Metabolism: clinical and experimental最新文献

{"title":"Uncovering mechanisms of thiazolidinediones on osteogenesis and adipogenesis using spatial fluxomics","authors":"Kristyna Brejchova ,&nbsp;Michal Rahm ,&nbsp;Andrea Benova ,&nbsp;Veronika Domanska ,&nbsp;Paul Reyes-Gutierez ,&nbsp;Martina Dzubanova ,&nbsp;Radka Trubacova ,&nbsp;Michaela Vondrackova ,&nbsp;Tomas Cajka ,&nbsp;Michaela Tencerova ,&nbsp;Milan Vrabel ,&nbsp;Ondrej Kuda","doi":"10.1016/j.metabol.2025.156157","DOIUrl":"10.1016/j.metabol.2025.156157","url":null,"abstract":"<div><h3>Objective</h3><div>Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs).</div></div><div><h3>Methods</h3><div>We developed ¹³C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs.</div></div><div><h3>Results</h3><div>Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy.</div></div><div><h3>Conclusions</h3><div>These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156157"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review & updated meta-analysis on the association between higher consumption of ultra processed foods and risk of diabetes and its complications: Letter to the editor","authors":"Jian Huang","doi":"10.1016/j.metabol.2025.156156","DOIUrl":"10.1016/j.metabol.2025.156156","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156156"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review & updated meta-analysis on the association between higher consumption of ultra processed foods and risk of diabetes and its complications: Response Letter","authors":"Matheus Souza,&nbsp;Felipe S. Moura,&nbsp;Luan C.V. Lima,&nbsp;Marcio J.M. Amaral","doi":"10.1016/j.metabol.2025.156155","DOIUrl":"10.1016/j.metabol.2025.156155","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156155"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fructose-induced progression of steatohepatitis involves disrupting aldolase B-AMPK signaling in methionine adenosyltransferase 1A deficient mice","authors":"Lucía Barbier-Torres ,&nbsp;María Luque-Urbano ,&nbsp;Jyoti Chhimwal ,&nbsp;Aaron E. Robinson ,&nbsp;David Fernández-Ramos ,&nbsp;Fernando Lopitz-Otsoa ,&nbsp;Jennifer E. Van Eyk ,&nbsp;Oscar Millet ,&nbsp;José M. Mato ,&nbsp;Shelly C. Lu","doi":"10.1016/j.metabol.2025.156154","DOIUrl":"10.1016/j.metabol.2025.156154","url":null,"abstract":"<div><h3>Objective</h3><div>Aldolases (ALDO) are sensors that regulate AMPK via binding to fructose 1,6-biphosphate (FBP), an intermediate of glucose and fructose metabolism. Fructose consumption is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) progression but whether ALDO-AMPK signaling is involved is unknown. Methionine adenosyltransferase alpha 1 (<em>Mat1a</em>) knockout (KO) mice have low hepatic S-adenosylmethionine (SAMe) level and spontaneously develop steatohepatitis. ALDOB methylation has not been reported and here we investigated whether SAMe level regulates ALDOB and ALDOB-AMPK signaling and whether fructose feeding accelerates MASLD progression by disrupting ALDOB-AMPK signaling.</div></div><div><h3>Methods</h3><div>Mass spectrometry identified ALDOB methylation sites and recombinant in vitro approaches assessed how methylation at those sites affects ALDOB oligomerization and activity. Primary hepatocytes cultured with high/low glucose and/or fructose and wild type (WT) and <em>Mat1a</em> KO mice fed with a high-fructose diet examined AMPK-ALDOB signaling and MASLD progression.</div></div><div><h3>Results</h3><div>In <em>Mat1a</em> KO livers ALDOB R173 is hypomethylated while ALDOB activity is enhanced. Recombinant ALDOB is methylated at R173 and R304 by protein arginine methyltransferase 1. Low hepatic SAMe level results in hypomethylated ALDOB, which favors the tetrameric form that has higher enzymatic activity, and higher capacity to signal to activate AMPK. Fructose, independently of glucose levels, inhibited AMPK activity and induced lipid accumulation in hepatocytes. <em>Mat1a</em> KO mice have hyperactivated AMPK and fructose feeding inhibits it, enhancing the accumulation of fat in the liver and the progression of MASLD.</div></div><div><h3>Conclusion</h3><div>Hepatic SAMe levels regulate ALDOB oligomeric state and enzymatic activity impacting on AMPK signaling and fructose-induced MASLD progression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156154"},"PeriodicalIF":10.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Start small, think big: MicroRNAs in diabetes mellitus and relevant cardiorenal-liver metabolic health spectrum","authors":"Junren Chen ,&nbsp;Maozhu Luo ,&nbsp;Ziwei Xing,&nbsp;Yu Chen,&nbsp;Cheng Peng,&nbsp;Dan Li","doi":"10.1016/j.metabol.2025.156153","DOIUrl":"10.1016/j.metabol.2025.156153","url":null,"abstract":"<div><div>Diabetes mellitus (DM), co-existing with metabolic disorder of cardio-renal-liver, is one of the most difficult problems in medicine that attracts global concern with high mortality. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that negatively regulates gene expression and exerts active against a large proportion of the transcriptome, due to their high evolutionary conservation. Emerging evidence prove that miRNAs are involved in the pathogenesis of DM and associated metabolic disorders, manifested by their variable alteration in the blood, urine, tissues, or organs, principally contributing to modulate the interconnections between DM and cardio-renal-liver metabolism. Mechanistically, miRNAs regulate various biological processes, such as metabolism of insulin, lipid, glucose, inflammatory response, fibrosis, oxidative stress, apoptosis, and angiogenesis, etc. This review emphasizes the function of miRNAs and highlights the physiopathological regulation of miRNA in DM and related complications, especially the dysfunction of cardiovascular system, kidneys, and liver, with the aim of providing promising biomarkers for assisting early diagnosis of DM with cardio-renal-liver- specific metabolic disorders, as well as for the development of miRNA-targeting agents.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156153"},"PeriodicalIF":10.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical insights into the potential of itaconate and its derivatives for liver disease therapy","authors":"Xiaodong Wu ,&nbsp;Yanhong Song ,&nbsp;Zhengwei Yuan ,&nbsp;Shuodong Wu","doi":"10.1016/j.metabol.2025.156152","DOIUrl":"10.1016/j.metabol.2025.156152","url":null,"abstract":"<div><div>Annually, approximately 3.5 % of the world's population dies of cirrhosis or liver cancer, and the burden of liver disease is steadily expanding owing to multiple factors such as alcohol consumption, irrational diets, viral transmission, and exposure to drugs and toxins. However, the lack of effective therapies and the adverse effects of some medications remain a threat to the management of liver disease. Recently, immunometabolism, as an emerging discipline, appears to be the focus of unprecedented research. As a natural metabolite that regulates cellular functions, itaconate is a crucial bridge connecting metabolism and immune response. Remodeling immune function through metabolic modulation may be a promising alternative for disease intervention strategies. In this review, we first briefly describe the historical origin of itaconate and the development of its derivatives. This was followed by a review of the molecular mechanisms by which itaconate regulated immune-metabolic responses. Furthermore, we analyzed the effects of itaconate regulation on immune cells of the hepatic system. Finally, we summarized the experimental evidence for itaconate and its derivatives in the therapeutic application of liver diseases. Itaconate is potentially an invaluable component of emerging therapeutic strategies for liver disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"165 ","pages":"Article 156152"},"PeriodicalIF":10.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143205840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leptin receptor neurons in the dorsomedial hypothalamus require distinct neuronal subsets for thermogenesis and weight loss","authors":"Marie Francois ,&nbsp;Laura Kaiser ,&nbsp;Yanlin He ,&nbsp;Yong Xu ,&nbsp;J. Michael Salbaum ,&nbsp;Sangho Yu ,&nbsp;Christopher D. Morrison ,&nbsp;Hans-Rudolf Berthoud ,&nbsp;Heike Münzberg","doi":"10.1016/j.metabol.2024.156100","DOIUrl":"10.1016/j.metabol.2024.156100","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable to increase energy expenditure and locomotion, but neither reproduced the beneficial metabolic effects observed after chemogenetic activation of dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons. We clarify that BAT-projecting dDMH/DHA neurons that innervate the raphe pallidus (RPa) are exclusively glutamatergic Lepr neurons. In contrast, projections of GABAergic or dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons overlapped in the ventromedial arcuate nucleus (vmARC), suggesting distinct energy expenditure pathways. Brain slice patch clamp recordings further demonstrate a considerable proportion of leptin-inhibited dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons, while removal of pre-synaptic (indirect) effects with synaptic blocker increased the proportion of leptin-activated dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons, suggesting that pre-synaptic Lepr neurons inhibit dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons. We conclude that stimulation of BAT-related, GABA- and glutamatergic dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons in combination mediate the beneficial metabolic effects. Our data support the idea that dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons integrate upstream Lepr neurons (e.g., originating from POA and ARC). We speculate that these neurons manage dynamic adaptations to a variety of environmental changes including ambient temperature and energy state.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Significance statement&lt;/h3&gt;&lt;div&gt;Our earlier work identified leptin receptor expressing neurons in the dDMH/DHA as an important thermoregulatory site. Dorsomedial hypothalamus (DMH) Lepr neurons participate in processing and integration of environmental exteroceptive signals like ambient temperature and circadian rhythm, as well as interoceptive signals including leptin and the gut hormone glucagon-like-peptide-1 (GLP1). The present work further characterizes dDMH/DHA&lt;sup&gt;Lepr&lt;/sup&gt; neurons as a mixed glutamatergic and GABAergic population, but with distinct axonal projection sites. Surprisingly, select activation of glutamatergic and/or GABAergic populations are all able to increase energy expenditure, but are unable to replicate the beneficial metabolic effects observed by Lepr activation. These findings highlighting dDMH/","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156100"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravital imaging reveals glucose-dependent cilia movement in pancreatic islets in vivo","authors":"Olha Melnyk ,&nbsp;Jeff Kaihao Guo ,&nbsp;Zipeng Alex Li ,&nbsp;Jeong Hun Jo ,&nbsp;Jing W. Hughes ,&nbsp;Amelia K. Linnemann","doi":"10.1016/j.metabol.2024.156105","DOIUrl":"10.1016/j.metabol.2024.156105","url":null,"abstract":"<div><div>Pancreatic islet cells harbor primary cilia, small sensory organelles that detect environmental changes to regulate hormone secretion and intercellular communication. While the sensory and signaling capacity of primary cilia are well-appreciated, it is less recognized that these organelles also possess active motility, including in dense multicellular tissues such as the pancreatic islet. In this manuscript, we use transgenic cilia reporter mice and an intravital imaging approach to quantitate primary cilia dynamics as it occurs in live mouse pancreatic islets. We validate this imaging workflow as suitable for studying islet cilia motion in real time <em>in vivo</em> and demonstrate that glucose stimulation corresponds to a change in cilia motility, which may be a physiologic measure of nutrient-dependent fluxes in islet cell function. Complementary <em>ex vivo</em> analysis of isolated islets further demonstrates that metabolic stress in the form of lipotoxicity impairs cilia motility and these effects can be reversed by glucose elevation. These findings suggest that cilia motility is sensitive to metabolic stress and highlight its potential functional role in beta cell adaptation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156105"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin neurons integrate GABA and dopamine inputs to regulate meal initiation","authors":"Kristine M. Conde ,&nbsp;HueyZhong Wong ,&nbsp;Shuzheng Fang ,&nbsp;Yongxiang Li ,&nbsp;Meng Yu ,&nbsp;Yue Deng ,&nbsp;Qingzhuo Liu ,&nbsp;Xing Fang ,&nbsp;Mengjie Wang ,&nbsp;Yuhan Shi ,&nbsp;Olivia Z. Ginnard ,&nbsp;Yuxue Yang ,&nbsp;Longlong Tu ,&nbsp;Hesong Liu ,&nbsp;Hailan Liu ,&nbsp;Na Yin ,&nbsp;Jonathan C. Bean ,&nbsp;Junying Han ,&nbsp;Megan E. Burt ,&nbsp;Sanika V. Jossy ,&nbsp;Yong Xu","doi":"10.1016/j.metabol.2024.156099","DOIUrl":"10.1016/j.metabol.2024.156099","url":null,"abstract":"<div><div>Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HT^DRN➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HT^DRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABA_A receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HT^DRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156099"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1","authors":"Teresa Mezza ,&nbsp;Nicolai J. Wewer Albrechtsen ,&nbsp;Gianfranco Di Giuseppe ,&nbsp;Pietro Manuel Ferraro ,&nbsp;Laura Soldovieri ,&nbsp;Gea Ciccarelli ,&nbsp;Michela Brunetti ,&nbsp;Giuseppe Quero ,&nbsp;Sergio Alfieri ,&nbsp;Enrico Celestino Nista ,&nbsp;Antonio Gasbarrini ,&nbsp;Vincenzo Tondolo ,&nbsp;Andrea Mari ,&nbsp;Alfredo Pontecorvi ,&nbsp;Andrea Giaccari ,&nbsp;Jens J. Holst","doi":"10.1016/j.metabol.2024.156087","DOIUrl":"10.1016/j.metabol.2024.156087","url":null,"abstract":"<div><h3>Aims</h3><div>A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance.</div></div><div><h3>Methods</h3><div>We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m²) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, <em>n</em> = 19), impaired glucose tolerant (IGT, <em>n</em> = 20) or newly diagnosed diabetes (DM) (<em>n</em> = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters.</div></div><div><h3>Results</h3><div>Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo.</div></div><div><h3>Conclusions</h3><div>Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"163 ","pages":"Article 156087"},"PeriodicalIF":10.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}