Diabetologia最新文献

{"title":"Mortality rates in people presenting with a new diabetes-related foot ulcer: a cohort study with implications for management","authors":"Naomi Holman, Arthur C. Yelland, Bob Young, Jonathan Valabhji, William Jeffcoate, Fran Game","doi":"10.1007/s00125-024-06262-w","DOIUrl":"https://doi.org/10.1007/s00125-024-06262-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>People with diabetes-related foot ulcers (DFUs) have high mortality rates. This analysis assesses the impact of selected risk factors on short-term mortality using a population registered in the National Diabetes Foot Care Audit (NDFA).</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Mortality rates at 12, 26 and 52 weeks was assessed in people with a new DFU registered by a specialist diabetes footcare service in the NDFA in England and Wales between April 2017 and March 2022. Poisson regression models were created to explore risk factors for mortality.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>In 71,000 people registered with a new DFU, mortality rates at 12, 26 and 52 weeks was 4.2%, 8.2% and 14.4%, respectively. At 26 weeks, higher mortality rates was associated with older age (rate ratio 2.15; 95% CI 2.03, 2.28, for age ≥80 years vs age 65–79 years), certain ulcer characteristics (area ≥1 cm² [1.50; 95% CI 1.42, 1.59], deep ulcers [1.26; 95% CI 1.18, 1.35] or hindfoot location [1.53; 95% CI 1.44, 1.62]) and recorded evidence of ischaemia in the lower limb (1.78; 95% CI 1.69, 1.88) and various comorbidities (heart failure [2.13; 95% CI 2.00, 2.26], myocardial infarction [1.45; 95% CI 1.29, 1.63], stroke [1.37; 95% CI 1.22, 1.53], renal replacement therapy [2.34; 95% CI 2.09, 2.61] and chronic kidney disease stage 3 or greater [1.20; 95% CI 1.12, 1.29]). The 26-week mortality rate exceeded 25% for 7.3% of all individuals, rising to 11.5% of those aged 65 years and older, and 22.1% of those aged 80 years and over.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Short-term mortality rates in people with a DFU is high. Teams managing people with DFUs should consider modifying the burdensome interventions and care required to heal such ulcers so maximising the quality of residual life, rather than focusing exclusively on healing.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325546","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 whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial","authors":"Cody J. Hanick, Courtney M. Peterson, Brenda C. Davis, Joan Sabaté, John H. Kelly","doi":"10.1007/s00125-024-06272-8","DOIUrl":"https://doi.org/10.1007/s00125-024-06272-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18–75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA_1c, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Compared with SMC (<i>n</i>=90 randomised; <i>n</i>=70 analysed), the PB+Ex (<i>n</i>=79 randomised; <i>n</i>=66 analysed) intervention decreased HbA_1c by an additional 14 mmol/mol (1.3%) at week 12 (−22 vs −7 mmol/mol [−2.0% vs −0.7%]; <i>p</i>&lt;0.0001) and 8 mmol/mol (0.7%) at week 24 (−16 vs −8 mmol/mol [−1.4% vs −0.7%]; <i>p</i>=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%; <i>p</i>=0.006), and 23% of PB+Ex participants with a baseline HbA_1c &lt;75 mmol/mol (&lt;9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (−2.7 kg; <i>p</i>&lt;0.0001), C-reactive protein (−11 nmol/l; <i>p</i>=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Trial registration</h3><p>ClinicalTrials.gov NCT03862963</p><h3 data-test=\"abstract-sub-heading\">Funding</h3><p>This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"89 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276795","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 DPP-4 inhibitor sitagliptin improves glycaemic control and early-stage diabetic nephropathy in adolescents with type 1 diabetes using the MiniMed 780G advanced hybrid closed-loop system: a randomised controlled trial","authors":"Nancy S. Elbarbary, Eman A. Ismail, Manal H. El-Hamamsy, Marwa Z. Ibrahim, Amal A. Elkholy","doi":"10.1007/s00125-024-06265-7","DOIUrl":"https://doi.org/10.1007/s00125-024-06265-7","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Dipeptidyl peptidase-4 (DPP-4) inhibition has beneficial effects on various metabolic indicators in diabetes. Stromal cell-derived factor-1 (SDF-1) is expressed in diverse organs including the kidneys and is cleaved and inactivated by DPP-4 enzyme. The aim of this study was to conduct a randomised controlled trial to assess the effect of sitagliptin on diabetic nephropathy when used as an add-on therapy to the advanced hybrid closed-loop (AHCL) system in adolescents with type 1 diabetes and nephropathy.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;This open-label, parallel-group, randomised controlled trial took place at the Pediatric Diabetes Clinic, Ain Shams University, Egypt. Forty-six adolescents aged 14.13 ± 2.43 years on the MiniMed 780G system for at least 6 months before study, with HbA&lt;sub&gt;1c&lt;/sub&gt; ≤69 mmol/mol (8.5%) and diabetic nephropathy in the form of microalbuminuria, were randomly assigned to two groups (&lt;i&gt;n&lt;/i&gt;=23 for each) based on a computer-generated randomisation sequence. The intervention group received oral sitagliptin 50 mg for 3 months. The other group used AHCL only and served as a control group. The primary outcome measure was the change in urinary albumin/creatinine ratio (UACR) after 3 months of administration of sitagliptin. The key secondary outcome measure was the change from baseline in SDF-1 levels after treatment.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;Data for all participants were analysed. No significant difference was found between the groups as regards baseline clinical and laboratory characteristics as well as AHCL system settings (&lt;i&gt;p&lt;/i&gt;&gt;0.05). Serum SDF-1 levels were higher in all individuals with type 1 diabetes vs healthy control individuals (&lt;i&gt;p&lt;/i&gt;&lt;0.001). After 3 months, sitagliptin resulted in a significant decrease of SDF-1 levels from 3.58 ± 0.73 to 1.99 ± 0.76 ng/ml (&lt;i&gt;p&lt;/i&gt;&lt;0.001), together with improvement of UACR from 7.27 ± 2.41 to 1.32 ± 0.31 mg/mmol (&lt;i&gt;p&lt;/i&gt;&lt;0.001). In addition, sitagliptin reduced postprandial glucose, sensor glucose, coefficient of variation and total daily dose of insulin, while time in range 3.9–10.0 mmol/l (70–180 mg/dl) and insulin-to-carbohydrate ratio were significantly increased. Sitagliptin was safe and well-tolerated without severe hypoglycaemia or diabetic ketoacidosis.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Conclusions/interpretation&lt;/h3&gt;&lt;p&gt;Sitagliptin as an add-on therapy to AHCL had a reno-protective effect for individuals with type 1 diabetes and diabetic nephropathy, in addition to the improvement of time in range while reducing glycaemic variability and without compromising safety.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Funding&lt;/h3&gt;&lt;p&gt;This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Trial registration&lt;/h3&gt;&lt;p&gt;ClinicalTrials.gov NCT06115460.&lt;/p","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231404","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":"Genetic evidence for efficacy of targeting IL-2, IL-6 and TYK2 signalling in the prevention of type 1 diabetes: a Mendelian randomisation study","authors":"Tea E. Heikkilä, Emilia K. Kaiser, Jake Lin, Dipender Gill, Jaakko J. Koskenniemi, Ville Karhunen","doi":"10.1007/s00125-024-06267-5","DOIUrl":"https://doi.org/10.1007/s00125-024-06267-5","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>We aimed to investigate the genetic evidence that supports the repurposing of drugs already licensed or in clinical phases of development for prevention of type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We obtained genome-wide association study summary statistics for the risk of type 1 diabetes, whole-blood gene expression and serum protein levels and investigated genetic polymorphisms near seven potential drug target genes. We used co-localisation to examine whether the same genetic variants that are associated with type 1 diabetes risk were also associated with the relevant drug target genetic proxies and used Mendelian randomisation to evaluate the direction and magnitude of the associations. Furthermore, we performed Mendelian randomisation analysis restricted to functional variants within the drug target genes.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Co-localisation revealed that the blood expression levels of <i>IL2RA</i> (encoding IL-2 receptor subunit α [IL2RA]), <i>IL6R</i> (encoding IL-6 receptor [IL6R]) and <i>IL6ST</i> (encoding IL-6 cytokine family signal transducer [IL6ST]) shared the same causal variant with type 1 diabetes liability near the corresponding genes (posterior probabilities 100%, 96.5% and 97.0%, respectively). The OR (95% CI) of type 1 diabetes per 1-SD increase in the genetically proxied gene expression of <i>IL2RA</i>, <i>IL6R</i> and <i>IL6ST</i> were 0.22 (0.17, 0.27), 1.98 (1.48, 2.65) and 1.90 (1.45, 2.48), respectively. Using missense variants, genetically proxied <i>TYK2</i> (encoding tyrosine kinase 2) expression levels were associated with type 1 diabetes risk (OR 0.61 [95% CI 0.54, 0.69]).</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Our findings support the targeting of IL-2, IL-6 and TYK2 signalling in prevention of type 1 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Data availability</h3><p>The analysis code is available at https://github.com/jkoskenniemi/T1DSCREEN, which also includes instructions on how to download the original GWAS summary statistics.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"8 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231349","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":"Metabolic health in people living with type 1 diabetes in Belgium: a repeated cross-sectional study","authors":"Astrid Lavens, Christophe De Block, Philippe Oriot, Laurent Crenier, Jean-Christophe Philips, Michel Vandenbroucke, An-Sofie Vanherwegen, Frank Nobels, Chantal Mathieu","doi":"10.1007/s00125-024-06273-7","DOIUrl":"https://doi.org/10.1007/s00125-024-06273-7","url":null,"abstract":"&lt;h3 data-test=\"abstract-sub-heading\"&gt;Aims/hypothesis&lt;/h3&gt;&lt;p&gt;Metabolic abnormalities such as central obesity, insulin resistance, dyslipidaemia and hypertension, often referred to as ‘the metabolic syndrome’ (or ‘combined metabolic abnormalities’), are increasingly being identified in people living with type 1 diabetes, accelerating the risk for CVD. As a result, in recent years, treatment in people living with type 1 diabetes has shifted to improving overall metabolic health rather than glucose control alone. In Belgium, diabetes care for people living with type 1 diabetes is centrally organised. The Initiative for Quality Improvement and Epidemiology in Diabetes, imposed by the Belgian health insurance system, has systematically collected data from patients on intensive insulin therapy treated in all 101 diabetes clinics in Belgium since 2001. The aim of this real-world study is to describe the evolution of treatment and metabolic health, including the prevalence of obesity and combined metabolic abnormalities, in people living with type 1 diabetes over the past 20 years, and to compare the treatment and prevalence of complications between those with and without combined metabolic abnormalities.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Methods&lt;/h3&gt;&lt;p&gt;We analysed data on adults (≥16 years old) living with type 1 diabetes, who were diagnosed at age ≤45 years and who had a diabetes duration ≥1 year, collected between 2001 and 2022. The evolution of HbA&lt;sub&gt;1c&lt;/sub&gt;, BMI, LDL-cholesterol, systolic BP, lipid-lowering therapy and antihypertensive therapy over time was analysed. The prevalence of individual and multiple metabolic abnormalities according to various definitions of the metabolic syndrome/combined metabolic abnormalities was analysed, and the association between combined metabolic abnormalities and metabolic health indicators, complications and treatment was investigated in the 2022 data.&lt;/p&gt;&lt;h3 data-test=\"abstract-sub-heading\"&gt;Results&lt;/h3&gt;&lt;p&gt;The final dataset consisted of 26,791 registrations of adults living with type 1 diabetes collected between 2001 and 2022. Although glycaemic and lipid control generally improved over time, the prevalence of obesity strongly increased (12.1% in 2001 vs 21.7% in 2022, &lt;i&gt;p&lt;/i&gt;&lt;0.0001), as did the presence of combined metabolic abnormalities (WHO criteria: 26.9% in 2001 vs 42.9% in 2022 in women, &lt;i&gt;p&lt;/i&gt;&lt;0.0001; 30.4% in 2001 vs 52.1% in 2022 in men, &lt;i&gt;p&lt;/i&gt;&lt;0.0001; WHO criteria without albuminuria: 22.3% in 2001 vs 40.6% in 2022 in women, &lt;i&gt;p&lt;/i&gt;&lt;0.0001; 25.1% in 2001 vs 49.2% in 2022 in men, &lt;i&gt;p&lt;/i&gt;&lt;0.0001; NCEP-ATPIII criteria: 39.9% in 2005 vs 57.2% in 2022 in women, &lt;i&gt;p&lt;/i&gt;&lt;0.0001; 40.8% in 2005 vs 60.9% in 2022 in men, &lt;i&gt;p&lt;/i&gt;&lt;0.0001; IDF criteria: 43.9% in 2005 vs 59.3% in 2022 in women, &lt;i&gt;p&lt;/i&gt;&lt;0.001; 33.7% in 2005 vs 50.0% in 2022 in men, &lt;i&gt;p&lt;/i&gt;&lt;0.0001). People with combined metabolic abnormalities had higher glucose levels compared to those without combined m","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"32 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231402","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/s00125-024-06263-9","DOIUrl":"https://doi.org/10.1007/s00125-024-06263-9","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231403","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":"Risk factors for Charcot foot development in individuals with diabetes mellitus","authors":"Georgios Tsatsaris, Neda Rajamand Ekberg, Tove Fall, Sergiu-Bogdan Catrina","doi":"10.1007/s00125-024-06271-9","DOIUrl":"https://doi.org/10.1007/s00125-024-06271-9","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Charcot foot is a complication of diabetes mellitus that has potentially disastrous consequences. Although it was first described in 1868 and found to be associated with diabetes in 1936, there is still uncertainty about the risk factors affecting the development of the condition. Here, we aim to identify risk factors for Charcot foot in a nationwide cohort study.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>A retrospective register-based cohort study was performed for the period 2001–2016, using nationwide registries. Individuals with diabetes and Charcot foot were identified and matched by diabetes type and with similar diabetes duration with individuals with diabetes but not Charcot foot. Logistic regression analyses were used to identify risk factors.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of 3397 participants with diabetes mellitus and Charcot foot and 27,662 control participants with diabetes but without Charcot foot were included. HbA_1c, duration of diabetes, micro- and macroalbuminuria, retinopathy and atherosclerosis (general and peripheral) were identified as risk factors for Charcot foot in participants with type 1 diabetes and participants with type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>In the most extensive study on Charcot foot to date, we identified distinctive and common risk factors associated with the development of Charcot foot in individuals with type 1 diabetes and type 2 diabetes.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"9 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231401","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":"60th EASD Annual Meeting of the European Association for the Study of Diabetes","authors":"","doi":"10.1007/s00125-024-06226-0","DOIUrl":"https://doi.org/10.1007/s00125-024-06226-0","url":null,"abstract":"","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"4 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170708","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":"An antifibrotic compound that ameliorates hyperglycaemia and fat accumulation in cell and HFD mouse models","authors":"Tsugumasa Toma, Nobukazu Miyakawa, Yuiichi Arakaki, Takuro Watanabe, Ryosei Nakahara, Taha F. S. Ali, Tanima Biswas, Mikio Todaka, Tatsuya Kondo, Mikako Fujita, Masami Otsuka, Eiichi Araki, Hiroshi Tateishi","doi":"10.1007/s00125-024-06260-y","DOIUrl":"https://doi.org/10.1007/s00125-024-06260-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Aims/hypothesis</h3><p>Appropriate management of blood glucose levels and the prevention of complications are important in the treatment of diabetes. We have previously reported on a compound named HPH-15 that is not only antifibrotic but also AMP-activated protein kinase (AMPK)-activating. In this study, we evaluated whether HPH-15 is useful as a therapeutic medication for diabetes.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We examined the effects of HPH-15 on AMPK activation, glucose uptake, fat accumulation and lactic acid production in L6-GLUT4, HepG2 and 3T3-L1 cells, as a model of muscle, liver and fat tissue, respectively. Additionally, we investigated the glucose-lowering, fat-accumulation-suppressing, antifibrotic and AMPK-activating effect of HPH-15 in mice fed a high-fat diet (HFD).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>HPH-15 at a concentration of 10 µmol/l increased AMPK activation, glucose uptake and membrane translocation of GLUT4 in each cell model to the same extent as metformin at 2 mmol/l. The production of lactic acid (which causes lactic acidosis) in HPH-15-treated cells was equal to or less than that observed in metformin-treated cells. In HFD-fed mice, HPH-15 lowered blood glucose from 11.1±0.3 mmol/l to 8.2±0.4 mmol/l (10 mg/kg) and 7.9±0.4 mmol/l (100 mg/kg) and improved insulin resistance. The HPH-15 (10 mg/kg) group showed the same level of AMPK activation as the metformin (300 mg/kg) group in all organs. The HPH-15-treated HFD-fed mice also showed suppression of fat accumulation and fibrosis in the liver and fat tissue; these effects were more significant than those obtained with metformin. Mice treated with high doses of HPH-15 also exhibited a 44% reduction in subcutaneous fat.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>HPH-15 activated AMPK at lower concentrations than metformin in vitro and in vivo and improved blood glucose levels and insulin resistance in vivo. In addition, HPH-15 was more effective than metformin at ameliorating fatty liver and adipocyte hypertrophy in HFD-fed mice. HPH-15 could be effective in preventing fatty liver, a common complication in diabetic individuals. Additionally, in contrast to metformin, high doses of HPH-15 reduced subcutaneous fat in HFD-fed mice. Presumably, HPH-15 has a stronger inhibitory effect on fat accumulation and fibrosis than metformin, accounting for the reduction of subcutaneous fat. Therefore, HPH-15 is potentially a glucose-lowering medication that can lower blood glucose, inhibit fat accumulation and ameliorate liver fibrosis.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"10 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160536","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":"Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C.","authors":"Nicholas A Wachowski, James A Pippin, Keith Boehm, Sumei Lu, Michelle E Leonard, Elisabetta Manduchi, Ursula W Parlin, Martin Wabitsch, Alessandra Chesi, Andrew D Wells, Struan F A Grant, Matthew C Pahl","doi":"10.1007/s00125-024-06261-x","DOIUrl":"https://doi.org/10.1007/s00125-024-06261-x","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Genome-wide association studies (GWAS) have identified hundreds of type 2 diabetes loci, with the vast majority of signals located in non-coding regions; as a consequence, it remains largely unclear which 'effector' genes these variants influence. Determining these effector genes has been hampered by the relatively challenging cellular settings in which they are hypothesised to confer their effects.</p><p><strong>Methods: </strong>To implicate such effector genes, we elected to generate and integrate high-resolution promoter-focused Capture-C, assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq datasets to characterise chromatin and expression profiles in multiple cell lines relevant to type 2 diabetes for subsequent functional follow-up analyses: EndoC-BH1 (pancreatic beta cell), HepG2 (hepatocyte) and Simpson-Golabi-Behmel syndrome (SGBS; adipocyte).</p><p><strong>Results: </strong>The subsequent variant-to-gene analysis implicated 810 candidate effector genes at 370 type 2 diabetes risk loci. Using partitioned linkage disequilibrium score regression, we observed enrichment for type 2 diabetes and fasting glucose GWAS loci in promoter-connected putative cis-regulatory elements in EndoC-BH1 cells as well as fasting insulin GWAS loci in SGBS cells. Moreover, as a proof of principle, when we knocked down expression of the SMCO4 gene in EndoC-BH1 cells, we observed a statistically significant increase in insulin secretion.</p><p><strong>Conclusions/interpretation: </strong>These results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings.</p><p><strong>Data availability: </strong>Raw and processed next-generation sequencing data for EndoC-BH1, HepG2, SGBS_undiff and SGBS_diff cells are deposited in GEO under the Superseries accession GSE262484. Promoter-focused Capture-C data are deposited under accession GSE262496. Hi-C data are deposited under accession GSE262481. Bulk ATAC-seq data are deposited under accession GSE262479. Bulk RNA-seq data are deposited under accession GSE262480.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139586","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}