Diabetologia最新文献

{"title":"Molecular mechanisms underlying glucose-dependent insulinotropic polypeptide secretion in human duodenal organoids","authors":"Nunzio Guccio, Constanza Alcaino, Emily L. Miedzybrodzka, Marta Santos-Hernández, Christopher A. Smith, Adam Davison, Rula Bany Bakar, Richard G. Kay, Frank Reimann, Fiona M. Gribble","doi":"10.1007/s00125-024-06293-3","DOIUrl":"https://doi.org/10.1007/s00125-024-06293-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine K cells in the proximal small intestine. This study aimed to explore the function of human K cells at the molecular and cellular levels.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>CRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids. Fluorescently labelled K cells were purified by FACS for RNA-seq and peptidomic analysis. GIP reporter organoids were employed for GIP secretion assays, live-cell imaging of Ca²⁺ using Fura-2 and cAMP using Epac-S-H187, and basic electrophysiological characterisation. The G protein-coupled receptor genes <i>GPR142</i> and <i>CASR</i> were knocked out to evaluate roles in amino acid sensing.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>RNA-seq of human duodenal K cells revealed enrichment of several G protein-coupled receptors involved in nutrient sensing, including <i>FFAR1</i>, <i>GPBAR1</i>, <i>GPR119</i>, <i>CASR</i> and <i>GPR142</i>. Glucose induced action potential firing and cytosolic Ca²⁺ elevation and caused a 1.8-fold increase in GIP secretion, which was inhibited by the sodium glucose co-transporter 1/2 (SGLT1/2) blocker sotagliflozin. Activation of the long-chain fatty acid receptor free fatty acid receptor 1 (FFAR1) induced a 2.7-fold increase in GIP secretion, while tryptophan and phenylalanine stimulated secretion by 2.8- and 2.1-fold, respectively. While <i>CASR</i> knockout blunted intracellular Ca²⁺ responses, a <i>CASR</i>/<i>GPR142</i> double knockout was needed to reduce GIP secretory responses to aromatic amino acids.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The newly generated human organoid K cell model enables transcriptomic and functional characterisation of nutrient-sensing pathways involved in human GIP secretion. Both calcium-sensing receptor (CASR) and G protein-coupled receptor 142 (GPR142) contribute to protein-stimulated GIP secretion. This model will be further used to identify potential targets for modulation of native GIP secretion in diabetes and obesity.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"1 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487568","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":"GLP-1 receptor agonists in lean diabetes in racial and ethnic minority groups: closing the treatment gap.","authors":"Felix P Chilunga,George F Mkoma","doi":"10.1007/s00125-024-06297-z","DOIUrl":"https://doi.org/10.1007/s00125-024-06297-z","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"21 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486350","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":"GLP-1 receptor agonists in lean diabetes in racial and ethnic minority groups: closing the treatment gap.","authors":"Felix P Chilunga, George F Mkoma","doi":"10.1007/s00125-024-06297-z","DOIUrl":"https://doi.org/10.1007/s00125-024-06297-z","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460185","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":"Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function","authors":"Qi Fu, Hao Dai, Sipeng Shen, Yunqiang He, Shuai Zheng, Hemin Jiang, Pan Gu, Min Sun, Xiaowei Zhu, Kuanfeng Xu, Tao Yang","doi":"10.1007/s00125-024-06291-5","DOIUrl":"https://doi.org/10.1007/s00125-024-06291-5","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (&lt;210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined &lt;i&gt;p&lt;/i&gt;=1.32 × 10&lt;sup&gt;−11&lt;/sup&gt;). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (&lt;i&gt;p&lt;/i&gt;=2.06 × 10&lt;sup&gt;−9&lt;/sup&gt;) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, &lt;i&gt;p&lt;/i&gt;=0.008).&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption acr","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"29 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451440","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":"Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance","authors":"Sakina Ali, Xavier Vidal-Gómez, Megan Piquet, Luisa Vergori, Gilles Simard, Séverine Dubois, Pierre-Henri Ducluzeau, Pascal Pomiès, Sarah Kamli-Salino, Mirela Delibégovic, Samir Henni, Frédéric Gagnadoux, Ramaroson Andriantsitohaina, M. Carmen Martínez","doi":"10.1007/s00125-024-06288-0","DOIUrl":"https://doi.org/10.1007/s00125-024-06288-0","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"39 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448105","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":"Fasting as an intervention to alter the impact of simulated night-shift work on glucose metabolism in healthy adults: a cluster randomised controlled trial","authors":"Stephanie Centofanti, Leonie K. Heilbronn, Gary Wittert, Jillian Dorrian, Alison M. Coates, David Kennaway, Charlotte Gupta, Jacqueline M. Stepien, Peter Catcheside, Crystal Yates, Linda Grosser, Raymond W. Matthews, Siobhan Banks","doi":"10.1007/s00125-024-06279-1","DOIUrl":"https://doi.org/10.1007/s00125-024-06279-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Night-shift work causes circadian misalignment and impairs glucose metabolism. We hypothesise that food intake during night shifts may contribute to this phenomenon.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>This open-label, multi-arm, single-site, parallel-group controlled trial involved a 6 day stay at the University of South Australia’s sleep laboratory (Adelaide, SA, Australia). Healthy, non-shift-working adults without obesity (<i>N</i>=55; age 24.5 ± 4.8 years; BMI 24.8 ± 2.8 kg/m²) were assigned to the next available run date and cluster randomised (1:1:1) to fasting-at-night (<i>N</i>=20), snack-at-night (<i>N</i>=17), or meal-at-night (<i>N</i>=18) conditions. One participant withdrew from each group, prior to starting the study. Due to study design, neither participants nor people collecting their measurements could be blinded. Statistical and laboratory staff were concealed to study allocation. Participants were fed at calculated energy balance, with the macronutrient composition of meals being similar across conditions. The primary outcomes were a linear mixed-effects model of glucose, insulin and NEFA AUC in response to a 75 g OGTT that was conducted prior to and after 4 consecutive nights of shift work plus 1 night of recovery sleep. Insulin sensitivity, insulinogenic and disposition indexes were also calculated.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Night-shift work impaired insulin sensitivity, as measured by insulin AUC (<i>p</i>=0.035) and the insulin sensitivity index (<i>p</i>=0.016) across all conditions. Insulin secretion, as measured by the insulinogenic index, was increased in the fasting-at-night condition only (<i>p</i>=0.030), resulting in a day×condition interaction in glucose AUC (<i>p</i>&lt;0.001) such that glucose tolerance was impaired in the meal-at night (+2.00 [95% CI 1.45, 2.56], <i>p</i>&lt;0.001) and snack at-night (+0.96 [0.36, 1.56], <i>p</i>=0.022) conditions vs the fasting-at-night (+0.34 [–0.21, 0.89]) condition. A day×condition interaction was also observed in NEFA AUC (<i>p</i>&lt;0.001), being higher in the meal-at-night (+0.07 [0.03, 0.10]. <i>p</i>=0.001) and snack-at-night (0.01 [–0.03, 0.05], <i>p</i>=0.045) conditions vs the fasting-at-night condition (–0.02 [–0.06, 0.01]). No adverse events occurred.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>The timing of food intake has a critical effect on glucose metabolism during simulated night-shift work, which was readily amendable to a meal re-timing intervention.</p><h3 data-test=\"abstract-sub-heading\">Trial Registration</h3><p>Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001556437</p><h3 data-test=\"abstract-sub-heading\">Funding</h3><p>This work was funded by the National Health and Medical Research Council (NHMRC), APP1099077.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"19 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448104","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":"The population-specific Thr44Met OCT3 coding variant affects metformin pharmacokinetics with subsequent effects on insulin sensitivity in C57Bl/6J mice","authors":"Qian Wang, Megan P. Leask, Kate Lee, Jagdish Jaiswal, Prasanna Kallingappa, Waruni Dissanayake, Chris Puli’uvea, Conor O’Sullivan, Huti Watson, Phillip Wilcox, Rinki Murphy, Troy L. Merry, Peter R. Shepherd","doi":"10.1007/s00125-024-06287-1","DOIUrl":"https://doi.org/10.1007/s00125-024-06287-1","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Metformin is an important first-line treatment for type 2 diabetes and acts by increasing the body’s ability to dispose of glucose. Metformin’s efficacy can be affected by genetic variants in the transporters that regulate its uptake into cells. The <i>SLC22A3</i> gene (also known as <i>EMT; EMTH; OCT3</i>) codes for organic cation transporter 3 (OCT3), which is a broad-specificity cation transporter that also transports metformin. Most <i>SLC22A3</i> variants reduce the rate of metformin transport but the rs8187715 variant (p.Thr44Met) is reported to increase uptake of metformin in vitro. However, the impact of this on in vivo metformin transport and efficacy is unknown. Very few carriers of this variant have been reported globally, but, notably, all were of Pacific Island descent. Therefore, this study aims to understand the prevalence of this variant in Polynesian peoples (Māori and Pacific peoples) and to understand its impact on metformin transport and efficacy in vivo.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>rs8187715 was genotyped in 310 individuals with Māori and Pacific ancestry recruited in Aotearoa New Zealand. To study this variant in a physiological context, an orthologous knockin mouse model with C57BL/6J background was used. Pharmacokinetic analysis compared uptake rate of metformin into tissues. Plasma growth/differentiation factor 15 (GDF-15) was also measured as a marker of metformin efficacy. Glucose and insulin tolerance was assessed after acute or sustained metformin treatment in knockin and wild-type control mice to examine the impact of the variant on metformin’s glycaemic control.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The minor allele frequency of this variant in the Māori and Pacific participants was 15.4%. There was no association of the variant with common metabolic parameters including diabetes status, BMI, blood pressure, lipids, or blood glucose and HbA_1c. However, in the orthologous knockin mouse model, the rate of metformin uptake into the blood and tissues was increased. Acute metformin dosing increased insulin sensitivity in variant knockin mice but this effect was lost after longer-term metformin treatment. Metformin’s effects on GDF-15 levels were also lost in variant knockin mice with longer-term metformin treatment.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>These data provide evidence that the <i>SLC22A3</i> rs8187715 variant accelerates metformin uptake rate in vivo. While this acutely improves insulin sensitivity, there was no increased effect of metformin with longer-term dosing. Thus, our finding of a high prevalence of this variant specifically in Māori and Pacific peoples identifies it as a potential population-specific pharmacogenetic marker with potential to guide metformin therapy in these peoples.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"40 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448154","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":"Up Front","authors":"","doi":"10.1007/s00125-024-06285-3","DOIUrl":"https://doi.org/10.1007/s00125-024-06285-3","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"231 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443861","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":"Beta cell-specific PAK1 enrichment ameliorates diet-induced glucose intolerance in mice by promoting insulin biogenesis and minimising beta cell apoptosis.","authors":"Miwon Ahn,Sangeeta Dhawan,Erika M McCown,Pablo A Garcia,Supriyo Bhattacharya,Roland Stein,Debbie C Thurmond","doi":"10.1007/s00125-024-06286-2","DOIUrl":"https://doi.org/10.1007/s00125-024-06286-2","url":null,"abstract":"AIMS/HYPOTHESISp21 (CDC42/RAC1) activated kinase 1 (PAK1) is depleted in type 2 diabetic human islets compared with non-diabetic human islets, and acute PAK1 restoration in the islets can restore insulin secretory function ex vivo. We hypothesised that beta cell-specific PAK1 enrichment in vivo can mitigate high-fat-diet (HFD)-induced glucose intolerance by increasing the functional beta cell mass.METHODSHuman islets expressing exogenous PAK1 specifically in beta cells were used for bulk RNA-seq. Human EndoC-βH1 cells overexpressing myc-tagged PAK1 were used for chromatin immunoprecipitation (ChIP) and ChIP-sequencing (ChIP-seq). Novel doxycycline-inducible beta cell-specific PAK1-expressing (iβPAK1-Tg) mice were fed a 45% HFD pre-induction for 3 weeks and for a further 3 weeks with or without doxycycline induction. These HFD-fed mice were evaluated for GTT, ITT, 6 h fasting plasma insulin and blood glucose, body composition, islet insulin content and apoptosis.RESULTSBeta cell-specific PAK1 enrichment in type 2 diabetes human islets resulted in decreased beta cell apoptosis and increased insulin content. RNA-seq showed an upregulation of INS gene transcription by PAK1. Using clonal human beta cells, we found that PAK1 protein was localised in the cytoplasm and the nucleus. ChIP studies revealed that nuclear PAK1 enhanced pancreatic and duodenal homeobox1 (PDX1) and neuronal differentiation 1 (NEUROD1) binding to the INS promoter in a glucose-responsive manner. Importantly, the iβPAK1-Tg mice, when challenged with HFD and doxycycline induction displayed enhanced glucose tolerance, increased islet insulin content and reduced beta cell apoptosis when compared with iβPAK1-Tg mice without doxycycline induction.CONCLUSIONS/INTERPRETATIONPAK1 plays an unforeseen and beneficial role in beta cells by promoting insulin biogenesis via enhancing the expression of PDX1, NEUROD1 and INS, along with anti-apoptotic effects, that culminate in increased insulin content and beta cell mass in vivo and ameliorate diet-induced glucose intolerance.DATA AVAILABILITYThe raw and processed RNA-seq data and ChIP-seq data, which has been made publicly available at Gene Expression Omnibus (GEO) at https://www.ncbi.nlm.nih.gov/geo/ , can be accessed in GSE239382.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"95 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439662","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":"Quantitative analysis of islet prohormone convertase 1/3 expression in human pancreas donors with diabetes.","authors":"Paola S Apaolaza,Yi-Chun Chen,Kavi Grewal,Yannik Lurz,Severin Boulassel,C Bruce Verchere,Teresa Rodriguez-Calvo","doi":"10.1007/s00125-024-06275-5","DOIUrl":"https://doi.org/10.1007/s00125-024-06275-5","url":null,"abstract":"AIMS/HYPOTHESISIslet prohormone-processing enzymes convert peptide hormone precursors to mature hormones. Defective beta cell prohormone processing and the release of incompletely processed peptide hormones are observed prior to the onset of diabetes, yet molecular mechanisms underlying impaired prohormone processing during the development of diabetes remains largely unknown. Previous studies have shown that prohormone convertase 1/3 (PC1/3) protein and mRNA expression levels are reduced in whole islets from donors with type 1 diabetes, although whether PC1/3-mediated prohormone processing in alpha and beta cells is disrupted in type 1 diabetes remained to be explored. Herein, we aimed to analyse the expression of PC1/3 in islets from non-diabetic donors, autoantibody-positive donors and donors diagnosed with type 1 diabetes or type 2 diabetes.METHODSImmunostaining and high-dimensional image analysis were performed on pancreatic sections from a cross-sectional cohort of 54 donors obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD) repository, to evaluate PC1/3 expression patterns in islet alpha, beta and delta cells at different stages of diabetes.RESULTSAlpha and beta cell morphology were altered in donors with type 1 diabetes, including decreased alpha and beta cell size. As expected, the insulin-positive and PC1/3-positive areas in the islets were both reduced, and this was accompanied by a reduced percentage of PC1/3-positive and insulin-positive/PC1/3-positive cells in islets. PC1/3 and insulin co-localisation was also reduced. The glucagon-positive area, as well as the percentage of glucagon-positive and glucagon-positive/PC1/3-positive cells in islets, was increased. PC1/3 and glucagon co-localisation was also increased in donors with type 1 diabetes. The somatostatin-positive cell area and somatostatin staining intensity were elevated in islets from donors with recent-onset type 1 diabetes.CONCLUSIONS/INTERPRETATIONOur high-resolution histomorphological analysis of human pancreatic islets from donors with and without diabetes has uncovered details of the cellular origin of islet prohormone peptide processing defects. Reduced beta cell PC1/3 and increased alpha cell PC1/3 in islets from donors with type 1 diabetes pinpointed the functional deterioration of beta cells and the concomitant potential increase in PC1/3 usage for prohormone processing in alpha cells during the pathogenesis of type 1 diabetes. Our finding of PC1/3 loss in beta cells may inform the discovery of new prohormone biomarkers as indicators of beta cell dysfunction, and the finding of elevated PC1/3 expression in alpha cells may encourage the design of therapeutic targets via leveraging alpha cell adaptation in diabetes.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"23 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439658","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}