Diabetes Pub Date : 2025-07-03 DOI: 10.2337/db24-1054

Maria S Svane, Morten Hindsø, Christoffer Martinussen, Carsten Dirksen, Nils B Jørgensen, Nora Hedbäck, Bolette Hartmann, Viggo B Kristiansen, Jens J Holst, Kirstine N Bojsen-Møller, Sten Madsbad

引用次数: 0

VAMP8 Is an Endosomal v-SNARE That Supports GLP-1 Receptor Recycling in Pancreatic β-Cells. VAMP8是一个支持胰β细胞GLP-1受体循环的内体v-SNARE。

Diabetes Pub Date : 2025-07-03 DOI: 10.2337/db24-0921

Liangwen Liu, Misty Marshall, Emmanuel Chadeuf, Jan Saras, Sebastian Barg

引用次数: 0

Therapeutic Targeting of the GIP Receptor-Revisiting the Controversies. GIP受体的靶向治疗——重新审视争议。

Diabetes Pub Date : 2025-06-16 DOI: 10.2337/db25-0393

Jonathan E Campbell, Daniel J Drucker

引用次数: 0

A Contemporary Rationale for Agonism of the GIP Receptor in the Treatment of Obesity. GIP受体激动作用治疗肥胖的当代基本原理。

Diabetes Pub Date : 2025-06-16 DOI: 10.2337/dbi24-0026

Ricardo J Samms, Kyle W Sloop

{"title":"A Contemporary Rationale for Agonism of the GIP Receptor in the Treatment of Obesity.","authors":"Ricardo J Samms, Kyle W Sloop","doi":"10.2337/dbi24-0026","DOIUrl":"https://doi.org/10.2337/dbi24-0026","url":null,"abstract":"In combatting the obesity crisis, leveraging mechanisms that lower body weight is critical. The finding that treatment with tirzepatide, a GIP and GLP-1 receptor agonist, produces profound weight loss highlights the value of activating the incretin receptors. Supporting this, recent studies have revealed mechanisms by which GIP receptor (GIPR) activation is beneficial in pancreatic islets, the central nervous system (CNS), and adipose tissue. Paradoxically, a hypothesis has emerged that GIPR antagonism could be an additional option in treating obesity. This concept stems from concern that GIP facilitates lipid uptake and storage in adipose tissue, although the lipid-buffering capacity of adipocytes versus other cell types is metabolically favorable. In this article, we highlight the natural physiology of the incretins, noting GIP as the primary incretin. In the CNS, GIPR agonism attenuates nausea and suppresses appetite, features that also help GLP-1 receptor agonism promote a negative energy balance. Further, we provide rationale that, in protecting against ectopic fat distribution and augmenting substrate utilization to promote insulin sensitivity, GIPR activity in adipose tissue is advantageous. Collectively, these attributes support GIPR agonism in the treatment of obesity and metabolic disease.","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304086","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}

引用次数: 0

GIP Receptor Antagonists in the Pharmacotherapy of Obesity: Physiologic, Genetic, and Clinical Rationale. 肥胖药物治疗中的GIP受体拮抗剂：生理、遗传和临床原理。

Diabetes Pub Date : 2025-06-16 DOI: 10.2337/dbi24-0027

Mette Marie Rosenkilde, Jyothis Thomas George, Murielle M Véniant, Jens Juul Holst

{"title":"GIP Receptor Antagonists in the Pharmacotherapy of Obesity: Physiologic, Genetic, and Clinical Rationale.","authors":"Mette Marie Rosenkilde, Jyothis Thomas George, Murielle M Véniant, Jens Juul Holst","doi":"10.2337/dbi24-0027","DOIUrl":"https://doi.org/10.2337/dbi24-0027","url":null,"abstract":"Obesity is a prevalent disease that also contributes to the incidence and severity of many other chronic diseases and health conditions. Treatment approaches include lifestyle intervention, bariatric surgery, and pharmacological approaches, with glucagon-like peptide 1 (GLP-1) receptor agonists approved specifically for weight loss having changed the treatment landscape significantly in the last 5 years. Targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor may enhance the metabolic benefits of GLP-1 receptor agonism. These beneficial effects are seen with both GIP receptor antagonism and GIP receptor agonism, although the mechanisms underlying this apparent paradox remain unknown. Here, we summarize the physiologic, genetic, and clinical evidence for pursuing GIP receptor antagonism to achieve metabolic and weight benefits. Both global and central nervous system knockout of GIP receptors protects mice fed a high-fat diet from obesity and insulin resistance. Genome-wide association studies in humans support this notion, correlating lower BMI with GIP receptor genetic variants with reduced function. Pharmacologic approaches in mice and monkeys confirm that GIP receptor antagonism enhances GLP-1-induced weight reduction and other metabolic benefits, and a phase 1 study provides proof of principle that beneficial effects extend to humans. GIP receptor antagonism may represent an important new mechanism to expand the treatment options available to individuals living with obesity.","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304087","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}

引用次数: 0

Differences in White Matter Microstructure in Children With Type 1 Diabetes Persist During Longitudinal Follow-up: Relation to Dysglycemia. 纵向随访期间1型糖尿病儿童白质微结构差异持续存在：与血糖异常有关

Diabetes Pub Date : 2025-06-02 DOI: 10.2337/db24-0684

Nelly Mauras, Qianheng Ma, Stuart A Weinzimer, Neil H White, Eva Tsalikian, Bruce Buckingham, Larry A Fox, William Tamborlane, Ana Maria Arbelaez, Michael Tansey, Tandy Aye, Allison Cato, Tamara Hershey, Kim Englert, Matthew Marzelli, Booil Jo, Allan Reiss

引用次数: 0

A Dual Stable Isotope Study of the Effect of Altitude and Simulated Flight on Glucose Metabolism in Type 1 Diabetes: A Randomized Crossover Study. 海拔高度和模拟飞行对1型糖尿病糖代谢影响的双稳定同位素研究：一项随机交叉研究。

Diabetes Pub Date : 2025-05-28 DOI: 10.2337/db25-0004

Ka Siu Fan, Fariba Shojaee-Moradie, Fereshteh Jeivad, Antonios Manoli, Ahmad Haidar, Monique Borg Inguanez, Fiona Sammut, Gerd Koehler, Victoria Edwards, Vivienne Lee, Agnieszka Falinska, Zosanglura Bawlchhim, Julia K Mader, A Margot Umpleby, David Russell-Jones

引用次数: 0

Smaller Pancreas Volume in Insulin-Dependent Monogenic Diabetes. 胰岛素依赖型单基因糖尿病患者胰腺体积减小。

Diabetes Pub Date : 2025-05-22 DOI: 10.2337/db25-0318

Jonathan M Williams, Melissa A Hilmes, Lisa R Letourneau-Freiberg, Balamurugan Kandasamy, Demetra Braun, Siri Atma W Greeley, Louis Philipson, Alvin C Powers, John Virostko, Daniel J Moore, Jordan J Wright

引用次数: 0

Diroximel Fumarate Acts Through Nrf2 to Attenuate Methylglyoxal-Induced Nociception in Mice and Decrease ISR Activation in DRG Neurons. 富马酸地洛西梅尔通过Nrf2作用于小鼠甲基乙二醛诱导的伤害感受，降低DRG神经元的ISR激活。

Diabetes Pub Date : 2025-05-01 DOI: 10.2337/db23-1025

Muhammad Saad Yousuf, Marisol Mancilla Moreno, Brodie J Woodall, Vikram Thakur, Jiahe Li, Lucy He, Rohita Arjarapu, Danielle Royer, Jennifer Zhang, Munmun Chattopadhyay, Peter M Grace, Theodore J Price

{"title":"Diroximel Fumarate Acts Through Nrf2 to Attenuate Methylglyoxal-Induced Nociception in Mice and Decrease ISR Activation in DRG Neurons.","authors":"Muhammad Saad Yousuf, Marisol Mancilla Moreno, Brodie J Woodall, Vikram Thakur, Jiahe Li, Lucy He, Rohita Arjarapu, Danielle Royer, Jennifer Zhang, Munmun Chattopadhyay, Peter M Grace, Theodore J Price","doi":"10.2337/db23-1025","DOIUrl":"10.2337/db23-1025","url":null,"abstract":"Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes pain hypersensitivity in mice by stimulating the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and subsequently activating the integrated stress response (ISR). We first established that Zucker diabetic fatty rats have enhanced MGO signaling, engage ISR, and develop pain hypersensitivity. Since nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of antioxidant proteins that neutralize MGO, we hypothesized that fumarates, like diroximel fumarate (DRF), will stimulate Nrf2 signaling, and prevent MGO-induced ISR and pain hypersensitivity. DRF (100 mg/kg) treated animals were protected from developing MGO (20 ng) induced mechanical and cold hypersensitivity. Mechanistically, DRF treatment protected against MGO-induced increase in p-eIF2α levels in the sciatic nerve and reduced loss of intraepidermal nerve fiber density. Using Nrf2 knockout mice, we demonstrate that Nrf2 is necessary for the antinociceptive effects of DRF. Cotreatment of MGO (1 µmol/L) with monomethyl fumarate (10, 20, and 50 µmol/L), the active metabolite of DRF, prevented ISR in both mouse and human dorsal root ganglia neurons. Our data show that targeting Nrf2 with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.Article highlights: ","PeriodicalId":93977,"journal":{"name":"Diabetes","volume":" ","pages":"827-837"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12015141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461277","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}

引用次数: 0

β-Cell Benchmarks: Defining Predictive Outcomes in Islet Transplantation. β-细胞基准：确定胰岛移植的预测结果。

Diabetes Pub Date : 2025-05-01 DOI: 10.2337/dbi24-0054

Shareen Forbes

引用次数: 0

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