Diabetes最新文献

{"title":"Phosphodiesterase 4 Inhibition Attenuates Diet-Induced Obesity and Activates BAT Thermogenic Pathways Through Central Mechanisms.","authors":"Hellen Veida-Raposo, Maria Amélia Montenegro de Andrade, Patrik Saul Barbosa Zarpellon, Michele de Souza Seixas, Luiza Mendonça Duarte, Rosa Elvira Alarcón-Yempén, Aline Alves de Jesus, Luciane Carla Alberici, Ricardo Maurício Leão, José Antunes-Rodrigues, Francisco José Albuquerque de Paula, Lucila Leico K Elias","doi":"10.2337/db25-1135","DOIUrl":"https://doi.org/10.2337/db25-1135","url":null,"abstract":"<p><strong>Article highlights: </strong>Metabolic alterations in obesity encompass impaired thermogenesis and sympathetic activity, underscoring the need for new metabolic targets to treat this disease. This study tested whether inhibition of PDE4 by rolipram enhances energy expenditure and brown adipose tissue activity. Rolipram reduced body weight and adiposity and increased brown adipose tissue temperature, UCP1 protein levels, noradrenaline levels, and enhanced excitability of hypothalamic paroventricular nucleus neurons. These findings suggest that central PDE4 inhibition promotes brown adipose tissue thermogenic activity and contributes to the metabolic effects of rolipram.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148979197","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":"Developmental Control of DNA Damage Responses in α- and β-Cells Shapes the Selective β-Cell Susceptibility in Diabetes.","authors":"Sneha S Varghese, Alessandro Giovanni Hernandez-De La Peña, Liu Wang, Victor Ruiz, Wilma Tixi, Aparamita Pandey, Laura Anchondo, Amy Chiu, Xiwei Wu, Senta K Georgia, Hung-Ping Shih, Zong Wei, Supriyo Bhattacharya, Sangeeta Dhawan","doi":"10.2337/db25-1027","DOIUrl":"10.2337/db25-1027","url":null,"abstract":"<p><p>Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in type 1 and type 2 diabetes. Although α-cell dysfunction also contributes to disease pathology, α-cells remain remarkably resistant to senescence and increased cell death under diabetogenic stress. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, whereas α-cells compensate for their greater DNA-damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental and postnatal epigenetic programs shape the differential DNA damage vulnerability of postnatal β- and α-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of β-cells from neonatal growth through adulthood. Complementing this developmental process, enhancer analyses reveal lineage-specific DNA damage response regulatory landscapes that are remodeled in β-cells under metabolic stress. Collectively, our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal β- and α-cells during growth and diabetes.</p><p><strong>Article highlights: </strong>Mechanisms underlying the differential susceptibility of pancreatic β- and α-cells to diabetogenic stress remain unclear. We investigated whether replication, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal β- and α-cells to DNA damage, a key driver of β-cell failure in diabetes. Replication introduces DNA damage vulnerability in both neonatal β- and α-cells, yet β-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens β-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic stress preferentially compromises β-cell repair fidelity. These findings reveal how developmental programs shape β-cell resilience and may influence lifelong diabetes risk.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1612-1628"},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13493214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450947","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":"Effects of Pharmacological GIP Infusion on Insulin, Glucagon, and Cardiovascular Responses During Hyperglycemia in Type 2 Diabetes.","authors":"Yixuan Sun, Cong Xie, Weikun Huang, Michelle Bound, Jacqueline Grivell, Karen L Jones, Michael Horowitz, Ian A Macdonald, Christopher K Rayner, Tongzhi Wu","doi":"10.2337/db26-0267","DOIUrl":"10.2337/db26-0267","url":null,"abstract":"<p><p>The pharmacological actions of glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D) remain incompletely defined. We evaluated the acute effects of intravenous GIP infusion at a pharmacological dose on glucose homeostasis and cardiovascular responses during hyperglycemia in individuals with T2D. Ten participants, whose T2D was managed by diet and/or metformin monotherapy (n = 4 men and 6 women; mean ± SEM age 68.2 ± 3.4 years, BMI 31.7 ± 1.2 kg/m2, HbA1c 6.9% ± 0.6%), were studied on two occasions in a double-blind, randomized, crossover design. During each study visit, hyperglycemia (∼15 mmol/L) was maintained for 210 min by variable intravenous (IV) glucose infusion, and GIP(1-42) (4 pmol/kg/min) or 0.9% saline was infused IV. Plasma insulin, C-peptide, glucagon, glucose infusion requirements, mean glucose/insulin ratio (M/I ratio; a surrogate for insulin sensitivity), heart rate, and blood pressure were assessed. GIP increased baseline-subtracted insulin and C-peptide responses between 0 and 210 min (mean ± SEM 8,717 ± 1,827 vs. 3,074 ± 698 mU/L*min, P = 0.003; and 383.1 ± 58.9 vs. 185.0 ± 35.0 nmol/L*min, P = 0.0005, respectively) and increased glucose infusion requirements to maintain hyperglycemia (mean ± SEM 6.1 ± 0.6 vs. 4.9 ± 0.4 mg/kg/min; P = 0.02), but attenuated glucagon suppression (P = 0.03) and reduced the M/I ratio (P < 0.0001). GIP also increased heart rate and reduced systolic and diastolic blood pressures (P < 0.01 each). These findings demonstrate that pharmacological GIP retains substantial biological activity in relatively well-controlled T2D, influencing both glucose metabolism and cardiovascular regulation.</p><p><strong>Article highlights: </strong>The clinical success of dual glucagon-like peptide 1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists has renewed interest in the pharmacological actions of GIP in type 2 diabetes (T2D), although its metabolic and cardiovascular effects remain incompletely understood. The study evaluated the effects of a pharmacological GIP infusion on glucose homeostasis and cardiovascular responses during hyperglycemia in individuals with T2D. GIP stimulated insulin secretion and increased whole-body glucose disposal during hyperglycemia while modestly attenuating glucagon suppression and impairing insulin sensitivity. GIP also augmented heart rate and reduced blood pressure. Our findings demonstrate that GIP remains biologically active in T2D and pharmacological doses modulate glucose metabolism and cardiovascular function.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1701-1708"},"PeriodicalIF":0.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450936","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":"Body Composition-Driven Phenotyping Reveals Obesity and Cardiometabolic Heterogeneity in Children Using a Tree-Like Representation.","authors":"Pei Xiao, Hong Cheng, Jingfan Xiong, Yinkun Yan, Junting Liu, Li Liu, Hongbo Dong, Yan Li, Peiyu Ye, Liwan Fu, Liwang Gao, Fangfang Chen, Xinying Shan, Lina Lan, Yanyan Li, Jie Mi","doi":"10.2337/db26-0136","DOIUrl":"https://doi.org/10.2337/db26-0136","url":null,"abstract":"<p><strong>Article highlights: </strong>Childhood obesity shows large differences in body composition and health risk that are not well captured by BMI or simple metabolic classifications, prompting the need for more precise characterization. This study aimed to determine whether a data-driven framework integrating detailed body composition measures could better describe obesity-related phenotypic heterogeneity and its relationship with cardiometabolic risk in children. We delineated a continuous body composition manifold encompassing fat-dominant, lean-dominant, and concomitant high-mass phenotypes, which captured diverging cardiometabolic risk trajectories and yielded modest incremental improvements in risk prediction. These findings support more precise risk stratification and provide a practical tool to improve early identification and prevention of obesity-related health complications in children.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763418","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":"Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion.","authors":"Ningning Zhang, Peng Lu, Yangyi Tong, Zhiwen Cao, Yinmeng Zhu, Yujia Gong, Nan Yin, Ruikai Yang, Muye Tong, Na Chen, Yuxiao Zhao, Chao Wu, Qian Li, Zhongyun Zhang, Xinyuan Zhou, Dongqin Gu, Yansong Liu, Qianyun Cheng, Zhiguo Zhang, Jieli Lu, Yufang Bi, Yong Geng, Weiqing Wang, Guang Ning, Jie Hong, Weiqiong Gu, Ruixin Liu, Jiqiu Wang","doi":"10.2337/db25-1108","DOIUrl":"https://doi.org/10.2337/db25-1108","url":null,"abstract":"<p><strong>Article highlights: </strong>A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765781","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":"Increased Risk of Infections in People Living With Diabetes.","authors":"Julia A Critchley, Iain M Carey, Umar A R Chaudhry, Liza Bowen, Derek G Cook, Tess Harris","doi":"10.2337/dbi26-0004","DOIUrl":"10.2337/dbi26-0004","url":null,"abstract":"<p><p>Infections represent major but underrecognized complications of type 1 diabetes (T1D), type 2 diabetes (T2D), and prediabetes. This recent overview includes use of linked U.K. primary care, hospitalization, and mortality data to examine infection risk for >800,000 individuals with diabetes or prediabetes, compared with an age-, sex-, and ethnicity-matched group without diabetes. We assessed 1) infections in primary care and requiring a prescription, 2) infections leading to hospitalization, and 3) infection-related mortality, over 5 years (2015-2019). Infection risks were consistently elevated across all forms of diabetes, compared with risk for those without diabetes. The highest relative risks were observed in T1D and lowest in prediabetes. While relative risks were similar across different ethnicities, the population burden of infections attributable to diabetes was highest among South Asians. There were independently strong graded associations for average HbA1c level and visit-to-visit HbA1c variability with infection risk, particularly for hospitalization infections. Among individuals with T1D, the strongest associations with infection risk were seen for elevated HbA1c levels, whereas for T2D, variability contributed more to the excess burden of infections. Infection-related mortality across all ICD-10 chapters was substantial, representing the third leading cause of death in T2D after cardiovascular disease and cancer. Further, it might be underreported, as sepsis is rarely coded as the underlying cause of death. These findings highlight the importance of improved glycemic control, earlier recognition and treatment of infections, and stronger emphasis on infection management in clinical guidelines. Incorporation of HbA1c variability into diabetes risk algorithms, and evaluation of interventions that might stabilize control, such as continuous glucose monitoring, may enhance infection prevention and reduce complications.</p><p><p></p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1381-1389"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148195328","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":"Colocalization of eQTLs With Type 2 Diabetes and Glycemic Traits Using Whole-Genome Sequences in Diverse Populations From the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.","authors":"Ningyuan Wang, Daniel A DiCorpo, Yixin Zhang, Erica Kleinbrink, Donna K Arnett, John Barnard, John Blangero, Donald W Bowden, April P Carson, Yii-Der Ida Chen, Mina K Chung, Joanne E Curran, Dawood Darbar, Ravindranath Duggirala, Patrick T Ellinor, Diane Fatkin, Myriam Fornage, Nancy Heard-Costa, Jiang He, Lifang Hou, Sharon L R Kardia, Charles Kooperberg, Ruth J F Loos, David D McManus, Braxton D Mitchell, Ryan L Minster, Kari E North, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Dan Roden, Jerome I Rotter, Moore B Shoemaker, Jonathan D Smith, David R Van Wagoner, Francois Aguet, Kristin Ardlie, Joshua C Bis, Jennifer A Brody, Brian E Cade, Clary B Clish, Paul S de Vries, James S Floyd, Barry I Freedman, Stacey Gabriel, Robert E Gerzsten, Mark O Goodarzi, Charles Gu, Xiuqing Guo, Namrata Gupta, Susan R Heckbert, Sarah Hsu, Yi-Jen Hung, Rita R Kalyani, Tanika N Kelly, Gregory L Kinney, Changwei Li, Simin Liu, Yongmei Liu, Donald M Lloyd-Jones, JoAnn E Manson, Rasika A Mathias, Josep M Mercader, Alanna C Morrison, Take Naseri, Suna Onengut, Nicholette D Palmer, Patricia A Peyser, Qibin Qi, Sridharan Raghavan, Alex P Reiner, Mary R Rooney, Magdalena Sevilla-Gonzalez, Chloe Sarnowski, Joshua D Smith, Jennifer A Smith, Nicole L Spartano, Usman Tahir, Kent D Taylor, Deirdre K Tobias, Russel P Tracy, Satupa'itea Viali, Heming Wang, Alexis C Wood, Lisa R Yanek, Wei Zhao, Yinan Zheng, Josée Dupuis, Ching-Ti Liu, Robert Sladek, Jennifer Wessel, James B Meigs, Alisa K Manning","doi":"10.2337/db25-0557","DOIUrl":"10.2337/db25-0557","url":null,"abstract":"<p><p>Large-scale multiancestry genome-wide association studies have identified hundreds of loci associated with type 2 diabetes (T2D) and glycemic traits, yet imputed genotyping arrays limit the detection of low-frequency and rare variants. Whole-genome sequencing (WGS) offers a more complete view of genetic variation, especially across diverse populations. We analyzed high-coverage (38×) WGS data from 21,913 T2D case subjects, 61,036 control subjects, and up to 50,011 individuals with no diabetes with fasting glucose, fasting insulin, and HbA1c from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine Program. We performed single-variant association testing, conditional analysis, fine-mapping, and Bayesian colocalization to identify genetic signals and assess regulatory relevance in diabetes-related tissues. We identified 76 distinct association signals across 34 loci, including novel variants at DUSP9 for T2D, and ROBO1, NDN, and MYT1 for HbA1c. Fine-mapping narrowed credible sets and improved causal variant resolution. Colocalization highlighted 80 expression signals in diabetes-related tissues, linking genetic associations to functional regulatory mechanisms. Our findings demonstrate the utility of WGS to uncover novel variants in diverse populations, enhance locus resolution, and link regulatory variation to disease-relevant tissues. This work refines the genetic architecture of T2D and glycemic traits and supports precision medicine efforts targeting diverse populations.</p><p><strong>Article highlights: </strong>We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1477-1491"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148221375","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":"α/β-Hydrolase Domain Containing 5 Supports Glucose-Stimulated Lipolysis and Insulin Secretion in Pancreatic β-Cells.","authors":"Lucy Kim, Siming Liu, Spencer Peachee, Syreine Richtsmeier, Claudia Jun, Gianna Sagona, Anamika Vikram, Aidan Freshly, Farakh Haider, Yumi Imai","doi":"10.2337/db25-1156","DOIUrl":"10.2337/db25-1156","url":null,"abstract":"<p><p>Adipose triglyceride (TG) lipase (ATGL) is the rate-limiting enzyme of TG catabolism at the surface of lipid droplets (LDs). In pancreatic β-cells, lipolysis by ATGL increases with glucose and produces metabolites that support glucose-stimulated insulin secretion (GSIS). Upregulation of lipolysis by glucose is blunted in human islets affected by type 2 diabetes. However, how glucose regulates lipolysis in β-cells is unknown. We found that glucose recruits ATGL coactivator α/β-hydrolase domain containing 5 (ABHD5) to LDs in INS-1 cells and human β-cells. ABHD5 recruitment to LDs was reduced by inhibitors of cAMP-dependent protein kinase (PKA) or the expression of PKA-resistant mutant ABHD5, indicating that PKA phosphorylation contributes to ABHD5 recruitment to LDs. Importantly, ABHD5 was indispensable for glucose-stimulated lipolysis in INS-1 cells and human β-cells. ABHD5 knockdown increased LDs and TG content in INS-1 cells and human islets, indicating that ABHD5 is a critical regulator of ATGL activity in β-cells. Additionally, GSIS was impaired in ABHD5-downregulated INS-1 cells and human pseudoislets, which agrees with a role of ATGL in supporting GSIS in β-cells. Thus, ABHD5 plays an important role in conferring glucose responsiveness in lipolysis and supporting insulin secretion in β-cells.</p><p><strong>Article highlights: </strong>Lipolysis is stimulated by glucose and supports glucose-stimulated insulin secretion in pancreatic β-cells. However, the mechanism by which glucose increases lipolysis in β-cells is unknown. We aimed to identify a glucose-responsive regulator of lipolysis in β-cells. Glucose promotes α/β-hydrolase domain containing 5 (ABHD5) recruitment to lipid droplets where lipolysis occurs, which is at least partially mediated by cAMP-dependent kinase A. ABHD5 is required for glucose-stimulated lipolysis and insulin secretion. ABHD5 is a potential target to restore glucose-stimulated lipolysis in β-cells affected by type 2 diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1411-1423"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148058975","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":"Morning Elevation in Insulin Enhances Afternoon Hepatic Glucose Disposal in Dogs by Increasing Both Insulin Signaling and Glucose Action.","authors":"Hannah L Waterman, Marta S Smith, Ben Farmer, Kalisha Yankey, Tristan Howard, Guillaume Kraft, Alan D Cherrington, Dale S Edgerton","doi":"10.2337/db26-0103","DOIUrl":"10.2337/db26-0103","url":null,"abstract":"<p><p>The second-meal phenomenon refers to the improved glycemic response to a subsequent identical meal. We previously showed that morning hyperinsulinemia is a key mediator, priming the liver for enhanced net hepatic glucose uptake (NHGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic clamp. Postprandial NHGU is regulated by three primary mechanisms: insulin action, initiated by hyperinsulinemia; glucose effectiveness (GE), driven by hyperglycemia; and the portal glucose signal (PGS), a neurally mediated signal activated by glucose delivery into the hepatoportal circulation. It remains unclear, however, which of these mechanisms govern the increase in afternoon NHGU following morning insulin exposure. To address this, dogs underwent a morning clamp with either a 4-h hyperinsulinemic prime (prime group) (n = 8) or basal insulin delivery (no-prime group) (n = 8). After a 1.5-h rest, both groups underwent an afternoon hyperglycemic clamp with portal glucose delivery under basal insulin conditions to isolate the effects of a morning insulin prime on afternoon glucose-mediated hepatic signals (GE and the PGS). Mean afternoon NHGU was significantly greater in the prime group (2.2 ± 0.3 mg/kg/min) compared with the no-prime group (0.1 ± 0.3 mg/kg/min; P = 0.005), accompanied by augmented net glycolytic and glycogen flux. These findings indicate that morning insulin can enhance glucose-mediated afternoon NHGU independently of a rise in afternoon insulin. However, maximal second-meal NHGU also requires elevated afternoon insulin. Together, these findings suggest that strategically timed early-day insulin or insulinotropic interventions could potentially improve hepatic responsiveness in settings of impaired postprandial glycemic control, such as insulin resistance or diabetes.</p><p><strong>Article highlights: </strong>Elevated morning insulin primes the liver for enhanced afternoon net hepatic glucose uptake (NHGU), but it is unclear whether augmentation of insulin action, glucose effectiveness, or the portal glucose signal mediates this effect. Dogs underwent a morning euglycemic clamp with either elevated or basal insulin delivery, followed by an afternoon euinsulinemic-hyperglycemic clamp to isolate the effect of morning insulin priming on afternoon glucose effectiveness and the portal glucose signal. Morning insulin priming enhanced afternoon NHGU via increased glucose-mediated mechanisms, though maximal afternoon NHGU also required elevated afternoon insulin. These findings identify mechanisms underlying insulin-induced hepatic metabolic memory, providing a framework to inform strategies improving postprandial glucose handling in diabetes.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1390-1402"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147978033","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":"The Potential of Composite Pig Islets-Kidney Xenotransplantation to Cure Diabetes and Renal Failure: A Suggested Modified Approach.","authors":"Benjamin D Bühler, Sara De Taeye, Kohei Kinoshita, Maho Terashita, Akihiro Maenaka, Gwen Lavalla, Lars Burdorf, Rita Bottino, David K C Cooper","doi":"10.2337/db25-0769","DOIUrl":"10.2337/db25-0769","url":null,"abstract":"<p><p>One-third of patients with diabetes will develop end-stage kidney disease, and approximately one-half of the patients requiring kidney transplantation in the U.S. suffer from diabetes. In 2002, Yamada, Sachs, and their colleagues explored the renal subcapsular site for islet implantation in a partially inbred miniature swine model. All pancreatectomized pigs that received autologous islets under the renal capsule maintained normoglycemia. The transplantation of a composite islets-kidney (i.e., the kidney with the revascularized autologous islets) into another pancreatectomized, bilaterally nephrectomized pig provided successful renal and islet function. In 2011, this model was extended successfully to nonhuman primates (NHPs). There are several hurdles to be overcome if this model is to be successfully translated into clinical practice, and xenotransplantation might resolve this problem. Pancreases harvested from gene-edited pigs could be sources of islets that could be isografted beneath the renal capsule of an identical cloned littermate. After allowing the islets to become vascularized over a period of 6-12 weeks, during which no immunosuppressive therapy would be required, the composite islets-kidney would then be transplanted into an immunosuppressed NHP or human recipient. On reperfusion of the graft, both renal and islet function should rapidly return. If sufficient islets have been transplanted with the kidney and the immunosuppressive regimen is successful, normoglycemia and normal renal function should be quickly achieved. However, a large number of genetically engineered neonatal donor piglets will be required to manufacture one therapeutic patient dose of islets, which may prove to be a logistical problem. Alternative approaches are discussed.</p><p><strong>Article highlights: </strong>Autologous islet implantation in the kidney subcapsular space of pigs and baboons and subsequent allotransplantation of the composite islet-kidney graft have been demonstrated to be successful, but the limited availability of human islets limits this approach in clinical practice. The implantation of neonatal pig islets under the kidney capsule of an identical cloned piglet and subsequent transplantation into a human patient with diabetic nephropathy could potentially correct both diabetes and renal failure. Neonatal pig islets can become revascularized in cloned littermates in the absence of immunosuppressive therapy, but a very large number of donors may be required.</p>","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"1340-1346"},"PeriodicalIF":0.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148207419","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}