HGP at week 12 (r = 0.64, P &lt; 0.001), but not with the increase in HGP on day 1 of empagliflozin administration (r = 0.09, P = ns). These results demonstrate that empagliflozin causes a long-term reduction in NE turnover and that the decrease in NE turnover was strongly correlated with the increase in HGP. Regulation of sympathetic activity by sodium–glucose cotransporter 2 inhibitors (SGLT2i) can explain some of the systemic actions of SGLT2i, but cannot explain the long-term SGLT2i-induced rise in HGP. ARTICLE HIGHLIGHTS Sodium–glucose cotransporter 2 inhibitors (SGLT2i) cause an increase in hepatic glucose production (HGP). We previously showed that SGLT2i cause a rapid (within 4 hours) increase in the total-body norepinephrine (NE) turnover rate, which could explain the increase in HGP. Because the increase in HGP caused by SGLT2i is long-lasting, we examined the long-term effect of SGLT2i on the NE turnover rate. Empagliflozin caused a decrease in total-body NE turnover at 1 day and at 12 weeks after starting therapy, despite an increase in glucose production, and the magnitude of decrease in NE turnover inversely correlated with the increase in HGP caused by empagliflozin.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"10 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645584","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}
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