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An antifibrotic compound that ameliorates hyperglycaemia and fat accumulation in cell and HFD mouse models 一种抗纤维化化合物,可改善细胞和高密度脂蛋白胆固醇(HFD)小鼠模型中的高血糖和脂肪堆积状况
IF 8.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-09 DOI: 10.1007/s00125-024-06260-y
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

Aims/hypothesis

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.

Methods

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).

Results

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.

Conclusions/interpretation

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.

Graphical Abstract

目的/假设适当控制血糖水平和预防并发症是治疗糖尿病的重要手段。我们曾报道过一种名为 HPH-15 的化合物,它不仅能抗纤维化,还能激活 AMP 激活蛋白激酶 (AMPK)。我们研究了 HPH-15 对分别作为肌肉、肝脏和脂肪组织模型的 L6-GLUT4、HepG2 和 3T3-L1 细胞中 AMPK 激活、葡萄糖摄取、脂肪积累和乳酸生成的影响。此外,我们还研究了 HPH-15 在高脂饮食(HFD)小鼠体内的降糖、抑制脂肪积累、抗纤维化和 AMPK 激活作用。结果 HPH-15 浓度为 10 µmol/l 时,在每种细胞模型中都能增加 AMPK 激活、葡萄糖摄取和 GLUT4 的膜转位,其增加程度与二甲双胍浓度为 2 mmol/l 时相同。经 HPH-15 处理的细胞产生的乳酸(导致乳酸酸中毒)与二甲双胍处理的细胞相同或更少。在高密度脂蛋白喂养的小鼠中,HPH-15可将血糖从11.1±0.3毫摩尔/升降至8.2±0.4毫摩尔/升(10毫克/千克)和7.9±0.4毫摩尔/升(100毫克/千克),并改善胰岛素抵抗。HPH-15(10毫克/千克)组与二甲双胍(300毫克/千克)组在所有器官中的AMPK激活水平相同。经 HPH-15 处理的高密度脂蛋白胆固醇喂养小鼠还显示出抑制肝脏和脂肪组织中脂肪堆积和纤维化的作用;这些作用比二甲双胍的作用更为显著。结论/解释HPH-15在体外和体内激活AMPK的浓度低于二甲双胍,并能改善体内血糖水平和胰岛素抵抗。此外,HPH-15 比二甲双胍更有效地改善高密度脂蛋白胆固醇喂养小鼠的脂肪肝和脂肪细胞肥大。HPH-15可有效预防糖尿病患者常见的并发症--脂肪肝。此外,与二甲双胍相反,高剂量的HPH-15可减少高密度脂蛋白喂养小鼠的皮下脂肪。据推测,HPH-15 对脂肪堆积和纤维化的抑制作用比二甲双胍更强,这也是皮下脂肪减少的原因。因此,HPH-15是一种潜在的降糖药物,可以降低血糖、抑制脂肪堆积和改善肝纤维化。 图文摘要
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引用次数: 0
Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C. 利用启动子聚焦捕获-C 在相关代谢细胞模型中揭示 2 型糖尿病效应基因。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-06 DOI: 10.1007/s00125-024-06261-x
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

Aims/hypothesis: 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.

Methods: 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).

Results: 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.

Conclusions/interpretation: These results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings.

Data availability: 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.

目的/假设:全基因组关联研究(GWAS)发现了数百个 2 型糖尿病基因位点,其中绝大多数信号位于非编码区;因此,这些变异对哪些 "效应 "基因产生影响在很大程度上仍不清楚。确定这些效应基因的工作受到了相对困难的细胞环境的阻碍:为了确定这些效应基因,我们选择生成并整合高分辨率启动子聚焦捕获-C、转座酶可接触染色质测序(ATAC-seq)和 RNA-seq 数据集,以描述与 2 型糖尿病相关的多个细胞系的染色质和表达谱,以便进行后续功能跟踪分析:这些细胞系包括:EndoC-BH1(胰腺β细胞)、HepG2(肝细胞)和辛普森-戈拉比-贝赫默综合征(SGBS;脂肪细胞):结果:随后进行的变异到基因分析在 370 个 2 型糖尿病风险基因位点上发现了 810 个候选效应基因。通过分区连锁不平衡得分回归,我们观察到 EndoC-BH1 细胞中与启动子连接的推定顺式调节元件富集了 2 型糖尿病和空腹血糖 GWAS 基因位点,SGBS 细胞中也富集了空腹胰岛素 GWAS 基因位点。此外,作为原理证明,当我们敲除 EndoC-BH1 细胞中 SMCO4 基因的表达时,我们观察到胰岛素分泌有显著的统计学增长:与相对具有挑战性的原代细胞设置相比,这些结果为在可控的细胞模型中比较组织特异性数据提供了资源:EndoC-BH1、HepG2、SGBS_undiff和SGBS_diff细胞的原始和处理过的新一代测序数据存放在GEO的Superseries accession GSE262484中。Promoter-focused Capture-C 数据以 GSE262496 编号保存。Hi-C 数据以登录号 GSE262481 保存。批量 ATAC-seq 数据以登录号 GSE262479 保存。批量 RNA-seq 数据以登录号 GSE262480 保存。
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引用次数: 0
Lifetime history of gestational diabetes and cognitive function in parous women in midlife. 妊娠糖尿病终生史与中年女性的认知功能。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-06 DOI: 10.1007/s00125-024-06270-w
Diana C Soria-Contreras, Siwen Wang, Jiaxuan Liu, Rebecca B Lawn, Makiko Mitsunami, Alexandra C Purdue-Smithe, Cuilin Zhang, Emily Oken, Jorge E Chavarro

Aims/hypothesis: We aimed to determine whether a history of gestational diabetes mellitus (GDM) is associated with cognitive function in midlife.

Methods: We conducted a secondary data analysis of the prospective Nurses' Health Study II. From 1989 to 2001, and then in 2009, participants reported their history of GDM. A subset participated in a cognition sub-study in 2014-2019 (wave 1) or 2018-2022 (wave 2). We included 15,906 parous participants (≥1 birth at ≥18 years) who completed a cognitive assessment and were free of CVD, cancer and diabetes before their first birth. The primary exposure was a history of GDM. Additionally, we studied exposure to GDM and subsequent type 2 diabetes mellitus (neither GDM nor type 2 diabetes, GDM only, type 2 diabetes only or GDM followed by type 2 diabetes) and conducted mediation analysis by type 2 diabetes. The outcomes were composite z scores measuring psychomotor speed/attention, learning/working memory and global cognition obtained with the Cogstate brief battery. Mean differences (β and 95% CI) in cognitive function by GDM were estimated using linear regression.

Results: The 15,906 participants were a mean of 62.0 years (SD 4.9) at cognitive assessment, and 4.7% (n=749) had a history of GDM. In models adjusted for age at cognitive assessment, race and ethnicity, education, wave of enrolment in the cognition sub-study, socioeconomic status and pre-pregnancy characteristics, women with a history of GDM had lower performance in psychomotor speed/attention (β -0.08; 95% CI -0.14, -0.01) and global cognition (β -0.06; 95% CI -0.11, -0.01) than those without a history of GDM. The lower cognitive performance in women with GDM was only partially explained by the development of type 2 diabetes.

Conclusions/interpretation: Women with a history of GDM had poorer cognition than those without GDM. If replicated, our findings support future research on early risk modification strategies for women with a history of GDM as a potential avenue to decrease their risk of cognitive impairment.

目的/假设:我们旨在确定妊娠糖尿病(GDM)病史是否与中年认知功能有关:我们对前瞻性的 "护士健康研究 II "进行了二次数据分析。从 1989 年到 2001 年,以及 2009 年,参与者都报告了他们的 GDM 病史。一部分人参加了 2014-2019 年(第 1 波)或 2018-2022 年(第 2 波)的认知子研究。我们纳入了 15906 名完成认知评估且在首次生育前无心血管疾病、癌症和糖尿病的准妈妈参与者(≥18 岁时生育≥1 次)。主要的暴露是有过 GDM 病史。此外,我们还研究了GDM暴露和随后的2型糖尿病(既非GDM也非2型糖尿病、仅GDM、仅2型糖尿病或GDM后2型糖尿病),并对2型糖尿病进行了中介分析。研究结果是通过Cogstate简易电池获得的精神运动速度/注意力、学习/工作记忆和整体认知的综合Z分数。使用线性回归法估算了 GDM 在认知功能方面的平均差异(β 和 95% CI):15906 名参与者在接受认知评估时的平均年龄为 62.0 岁(标准差为 4.9),4.7%(n=749)的人有 GDM 病史。在根据认知评估时的年龄、种族和民族、教育程度、参加认知子研究的波次、社会经济状况和孕前特征进行调整后的模型中,与无 GDM 史的女性相比,有 GDM 史的女性在精神运动速度/注意力(β -0.08;95% CI -0.14,-0.01)和全面认知(β -0.06;95% CI -0.11,-0.01)方面的表现较低。患有 GDM 的女性认知能力较低,这只能部分归因于 2 型糖尿病的发展:有 GDM 病史的妇女比没有 GDM 病史的妇女认知能力更差。如果我们的研究结果得到证实,我们将支持未来针对有 GDM 病史的妇女开展早期风险调整策略的研究,以此作为降低其认知障碍风险的潜在途径。
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引用次数: 0
HbA1c variability is independently associated with progression of diabetic kidney disease in an urban multi-ethnic cohort of people with type 1 diabetes. 在一个 1 型糖尿病患者的城市多种族队列中,HbA1c 变异与糖尿病肾病的进展密切相关。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 Epub Date: 2024-06-20 DOI: 10.1007/s00125-024-06197-2
Ananya Muthukumar, Layla Badawy, Anastasios Mangelis, Prashant Vas, Stephen Thomas, Aicha Gouber, Salma Ayis, Janaka Karalliedde

Aims/hypothesis: The role of HbA1c variability in the progression of diabetic kidney disease is unclear, with most studies to date performed in White populations and limited data on its role in predicting advanced kidney outcomes. Our aim was to evaluate if long-term intra-individual HbA1c variability is a risk factor for kidney disease progression (defined as an eGFR decline of ≥50% from baseline with a final eGFR of <30 ml/min per 1.73 m2) in an ethnically heterogeneous cohort of people with type 1 diabetes with a preserved eGFR ≥45 ml/min per 1.73 m2 at baseline.

Methods: Electronic health record data from people attending outpatient clinics between 2004 and 2018 in two large university hospitals in London were collected. HbA1c variability was assessed using three distinct methods: (1) SD of HbA1c (SD-HbA1c); (2) visit-adjusted SD (adj-HbA1c): SD-HbA1c/√n/(n-1), where n is the number of HbA1c measurements per participant; and (3) CV (CV-HbA1c): SD-HbA1c/mean-HbA1c. All participants had six or more follow-up HbA1c measurements. The eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration equation and clinical/biochemical results from routine care were extracted from electronic health records.

Results: In total, 3466 participants (50% female, 78% White, 13% African Caribbean, 3% Asian and 6% of mixed heritage or self-reporting as 'other') were followed for a median (IQR) of 8.2 (4.2-11.6) years. Of this cohort, 249 (7%) showed kidney disease progression. Higher HbA1c variability was independently associated with a higher risk of kidney disease progression, with HRs (95% CIs) of 7.76 (4.54, 13.26), 2.62 (1.75, 3.94) and 5.46 (3.40, 8.79) (lowest vs highest HbA1c variability quartile) for methods 1-3, respectively. Increasing age, baseline HbA1c, systolic BP and urinary albumin/creatinine ratio were also associated with kidney disease progression (p<0.05 for all). African Caribbean ethnicity was associated with an increased risk of kidney disease progression (HR [95% CI] 1.47 [1.09, 1.98], 1.76 [1.32, 2.36] and 1.57 [1.17, 2.12] for methods 1-3, respectively) and this effect was independent of glycaemic variability and other traditional risk factors.

Conclusions/interpretation: We observed an independent association between HbA1c variability, evaluated using three distinct methods, and significant kidney disease progression in a multi-ethnic type 1 diabetes cohort. Further studies are needed to elucidate the mechanisms that may explain our results and evaluate if HbA1c variability is a modifiable risk factor for preventing diabetic kidney disease progression.

目的/假设:HbA1c 变异性在糖尿病肾病进展中的作用尚不清楚,迄今为止的大多数研究都是在白种人中进行的,有关其在预测晚期肾病结果中的作用的数据有限。我们的目的是评估在基线eGFR≥45 ml/min per 1.73 m2的1型糖尿病患者种族异质性队列中,长期个体内HbA1c变异性是否是肾脏疾病进展(定义为eGFR从基线下降≥50%,最终eGFR为2)的风险因素:收集了伦敦两家大型大学医院2004年至2018年间门诊患者的电子健康记录数据。使用三种不同的方法评估 HbA1c 变异性:(1)HbA1c 的 SD(SD-HbA1c);(2)就诊调整 SD(adj-HbA1c):SD-HbA1c/√n/(n-1),其中 n 为每位参与者的 HbA1c 测量次数;(3) CV(CV-HbA1c):SD-HbA1c/mean-HbA1c 。所有参与者都进行了六次或六次以上的随访 HbA1c 测量。eGFR 采用慢性肾脏病流行病学协作方程进行测量,常规护理的临床/生化结果从电子健康记录中提取:共对 3466 名参与者(50% 为女性,78% 为白人,13% 为非洲加勒比海人,3% 为亚洲人,6% 为混合血统或自称 "其他")进行了中位数(IQR)为 8.2(4.2-11.6)年的随访。其中 249 人(7%)出现肾病进展。HbA1c 变异性越高,肾病进展的风险越高,方法 1-3 的 HRs(95% CIs)分别为 7.76(4.54,13.26)、2.62(1.75,3.94)和 5.46(3.40,8.79)(最低与最高 HbA1c 变异性四分位数)。年龄、基线 HbA1c、收缩压和尿白蛋白/肌酐比值的增加也与肾病进展有关(p结论/解释:我们在一个多种族 1 型糖尿病队列中观察到,使用三种不同方法评估的 HbA1c 变异与肾脏疾病的显著进展之间存在独立关联。我们需要进一步研究,以阐明可能解释我们的结果的机制,并评估 HbA1c 变异性是否是预防糖尿病肾病进展的可调节风险因素。
{"title":"HbA<sub>1c</sub> variability is independently associated with progression of diabetic kidney disease in an urban multi-ethnic cohort of people with type 1 diabetes.","authors":"Ananya Muthukumar, Layla Badawy, Anastasios Mangelis, Prashant Vas, Stephen Thomas, Aicha Gouber, Salma Ayis, Janaka Karalliedde","doi":"10.1007/s00125-024-06197-2","DOIUrl":"10.1007/s00125-024-06197-2","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>The role of HbA<sub>1c</sub> variability in the progression of diabetic kidney disease is unclear, with most studies to date performed in White populations and limited data on its role in predicting advanced kidney outcomes. Our aim was to evaluate if long-term intra-individual HbA<sub>1c</sub> variability is a risk factor for kidney disease progression (defined as an eGFR decline of ≥50% from baseline with a final eGFR of <30 ml/min per 1.73 m<sup>2</sup>) in an ethnically heterogeneous cohort of people with type 1 diabetes with a preserved eGFR ≥45 ml/min per 1.73 m<sup>2</sup> at baseline.</p><p><strong>Methods: </strong>Electronic health record data from people attending outpatient clinics between 2004 and 2018 in two large university hospitals in London were collected. HbA<sub>1c</sub> variability was assessed using three distinct methods: (1) SD of HbA<sub>1c</sub> (SD-HbA<sub>1c</sub>); (2) visit-adjusted SD (adj-HbA<sub>1c</sub>): SD-HbA<sub>1c</sub>/√n/(n-1), where n is the number of HbA<sub>1c</sub> measurements per participant; and (3) CV (CV-HbA<sub>1c</sub>): SD-HbA<sub>1c</sub>/mean-HbA<sub>1c</sub>. All participants had six or more follow-up HbA<sub>1c</sub> measurements. The eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration equation and clinical/biochemical results from routine care were extracted from electronic health records.</p><p><strong>Results: </strong>In total, 3466 participants (50% female, 78% White, 13% African Caribbean, 3% Asian and 6% of mixed heritage or self-reporting as 'other') were followed for a median (IQR) of 8.2 (4.2-11.6) years. Of this cohort, 249 (7%) showed kidney disease progression. Higher HbA<sub>1c</sub> variability was independently associated with a higher risk of kidney disease progression, with HRs (95% CIs) of 7.76 (4.54, 13.26), 2.62 (1.75, 3.94) and 5.46 (3.40, 8.79) (lowest vs highest HbA<sub>1c</sub> variability quartile) for methods 1-3, respectively. Increasing age, baseline HbA<sub>1c</sub>, systolic BP and urinary albumin/creatinine ratio were also associated with kidney disease progression (p<0.05 for all). African Caribbean ethnicity was associated with an increased risk of kidney disease progression (HR [95% CI] 1.47 [1.09, 1.98], 1.76 [1.32, 2.36] and 1.57 [1.17, 2.12] for methods 1-3, respectively) and this effect was independent of glycaemic variability and other traditional risk factors.</p><p><strong>Conclusions/interpretation: </strong>We observed an independent association between HbA<sub>1c</sub> variability, evaluated using three distinct methods, and significant kidney disease progression in a multi-ethnic type 1 diabetes cohort. Further studies are needed to elucidate the mechanisms that may explain our results and evaluate if HbA<sub>1c</sub> variability is a modifiable risk factor for preventing diabetic kidney disease progression.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431656","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}
引用次数: 0
Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans. 药物靶向 1 型大麻素受体可影响免疫细胞与胰岛之间的串联,从而减轻人类的胰岛炎。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 Epub Date: 2024-06-12 DOI: 10.1007/s00125-024-06193-6
Elise Wreven, María Soledad Ruiz de Adana, Stéphan Hardivillé, Valery Gmyr, Julie Kerr-Conte, Mikael Chetboun, Gianni Pasquetti, Nathalie Delalleau, Julien Thévenet, Anaïs Coddeville, María José Vallejo Herrera, Liad Hinden, Inmaculada Concepción Benavides Espínola, Mireia Gómez Duro, Lourdes Sanchez Salido, Francisca Linares, Francisco-Javier Bermúdez-Silva, Joseph Tam, Caroline Bonner, Josephine M Egan, Gabriel Olveira, Natalia Colomo, François Pattou, Isabel González-Mariscal
<p><strong>Aims/hypothesis: </strong>Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process.</p><p><strong>Methods: </strong>CD4<sup>+</sup> T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1β, TNF-α, IFN-γ) for 24-48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry.</p><p><strong>Results: </strong>CNR1 expression was upregulated in circulating CD4<sup>+</sup> T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function.</p><p><strong>Conclusions/interpretation: </strong>These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor.</p><p><strong>Data availability: </strong>Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121
目的/假设:胰岛炎是自身免疫性 1 型糖尿病前期炎症的标志,会导致功能性 beta 细胞的最终丧失。然而,即使面对持续的胰岛炎,功能性β细胞也能持续存在。尽管免疫抑制治疗取得了进展,但维持功能性β细胞以防止胰岛炎恶化和高血糖仍然是一项挑战。存在于免疫细胞和β细胞中的大麻素 1 型受体(CB1R)可调节炎症和β细胞功能。在此,我们建立了一个反映人类胰岛炎的体外模型,以研究 CB1R 在这一过程中的作用:方法:从男性和女性 1 型糖尿病患者及非糖尿病患者的外周血单核细胞(PBMCs)中分离出 CD4+ T 淋巴细胞,提取 RNA 并通过实时 PCR 分析 mRNA 表达。从数据挖掘中获得了 1 型糖尿病供体的单β细胞表达。在溶解的细胞外基质凝胶中,将来自男性和女性遗体供体的患者胰岛与相同的供体 PBMCs 共同进行三维培养,并与细胞因子(IL-1β、TNF-α、IFN-γ)在载体或浓度不断增加的 CB1R 阻断剂 JD-5037 的作用下培养 24-48 小时。使用 CRISPR/Cas9 技术消减 CNR1(编码 CB1R)的表达。通过活细胞探针和实时 PCR 检测存活率、细胞内应力和信号传导。在灌注系统中,以葡萄糖刺激的胰岛素分泌来测定胰岛功能。免疫细胞渗入胰岛的情况通过显微镜进行监测。用 JD-5037 对 7 周龄的非肥胖糖尿病小鼠治疗 1 周,然后安乐死。通过流式细胞术对浸润胰岛的免疫细胞进行分析:结果:1 型糖尿病患者的循环 CD4+ T 细胞中 CNR1 表达上调(比健康人高 6.9 倍),1 型糖尿病供体分选的胰岛β细胞中 CNR1 表达也上调(比健康人高 3.6 倍)。外周限制性 CB1R 反向激动剂 JD-5037 阻止了人类和小鼠胰岛炎的发生。从机理上讲,CB1R 阻断阻止了胰岛 NO 的产生,并改善了未折叠蛋白反应的 ATF6 部分。因此,人胰岛中细胞因子/趋化因子的表达减少,从而使胰岛细胞的活力和功能得以维持:这些结果表明,CB1R 可能是治疗 1 型糖尿病的一个有趣靶点,同时强调了胰岛炎的调节机制。此外,这些发现可能适用于胰岛炎症也是病理生理因素的 2 型糖尿病:分选的人类β细胞的转录组分析来自基因表达总库数据库,登录号:GSE121863。GSE121863 可在 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161 上查阅。
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引用次数: 0
The gut microbiota and diabetes: research, translation, and clinical applications - 2023 Diabetes, Diabetes Care, and Diabetologia Expert Forum. 肠道微生物群与糖尿病:研究、转化和临床应用 - 2023 年《糖尿病》、《糖尿病护理》和《糖尿病学》专家论坛。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 Epub Date: 2024-06-24 DOI: 10.1007/s00125-024-06198-1
Mariana Byndloss, Suzanne Devkota, Frank Duca, Jan Hendrik Niess, Max Nieuwdorp, Marju Orho-Melander, Yolanda Sanz, Valentina Tremaroli, Liping Zhao

This article summarises the state of the science on the role of the gut microbiota (GM) in diabetes from a recent international expert forum organised by Diabetes, Diabetes Care, and Diabetologia, which was held at the European Association for the Study of Diabetes 2023 Annual Meeting in Hamburg, Germany. Forum participants included clinicians and basic scientists who are leading investigators in the field of the intestinal microbiome and metabolism. Their conclusions were as follows: (1) the GM may be involved in the pathophysiology of type 2 diabetes, as microbially produced metabolites associate both positively and negatively with the disease, and mechanistic links of GM functions (e.g. genes for butyrate production) with glucose metabolism have recently emerged through the use of Mendelian randomisation in humans; (2) the highly individualised nature of the GM poses a major research obstacle, and large cohorts and a deep-sequencing metagenomic approach are required for robust assessments of associations and causation; (3) because single time point sampling misses intraindividual GM dynamics, future studies with repeated measures within individuals are needed; and (4) much future research will be required to determine the applicability of this expanding knowledge to diabetes diagnosis and treatment, and novel technologies and improved computational tools will be important to achieve this goal.

本文总结了最近由《糖尿病》(Diabetes)、《糖尿病护理》(Diabetes Care)和《糖尿病学》(Diabetologia)组织的国际专家论坛上有关肠道微生物群(GM)在糖尿病中作用的科学现状。论坛参与者包括临床医生和基础科学家,他们都是肠道微生物组和新陈代谢领域的主要研究人员。他们的结论如下(1) 微生物组可能与 2 型糖尿病的病理生理学有关,因为微生物组产生的代谢物与该疾病既有正相关又有负相关。(2) 基因改造的高度个体化性质构成了研究的主要障碍,要对相关性和因果关系进行可靠的评估,需要大量的队列和深度测序的元基因组方法;(3) 由于单个时间点取样会错过个体内基因组的动态变化,因此未来的研究需要在个体内进行重复测量;以及 (4) 要确定这些不断扩展的知识在糖尿病诊断和治疗中的适用性,未来需要开展大量研究,而新技术和改进的计算工具对实现这一目标非常重要。
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引用次数: 0
The islet tissue plasminogen activator/plasmin system is upregulated with human islet amyloid polypeptide aggregation and protects beta cells from aggregation-induced toxicity. 胰岛组织纤溶酶原激活剂/纤溶酶系统随着人胰岛淀粉样多肽的聚集而上调,并保护β细胞免受聚集引起的毒性。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 Epub Date: 2024-09-09 DOI: 10.1007/s00125-024-06161-0
Nathalie Esser, Meghan F Hogan, Andrew T Templin, Rehana Akter, Brendy S Fountaine, Joseph J Castillo, Assam El-Osta, Lakshan Manathunga, Alexander Zhyvoloup, Daniel P Raleigh, Sakeneh Zraika, Rebecca L Hull, Steven E Kahn

Aims/hypothesis: Apart from its fibrinolytic activity, the tissue plasminogen activator (tPA)/plasmin system has been reported to cleave the peptide amyloid beta, attenuating brain amyloid deposition in Alzheimer's disease. As aggregation of human islet amyloid polypeptide (hIAPP) is toxic to beta cells, we sought to determine whether activation of the fibrinolytic system can also reduce islet amyloid deposition and its cytotoxic effects, which are both observed in type 2 diabetes.

Methods: The expression of Plat (encoding tPA) and plasmin activity were measured in isolated islets from amyloid-prone hIAPP transgenic mice or non-transgenic control islets expressing non-amyloidogenic mouse islet amyloid polypeptide cultured in the absence or presence of the amyloid inhibitor Congo Red. Plat expression was also determined in hIAPP-treated primary islet endothelial cells, bone marrow-derived macrophages (BMDM) and INS-1 cells, in order to determine the islet cell type(s) producing tPA in response to hIAPP aggregation. Cell-free thioflavin-T assays and MS were used to respectively monitor hIAPP aggregation kinetics and investigate plasmin cleavage of hIAPP. Cell viability was assessed in INS-1 beta cells treated with hIAPP with or without plasmin. Finally, to confirm the findings in human samples, PLAT expression was measured in freshly isolated islets from donors with and without type 2 diabetes.

Results: In isolated islets from transgenic mice, islet Plat expression and plasmin activity increased significantly with the process of amyloid deposition (p≤0.01, n=5); these effects were not observed in islets from non-transgenic mice and were blocked by Congo Red (p≤0.01, n=4). In response to hIAPP exposure, Plat expression increased in BMDM and INS-1 cells vs vehicle-treated cells (p≤0.05, n=4), but not in islet endothelial cells. Plasmin reduced hIAPP fibril formation in a dose-dependent manner in a cell-free system, and restored hIAPP-induced loss of cell viability in INS-1 beta cells (p≤0.01, n=5). Plasmin cleaved monomeric hIAPP, inducing a rapid decrease in the abundance of full-length hIAPP and the appearance of hIAPP 1-11 and 12-37 fragments. hIAPP 12-37, which contains the critical amyloidogenic region, was not toxic to INS-1 cells. Finally, PLAT expression was significantly increased by 2.4-fold in islets from donors with type 2 diabetes (n=4) vs islets from donors without type 2 diabetes (n=7) (p≤0.05).

Conclusions/interpretation: The fibrinolytic system is upregulated in islets with hIAPP aggregation. Plasmin rapidly degrades hIAPP, limiting its aggregation into amyloid and thus protecting beta cells from hIAPP-induced toxicity. Thus, increasing islet plasmin activity might be a strategy to limit beta cell loss in type 2 diabetes.

目的/假设:据报道,组织纤溶酶原激活剂(tPA)/纤溶酶系统除了具有纤溶活性外,还能裂解肽类淀粉样蛋白β,从而减轻阿尔茨海默氏症的脑淀粉样蛋白沉积。由于人胰岛淀粉样多肽(hIAPP)的聚集对β细胞有毒性,我们试图确定激活纤溶系统是否也能减少胰岛淀粉样沉积及其细胞毒性作用,这两种作用在2型糖尿病中都能观察到:方法:在无淀粉样蛋白抑制剂刚果红或有淀粉样蛋白抑制剂的情况下,测量易产生淀粉样蛋白的 hIAPP 转基因小鼠或表达非淀粉样蛋白小鼠胰岛淀粉样多肽的非转基因对照小鼠离体胰岛中 Plat(编码 tPA)的表达和纤溶酶活性。此外,还测定了经 hIAPP 处理的原代胰岛内皮细胞、骨髓衍生巨噬细胞(BMDM)和 INS-1 细胞中 Plat 的表达,以确定对 hIAPP 聚合反应产生 tPA 的胰岛细胞类型。无细胞硫黄素-T测定法和质谱法分别用于监测hIAPP聚集动力学和研究hIAPP的血浆蛋白酶裂解。在使用或不使用plasmin处理hIAPP的INS-1β细胞中评估了细胞活力。最后,为了证实在人体样本中的发现,对患有和未患有 2 型糖尿病的供体新鲜分离的胰岛进行了 PLAT 表达测定:结果:在转基因小鼠分离的胰岛中,胰岛Plat的表达和plasmin的活性随着淀粉样蛋白的沉积过程显著增加(p≤0.01,n=5);在非转基因小鼠的胰岛中没有观察到这些影响,并且被刚果红阻断(p≤0.01,n=4)。在暴露于 hIAPP 的情况下,BMDM 和 INS-1 细胞与车辆处理的细胞相比,Plat 表达增加(p≤0.05,n=4),但在胰岛内皮细胞中没有增加。在无细胞系统中,Plasmin 以剂量依赖的方式减少了 hIAPP 纤维的形成,并恢复了 hIAPP 诱导的 INS-1 β 细胞活力丧失(p≤0.01,n=5)。Plasmin 可裂解单体 hIAPP,使全长 hIAPP 的丰度迅速下降,并出现 hIAPP 1-11 和 12-37 片段。最后,2型糖尿病供体的胰岛(n=4)与非2型糖尿病供体的胰岛(n=7)相比,PLAT的表达明显增加了2.4倍(p≤0.05):纤溶系统在hIAPP聚集的胰岛中上调。血浆蛋白酶能迅速降解 hIAPP,限制其聚集成淀粉样蛋白,从而保护β细胞免受 hIAPP 诱导的毒性。因此,提高胰岛蛋白酶的活性可能是限制2型糖尿病患者β细胞损失的一种策略。
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引用次数: 0
Activation of the hypoxia-inducible factor pathway by roxadustat improves glucose metabolism in human primary myotubes from men. 罗沙司他激活缺氧诱导因子通路可改善人类原发性男性肌管的葡萄糖代谢。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 Epub Date: 2024-05-30 DOI: 10.1007/s00125-024-06185-6
Selina Mäkinen, Sreesha Sree, Tuulia Ala-Nisula, Henric Kultalahti, Peppi Koivunen, Heikki A Koistinen
<p><strong>Aims/hypothesis: </strong>Hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) enzymes regulate adaptive cellular responses to low oxygen concentrations. Inhibition of HIF-P4Hs leads to stabilisation of hypoxia-inducible factors (HIFs) and activation of the HIF pathway affecting multiple biological processes to rescue cells from hypoxia. As evidence from animal models suggests that HIF-P4H inhibitors could be used to treat metabolic disorders associated with insulin resistance, we examined whether roxadustat, an HIF-P4H inhibitor approved for the treatment of renal anaemia, would have an effect on glucose metabolism in primary human myotubes.</p><p><strong>Methods: </strong>Primary skeletal muscle cell cultures, established from biopsies of vastus lateralis muscle from men with normal glucose tolerance (NGT) (n=5) or type 2 diabetes (n=8), were treated with roxadustat. Induction of HIF target gene expression was detected with quantitative real-time PCR. Glucose uptake and glycogen synthesis were investigated with radioactive tracers. Glycolysis and mitochondrial respiration rates were measured with a Seahorse analyser.</p><p><strong>Results: </strong>Exposure to roxadustat stabilised nuclear HIF1α protein expression in human myotubes. Treatment with roxadustat led to induction of HIF target gene mRNAs for GLUT1 (also known as SLC2A1), HK2, MCT4 (also known as SLC16A4) and HIF-P4H-2 (also known as PHD2 or EGLN1) in myotubes from donors with NGT, with a blunted response in myotubes from donors with type 2 diabetes. mRNAs for LDHA, PDK1 and GBE1 were induced to a similar degree in myotubes from donors with NGT or type 2 diabetes. Exposure of myotubes to roxadustat led to a 1.4-fold increase in glycolytic rate in myotubes from men with NGT (p=0.0370) and a 1.7-fold increase in myotubes from donors with type 2 diabetes (p=0.0044), with no difference between the groups (p=0.1391). Exposure to roxadustat led to a reduction in basal mitochondrial respiration in both groups (p<0.01). Basal glucose uptake rates were similar in myotubes from donors with NGT (20.2 ± 2.7 pmol mg<sup>-1</sup> min<sup>-1</sup>) and type 2 diabetes (25.3 ± 4.4 pmol mg<sup>-1</sup> min<sup>-1</sup>, p=0.4205). Treatment with roxadustat enhanced insulin-stimulated glucose uptake in myotubes from donors with NGT (1.4-fold vs insulin-only condition, p=0.0023). The basal rate of glucose incorporation into glycogen was lower in myotubes from donors with NGT (233 ± 12.4 nmol g<sup>-1</sup> h<sup>-1</sup>) than in myotubes from donors with type 2 diabetes (360 ± 40.3 nmol g<sup>-1</sup> h<sup>-1</sup>, p=0.0344). Insulin increased glycogen synthesis by 1.9-fold (p=0.0025) in myotubes from donors with NGT, whereas roxadustat did not affect their basal or insulin-stimulated glycogen synthesis. Insulin increased glycogen synthesis by 1.7-fold (p=0.0031) in myotubes from donors with type 2 diabetes. While basal glycogen synthesis was unaffected by roxadustat, pretreatment with
目的/假说:缺氧诱导因子脯氨酰 4-羟化酶(HIF-P4H)调节细胞对低氧浓度的适应性反应。抑制 HIF-P4Hs 会导致缺氧诱导因子(HIF)的稳定,并激活影响多种生物过程的 HIF 通路,从而将细胞从缺氧状态中解救出来。动物模型的证据表明,HIF-P4H 抑制剂可用于治疗与胰岛素抵抗有关的代谢紊乱,因此我们研究了已获准用于治疗肾性贫血的 HIF-P4H 抑制剂罗沙司他是否会对原代人类肌管的葡萄糖代谢产生影响:用罗沙司他(roxadustat)处理从正常糖耐量(NGT)(n=5)或 2 型糖尿病(n=8)男性的阔筋膜肌肉活组织中提取的原代骨骼肌细胞培养物。用实时定量 PCR 检测 HIF 靶基因的诱导表达。使用放射性示踪剂对葡萄糖摄取和糖原合成进行了研究。使用海马分析仪测量糖酵解和线粒体呼吸速率:结果:暴露于罗克司他可稳定人肌管中核 HIF1α 蛋白的表达。罗沙司他能诱导 NGT 捐献者肌管中 HIF 靶基因 mRNA 的表达,包括 GLUT1(又称 SLC2A1)、HK2、MCT4(又称 SLC16A4)和 HIF-P4H-2(又称 PHD2 或 EGLN1),而 2 型糖尿病捐献者肌管中的反应较弱。LDHA、PDK1和GBE1的mRNA在NGT或2型糖尿病供体的肌管中的诱导程度相似。将肌肉管暴露于罗沙司他会使 NGT 男性供体的肌肉管中的糖酵解率增加 1.4 倍(p=0.0370),使 2 型糖尿病供体的肌肉管中的糖酵解率增加 1.7 倍(p=0.0044),组间无差异(p=0.1391)。接触罗沙司他会导致两组 2 型糖尿病患者的基础线粒体呼吸减少(p-1 min-1)(25.3 ± 4.4 pmol mg-1 min-1,p=0.4205)。使用罗沙司他可提高NGT供体肌管在胰岛素刺激下的葡萄糖摄取量(1.4倍于纯胰岛素条件,p=0.0023)。NGT供体的肌细胞葡萄糖掺入糖原的基础速率(233 ± 12.4 nmol g-1 h-1)低于2型糖尿病供体的肌细胞(360 ± 40.3 nmol g-1 h-1,p=0.0344)。胰岛素使NGT供体的肌细胞糖原合成增加了1.9倍(p=0.0025),而罗沙司他不影响其基础糖原合成或胰岛素刺激的糖原合成。在 2 型糖尿病供体的肌细胞中,胰岛素使糖原合成增加了 1.7 倍(p=0.0031)。虽然基础糖原合成不受罗沙司他的影响,但用罗沙司他预处理后,2型糖尿病供体的肌管在胰岛素刺激下的糖原合成会增强(p=0.0345):无论是否患有糖尿病,罗沙司他都能增加原代人类肌管中的糖酵解并抑制线粒体呼吸。罗沙司他还可改善胰岛素对 2 型糖尿病供体肌细胞糖原合成的作用。
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引用次数: 0
The role of PCSK9 in glomerular lipid accumulation and renal injury in diabetic kidney disease. PCSK9 在糖尿病肾病肾小球脂质积累和肾损伤中的作用。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 Epub Date: 2024-06-15 DOI: 10.1007/s00125-024-06191-8
Meiyan Wu, Chang-Yun Yoon, Jimin Park, Gyuri Kim, Bo Young Nam, Seonghun Kim, Jung Tak Park, Seung Hyeok Han, Shin-Wook Kang, Tae-Hyun Yoo

Aims/hypothesis: Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD.

Methods: In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions.

Results: A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes.

Conclusions/interpretation: The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD.

目的/假设:肾小球脂质积聚是糖尿病肾病(DKD)的一个显著特征;然而,其确切的内在机制需要进一步阐明。最近的证据表明,9 型潜血蛋白酶/kexin(PCSK9)在细胞内脂质平衡中发挥作用。尽管 PCSK9 存在于肾脏中,但其在肾细胞内的作用以及与肾脏疾病的相关性在很大程度上仍未得到探索。因此,我们研究了细胞内 PCSK9 在糖尿病条件下调节肾小球和荚膜细胞内脂质积累和平衡的作用。此外,我们还旨在确定导致荚膜细胞损伤的病理生理机制,这种损伤与糖尿病患者细胞内 PCSK9 诱导的脂质积累有关:本研究从人类肾脏活检组织中分离出肾小球,并进行了肾小球基因表达分析。此外,还利用db/db和db/m小鼠进行了肾小球基因表达谱分析。我们采用高脂饮食和低剂量腹腔注射链脲佐菌素的方法,在 C57BL/6 和 Pcsk9 基因敲除(KO)小鼠中建立了 DKD 模型。我们分析了肾皮质中的胆固醇和三酰甘油水平。脂滴采用 BODIPY 染色法进行评估。在糖尿病条件下,我们使用慢病毒和 siRNA 转染技术分别诱导条件永生化小鼠荚膜细胞中 PCSK9 表达的上调和下调:结果:在糖尿病患者的肾小球中观察到 PCSK9 的转录水平明显下降。在糖尿病条件下,动物荚膜细胞中 PCSK9 的表达也有所降低。我们观察到,与野生型(WT)DKD 小鼠相比,Pcsk9 KO DKD 小鼠肾脏组织中的脂质积累明显较高。此外,与 WT 模型相比,Pcsk9 KO DKD 小鼠的线粒体数量明显减少,同时线粒体体积明显增大。此外,在 WT 和 Pcsk9 KO DKD 小鼠中都观察到了白蛋白尿和荚膜足突脱落,其中 KO DKD 小鼠的表现更为明显。暴露于糖尿病刺激下的小鼠荚膜固定化细胞表现出细胞内脂质堆积、线粒体损伤和细胞凋亡,Pcsk9过表达可改善这些症状,而Pcsk9敲除则会加重小鼠荚膜细胞的这些症状:PCSK9在荚膜细胞中的下调与脂质积累有关,脂质积累会导致线粒体功能障碍、细胞凋亡和肾损伤。本研究揭示了 PCSK9 可能参与 DKD 肾小球脂质蓄积和荚膜损伤的病理生理学过程。
{"title":"The role of PCSK9 in glomerular lipid accumulation and renal injury in diabetic kidney disease.","authors":"Meiyan Wu, Chang-Yun Yoon, Jimin Park, Gyuri Kim, Bo Young Nam, Seonghun Kim, Jung Tak Park, Seung Hyeok Han, Shin-Wook Kang, Tae-Hyun Yoo","doi":"10.1007/s00125-024-06191-8","DOIUrl":"10.1007/s00125-024-06191-8","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD.</p><p><strong>Methods: </strong>In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions.</p><p><strong>Results: </strong>A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes.</p><p><strong>Conclusions/interpretation: </strong>The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327376","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}
引用次数: 0
Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults. 发现并验证可预测波多黎各成年人胰岛素抵抗和糖尿病进展或消退的血浆、唾液和多流体血浆-唾液代谢组评分。
IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 Epub Date: 2024-05-21 DOI: 10.1007/s00125-024-06169-6
Danielle E Haslam, Liming Liang, Kai Guo, Marijulie Martínez-Lozano, Cynthia M Pérez, Chih-Hao Lee, Evangelia Morou-Bermudez, Clary Clish, David T W Wong, JoAnn E Manson, Frank B Hu, Meir J Stampfer, Kaumudi Joshipura, Shilpa N Bhupathiraju

Aims/hypothesis: Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites.

Methods: We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA1c) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors.

Results: Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures.

Conclusions/interpretation: The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.

目的/假设:许多研究探讨了血浆代谢物与 2 型糖尿病进展之间的关系,但很少有研究探讨唾液和多流体代谢物:我们使用 LC/MS 测量了圣胡安超重成年人纵向研究中波多黎各成年人的血浆(n=1051)和唾液(n=635)代谢物。我们使用弹性净回归法确定了血浆、唾液和多流体血浆-唾液代谢组得分,这些得分可预测训练集(人数=509)中的基线 HOMA-IR,并在测试集(人数=340)中验证了这些得分。我们使用多变量考克斯比例危险模型估算了预测胰岛素抵抗的基线代谢组评分与3年后发生的2型糖尿病(54人)和糖尿病前期(以糖耐量受损、空腹血糖受损和/或高HbA1c为特征)(130人)的相关性,以及从糖尿病前期向正常血糖回归(122人)的相关性,并对传统的糖尿病相关风险因素进行了调整:预测胰岛素抵抗的血浆、唾液和多流体血浆-唾液代谢组评分包括来自果糖、酪氨酸、脂质和氨基酸代谢的高权重代谢物。血浆(HR 1.99 [95% CI 1.18, 3.38];p=0.01)和多唾液(1.80 [1.06, 3.07];p=0.03)代谢组评分每增加一个标准差,罹患 2 型糖尿病的风险就会增加。唾液代谢组评分与糖尿病前期相关(1.48 [1.17, 1.86]; p=0.001)。在调整脂肪含量的模型中,所有三个代谢组得分都与从糖尿病前期向正常血糖回归的可能性较低显著相关(血浆的 HR 值为 0.72,唾液的 HR 值为 0.78,多流体的 HR 值为 0.72),但在调整血脂和血糖测量时,相关性减弱:预测胰岛素抵抗的血浆代谢组学评分比唾液代谢组学评分与2型糖尿病发病的相关性更强。只有唾液代谢组评分与糖尿病前期相关。
{"title":"Discovery and validation of plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance and diabetes progression or regression among Puerto Rican adults.","authors":"Danielle E Haslam, Liming Liang, Kai Guo, Marijulie Martínez-Lozano, Cynthia M Pérez, Chih-Hao Lee, Evangelia Morou-Bermudez, Clary Clish, David T W Wong, JoAnn E Manson, Frank B Hu, Meir J Stampfer, Kaumudi Joshipura, Shilpa N Bhupathiraju","doi":"10.1007/s00125-024-06169-6","DOIUrl":"10.1007/s00125-024-06169-6","url":null,"abstract":"<p><strong>Aims/hypothesis: </strong>Many studies have examined the relationship between plasma metabolites and type 2 diabetes progression, but few have explored saliva and multi-fluid metabolites.</p><p><strong>Methods: </strong>We used LC/MS to measure plasma (n=1051) and saliva (n=635) metabolites among Puerto Rican adults from the San Juan Overweight Adults Longitudinal Study. We used elastic net regression to identify plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting baseline HOMA-IR in a training set (n=509) and validated these scores in a testing set (n=340). We used multivariable Cox proportional hazards models to estimate HRs for the association of baseline metabolomic scores predicting insulin resistance with incident type 2 diabetes (n=54) and prediabetes (characterised by impaired glucose tolerance, impaired fasting glucose and/or high HbA<sub>1c</sub>) (n=130) at 3 years, along with regression from prediabetes to normoglycaemia (n=122), adjusting for traditional diabetes-related risk factors.</p><p><strong>Results: </strong>Plasma, saliva and multi-fluid plasma-saliva metabolomic scores predicting insulin resistance included highly weighted metabolites from fructose, tyrosine, lipid and amino acid metabolism. Each SD increase in the plasma (HR 1.99 [95% CI 1.18, 3.38]; p=0.01) and multi-fluid (1.80 [1.06, 3.07]; p=0.03) metabolomic scores was associated with higher risk of type 2 diabetes. The saliva metabolomic score was associated with incident prediabetes (1.48 [1.17, 1.86]; p=0.001). All three metabolomic scores were significantly associated with lower likelihood of regressing from prediabetes to normoglycaemia in models adjusting for adiposity (HRs 0.72 for plasma, 0.78 for saliva and 0.72 for multi-fluid), but associations were attenuated when adjusting for lipid and glycaemic measures.</p><p><strong>Conclusions/interpretation: </strong>The plasma metabolomic score predicting insulin resistance was more strongly associated with incident type 2 diabetes than the saliva metabolomic score. Only the saliva metabolomic score was associated with incident prediabetes.</p>","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":null,"pages":null},"PeriodicalIF":8.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075601","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}
引用次数: 0
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Diabetologia
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