Diabetes最新文献_第2页

When does metabolic memory start? Insights from the AMD Annals Initiative on stringent HbA1c targets. 代谢记忆何时开始？AMD 年报倡议对严格 HbA1c 目标的启示。

IF 7.7 1区医学

Diabetes Pub Date : 2024-10-17 DOI: 10.2337/db24-0166

Giuseppina T. Russo, Antonio Nicolucci, Giuseppe Lucisano, Maria Chiara Rossi, Antonio Ceriello, Francesco Prattichizzo, Valeria Manicardi, Alberto Rocca, Paolo Di Bartolo, Salvatore De Cosmo, Graziano Di Cianni, Riccardo Candido

{"title":"When does metabolic memory start? Insights from the AMD Annals Initiative on stringent HbA1c targets.","authors":"Giuseppina T. Russo, Antonio Nicolucci, Giuseppe Lucisano, Maria Chiara Rossi, Antonio Ceriello, Francesco Prattichizzo, Valeria Manicardi, Alberto Rocca, Paolo Di Bartolo, Salvatore De Cosmo, Graziano Di Cianni, Riccardo Candido","doi":"10.2337/db24-0166","DOIUrl":"https://doi.org/10.2337/db24-0166","url":null,"abstract":"Early, intensive glycemic control in T2D patients is associated with long-term benefits on cardiovascular disease (CVD) development. Evidence on benefits of achieving HbA1c targets close to normal values is scant. Subjects with newly-diagnosed T2D, without CVD at baseline, were identified in an Italian clinical registry (N=251,339). We adopted three definitions of early exposure periods (0–1, 0–2 and 0–3 years). Mean HbA1c was categorized into HbA1c &lt; 5.7%, 5.7-6.4%, 6.5-7.0%, 7.1-8.0%, and &gt;8.0%. The outcome was the incidence of major cardiovascular events. After a mean follow-up of 4.6±2.9 years, at multivariate Cox regression analysis, compared with mean HbA1c &lt;5.7% during the first year after diagnosis, the increase in the risk of CVD was 24%, 42%, 49% and 56% for patients with HbA1c of 5.7%-6.4%, 6.5%-7.0%, 7.1%-8.0%, and &gt;8.0%, respectively. The same trend was documented in all exposure periods. In conclusion, our data support that an early achievement of stringent targets of HbA1c &lt;5.7% is worthy for CVD prevention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448161","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

1-hour postload glucose is a more sensitive marker of impaired β-cell function than 2-hour postload glucose 与负荷后 2 小时葡萄糖相比，负荷后 1 小时葡萄糖是更灵敏的β细胞功能受损标志物

IF 7.7 1区医学

Diabetes Pub Date : 2024-10-17 DOI: 10.2337/db24-0652

Jingyi Lu, Jiaying Ni, Hang Su, Xingxing He, Wei Lu, Wei Zhu, Yufei Wang, Xiaojing Ma, Yuqian Bao, Jian Zhou

{"title":"1-hour postload glucose is a more sensitive marker of impaired β-cell function than 2-hour postload glucose","authors":"Jingyi Lu, Jiaying Ni, Hang Su, Xingxing He, Wei Lu, Wei Zhu, Yufei Wang, Xiaojing Ma, Yuqian Bao, Jian Zhou","doi":"10.2337/db24-0652","DOIUrl":"https://doi.org/10.2337/db24-0652","url":null,"abstract":"There is evidence that 1-h plasma glucose (PG) during the 75-g oral glucose tolerance test (OGTT) is superior to 2-h PG in predicting diabetes. We aimed to investigate the characteristics of insulin sensitivity and β-cell function behind this observation. After age, sex and BMI matching, 496 subjects selected from 3965 non-diabetic individuals at high risk of type 2 diabetes in a tertiary medical center were categorized into four groups in a 1:1:1:1 ratio based on OGTT results: 1) 1 h &lt; 8.6 mmol/L and 2 h &lt; 7.8 mmol/L (normal glucose tolerance [NGT] /1h-normal); 2) 1 h ≥ 8.6 mmol/L and 2 h &lt; 7.8 mmol/L (NGT/1h-high); 3) 1 h &lt; 8.6 mmol/L and 2 h ≥ 7.8 mmol/L (impaired glucose tolerance [IGT]/1h-normal); and 4) 1 h ≥ 8.6 mmol/L and 2 h ≥ 7.8 mmol/L (IGT/1h-high). Compared with subjects with IGT/1h-normal, those with NGT/1h-high exhibited similar extent of insulin resistance but lower early-phase insulin secretion. Additionally, participants with NGT/1h-high had lower disposition index at both 0-30 min and 0-120 min than those with IGT/1h-normal. The fitted regression line relating PG to log-transformed disposition index (0-30 min and 0-120 min) was significantly steeper for 1-h than 2-h PG. In conclusion, 1-h PG seemed to be more sensitive to the deterioration in β-cell function than 2-h PG. The use of 1-h PG may identify individuals at high risk of type 2 diabetes at an earlier stage","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448201","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

NMDA Receptors in POMC Neurons Connect Exercise With Insulin Sensitivity POMC 神经元中的 NMDA 受体将运动与胰岛素敏感性联系在一起

IF 7.7 1区医学

Diabetes Pub Date : 2024-10-14 DOI: 10.2337/dbi24-0002

Bryan Portillo, Eunsang Hwang, Jason Ajwani, Kyle Grose, Linh Lieu, Briana Wallace, Anita Kabahizi, Joel K. Elmquist, Kevin W. Williams

{"title":"NMDA Receptors in POMC Neurons Connect Exercise With Insulin Sensitivity","authors":"Bryan Portillo, Eunsang Hwang, Jason Ajwani, Kyle Grose, Linh Lieu, Briana Wallace, Anita Kabahizi, Joel K. Elmquist, Kevin W. Williams","doi":"10.2337/dbi24-0002","DOIUrl":"https://doi.org/10.2337/dbi24-0002","url":null,"abstract":"Increased arcuate proopiomelanocortin (POMC) neuron activity improves glucose metabolism and reduces appetite, facilitating weight loss. We recently showed that arcuate POMC neurons are activated by exercise. However, the role of excitatory glutamatergic input in these neurons and the metabolic outcomes of exercise remains undefined. To investigate this, we developed a mouse model with NMDA receptors (NMDARs) selectively deleted from POMC neurons of adult mice. We performed metabolic assessments, including the monitoring of body weight, body composition analysis, and glucometabolic tolerance tests. We also examined the metabolic outcomes of these mice in response to exercise, including changes in arcuate POMC neuronal activity and insulin sensitivity. Loss of NMDARs in POMC neurons failed to alter body weight or body composition. Notably, however, we did observe a marked impairment in glucose tolerance and insulin sensitivity. Additionally, exercise resulted in activation of arcuate POMC neurons and a sustained improvement in insulin sensitivity, an effect that was abrogated in mice deficient for NMDARs in POMC neurons when compared with their respective sedentary controls. This underscores an important link among exercise, hypothalamic neuron function, and metabolic health. Moreover, this highlights an underappreciated role of hypothalamic POMC neurons in mediating beneficial effects of exercise on glucose metabolism.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440216","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

One Nervous System: Critical Links Between Central and Peripheral Nervous System Health and Implications for Obesity and Diabetes 一个神经系统：中枢神经系统与外周神经系统健康之间的重要联系以及对肥胖症和糖尿病的影响

IF 7.7 1区医学

Diabetes Pub Date : 2024-10-14 DOI: 10.2337/dbi24-0004

Kristy L. Townsend

{"title":"One Nervous System: Critical Links Between Central and Peripheral Nervous System Health and Implications for Obesity and Diabetes","authors":"Kristy L. Townsend","doi":"10.2337/dbi24-0004","DOIUrl":"https://doi.org/10.2337/dbi24-0004","url":null,"abstract":"There are key differences between the central nervous system (CNS) (brain and spinal cord) and peripheral nervous system (PNS), such as glial cell types, whether there is protection by the blood-brain barrier, modes of synaptic connections, etc. However, there are many more similarities between these two arms of the nervous system, including neuronal structure and function, neuroimmune and neurovascular interactions, and, perhaps most essentially, the balance between neural plasticity (including processes like neuron survival, neurite outgrowth, synapse formation, gliogenesis) and neurodegeneration (neuronal death, peripheral neuropathies like axonopathy and demyelination). This article brings together current research evidence on shared mechanisms of nervous system health and disease between the CNS and PNS, particularly with metabolic diseases like obesity and diabetes. This evidence supports the claim that the two arms of the nervous system are critically linked and that previously understudied conditions of central neurodegeneration or peripheral neurodegeneration may actually be manifesting across the entire nervous system at the same time, through shared genetic and cellular mechanisms. This topic has been critically underexplored due to the research silos between studies of the brain and studies of peripheral nerves and an overemphasis on the brain in neuroscience as a field of study. There are likely shared and linked mechanisms for how neurons stay healthy versus undergo damage and disease among this one nervous system in the body—providing new opportunities for understanding neurological disease etiology and future development of neuroprotective therapeutics.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440218","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

Brain Defense of Glycemia in Health and Diabetes 健康和糖尿病患者大脑对血糖的防御能力

IF 7.7 1区医学

Diabetes Pub Date : 2024-10-14 DOI: 10.2337/dbi24-0001

Zaman Mirzadeh, Chelsea Faber

引用次数: 0

Role of Sec61α2 translocon in insulin biosynthesis Sec61α2 转座子在胰岛素生物合成中的作用

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-26 DOI: 10.2337/db24-0115

Xiaoxi Xu, Thomas W. Bell, Truc Le, Ivy Zhao, Emily Walker, Yiqing Wang, Ning Xu, Scott A. Soleimanpour, Holger A. Russ, Ling Qi, Billy Tsai, Ming Liu, Peter Arvan

{"title":"Role of Sec61α2 translocon in insulin biosynthesis","authors":"Xiaoxi Xu, Thomas W. Bell, Truc Le, Ivy Zhao, Emily Walker, Yiqing Wang, Ning Xu, Scott A. Soleimanpour, Holger A. Russ, Ling Qi, Billy Tsai, Ming Liu, Peter Arvan","doi":"10.2337/db24-0115","DOIUrl":"https://doi.org/10.2337/db24-0115","url":null,"abstract":"Translocational regulation of proinsulin biosynthesis in pancreatic β-cells is unknown, although several studies have reported an important accessory role for the Translocon-Associated Protein complex to assist preproinsulin delivery into the endoplasmic reticulum via the heterotrimeric Sec61 translocon (comprised of α, β, and γ subunits). The actual protein-conducting channel is the α–subunit encoded either by Sec61A1 or its paralog Sec61A2. Although the underlying channel selectivity for preproinsulin translocation is unknown, almost all studies of Sec61α to date have focused on Sec61α1. There is currently no evidence to suggest that this gene product plays a major role in proinsulin production, whereas genome-wide association studies indicate linkage of Sec61A2 with diabetes. Here, we report that evolutionary differences in mouse preproinsulin signal peptides affect proinsulin biosynthesis. Moreover, we find that although some preproinsulin translocation can proceed through Sec61α1, Sec61α2 has a greater impact on proinsulin biosynthesis in pancreatic β-cells. Remarkably, Sec61α2-translocon deficiency exerts a significant inhibitory effect on the biosynthesis of preproinsulin itself, including a disproportionate increase of full-length nacent chain unreleased from ribosomes. This study not only reveals novel translocational regulation of proinsulin biosynthesis, but also provides a rationale for genetic evidence suggesting an important role of Sec61α2 in maintaining blood glucose homeostasis.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324929","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

Deficiency of the hemoglobin-haptoglobin receptor, CD163, worsens insulin sensitivity in obese male mice 血红蛋白-aptoglobin 受体 CD163 的缺失会降低肥胖雄性小鼠对胰岛素的敏感性

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-26 DOI: 10.2337/db24-0405

Michael W. Schleh, Magdalene Ameka, Alec Rodriguez, Hasty Alyssa H.

{"title":"Deficiency of the hemoglobin-haptoglobin receptor, CD163, worsens insulin sensitivity in obese male mice","authors":"Michael W. Schleh, Magdalene Ameka, Alec Rodriguez, Hasty Alyssa H.","doi":"10.2337/db24-0405","DOIUrl":"https://doi.org/10.2337/db24-0405","url":null,"abstract":"Excessive iron accumulation in metabolic organs such as the adipose tissue, liver, and skeletal muscle is associated with increased diabetes risk. Tissue-resident macrophages serve multiple roles including managing inflammatory tone and regulating parachymal iron homeostasis; thus protecting against metabolic dysfunction upon iron overload. The scavenger receptor CD163 is uniquely present on tissue-resident macrophages, and plays a significant role in iron homeostasis by clearing extracellular hemoglobin-haptoglobin complexes, thereby limiting oxidative damage caused by free hemoglobin in metabolic tissues. We show that the absence of CD163 exacerbates glucose intolerance and insulin resistance in male mice with obesity. Additionally, loss of CD163 reduced the expression of iron regulatory genes (Tfr1, Cisd1, Slc40a1) in adipose tissue macrophages and anti-inflammatory (M2-like) bone marrow-derived macrophages (BMDMs). Further, CD163 deficiency mediated a pro-inflammatory shift and limited hemoglobin scavenging specifically in M2-like BMDMs. To this end, iron buffering was diminished in inguinal white adipose tissue (iWAT) macrophages in vivo, which culminated in iron spillover into adipocytes and CD45+CD11B− non-myeloid immune cells in iWAT. These findings show that CD163 on tissue-resident macrophages is critical for their anti-inflammatory and hemoglobin scavenging roles, and its absence results in impaired systemic insulin action in an obese setting.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324930","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

Optimised proteomic analysis of insulin granules from MIN6 cells identifies Scamp3, a novel regulator of insulin secretion and content. 对 MIN6 细胞胰岛素颗粒的优化蛋白质组分析发现了胰岛素分泌和含量的新型调节因子 Scamp3。

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-25 DOI: 10.2337/db24-0355

Nicholas Norris, Belinda Yau, Carlo Famularo, Hayley Webster, Thomas Loudovaris, Helen E. Thomas, Mark Larance, Alistair M. Senior, Melkam A. Kebede

{"title":"Optimised proteomic analysis of insulin granules from MIN6 cells identifies Scamp3, a novel regulator of insulin secretion and content.","authors":"Nicholas Norris, Belinda Yau, Carlo Famularo, Hayley Webster, Thomas Loudovaris, Helen E. Thomas, Mark Larance, Alistair M. Senior, Melkam A. Kebede","doi":"10.2337/db24-0355","DOIUrl":"https://doi.org/10.2337/db24-0355","url":null,"abstract":"Pancreatic β-cells in the Islets of Langerhans are key to maintaining glucose homeostasis, by secreting the peptide hormone insulin. Insulin is packaged within vesicles named insulin secretory granules (ISGs), that have recently been considered to have intrinsic structures and proteins that regulate insulin granule maturation, trafficking, and secretion. Previously, studies have identified a handful of novel ISG-associated proteins using different separation techniques. Here, this study combines an optimized ISG isolation technique and mass spectrometry-based proteomics, with an unbiased protein correlation profiling and targeted machine learning approach to uncover 211 ISG-associated proteins with confidence. Four of these proteins: Syntaxin-7, Synaptophysin, Synaptotagmin-13 and Scamp3 have not been previously ISG-associated. Through colocalization analysis of confocal imaging we validate the association of these proteins to the ISG in MIN6 and human β-cells. We further validate the role for one (Scamp3) in regulating insulin content and secretion from β-cells for the first time. Scamp3 knock-down INS-1 cells show a reduction in insulin content and dysfunctional insulin secretion. These data provide the basis for future investigation of Scamp3 in β-cell biology and the regulation of insulin secretion.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321250","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

Microglia Mediate Metabolic Dysfunction from Common Air Pollutants through NF-κB Signaling 小胶质细胞通过 NF-κB 信号介导常见空气污染物造成的代谢功能障碍

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-25 DOI: 10.2337/db24-0110

Lucas K. Debarba, Hashan S.M. Jayarathne, Lukas Stilgenbauer, Ana L.Terra dos Santos, Lisa Koshko, Sydney Scofield, Ryan Sullivan, Abhijit Mandal, Ulrike Klueh, Marianna Sadagurski

{"title":"Microglia Mediate Metabolic Dysfunction from Common Air Pollutants through NF-κB Signaling","authors":"Lucas K. Debarba, Hashan S.M. Jayarathne, Lukas Stilgenbauer, Ana L.Terra dos Santos, Lisa Koshko, Sydney Scofield, Ryan Sullivan, Abhijit Mandal, Ulrike Klueh, Marianna Sadagurski","doi":"10.2337/db24-0110","DOIUrl":"https://doi.org/10.2337/db24-0110","url":null,"abstract":"The prevalence of Type 2 Diabetes (T2D) poses a significant health challenge yet the contribution of air pollutants to T2D epidemics remains understudied. Several studies demonstrated a correlation between exposure to volatile organic compounds (VOCs) in indoor/outdoor environments, and T2D. Here, we conducted the first meta-analysis, establishing a robust association between exposure to benzene, a prevalent airborne VOC, and insulin resistance in humans across all ages. We utilized a controlled benzene exposure system, continuous glucose monitoring (CGM) approach and indirect calorimetry in mice, to investigate the underlying mechanisms. Following exposure, disruptions in energy homeostasis, accompanied by modifications in the hypothalamic transcriptome and alterations in insulin and immune signaling, were observed exclusively in males, leading to a surge in blood glucose levels. In agreement, RNA-sequencing of microglia reveals increased expression of genes associated with immune response and NF-κB signaling. Selective ablation of IKKβ in immune cells (Cx3cr1GFPΔIKK) or exclusively in microglia (Tmem119ERΔIKK) in adult mice alleviated benzene-induced gliosis, restored energy homeostasis, hypothalamic gene expression, and protected against hyperglycemia. We conclude that the microglial NF-κB pathway plays a critical role in chemical-induced metabolic disturbances, revealing a vital pathophysiological mechanism linking exposure to airborne toxicants and the onset of metabolic diseases.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321251","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

Podocyte-Specific Expression of the Stress Response Protein REDD1 is Necessary for Diabetes-induced Podocytopenia 应激反应蛋白 REDD1 在荚膜细胞中的特异性表达是糖尿病诱导的荚膜细胞减少症的必要条件

IF 7.7 1区医学

Diabetes Pub Date : 2024-09-25 DOI: 10.2337/db24-0533

Siddharth Sunilkumar, Esma I. Yerlikaya, Allyson L. Toro, Han Chen, Yandong Zhou, Donald L. Gill, Scot R. Kimball, Michael D. Dennis

{"title":"Podocyte-Specific Expression of the Stress Response Protein REDD1 is Necessary for Diabetes-induced Podocytopenia","authors":"Siddharth Sunilkumar, Esma I. Yerlikaya, Allyson L. Toro, Han Chen, Yandong Zhou, Donald L. Gill, Scot R. Kimball, Michael D. Dennis","doi":"10.2337/db24-0533","DOIUrl":"https://doi.org/10.2337/db24-0533","url":null,"abstract":"Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and effective treatment modalities that fully address its molecular etiology are lacking. Prior studies support that the stress response protein REDD1 (Regulated in Development and DNA Damage 1) contributes to the development of diabetic complications. This study investigated a potential role for REDD1 expression in podocytes in diabetes-induced podocyte loss and compromised glomerular filtration. Podocyte-specific REDD1 deletion protected against renal injury, as evidenced by reduced albuminuria, glomerular hypertrophy, and mesangial matrix deposition in streptozotocin (STZ)-induced diabetic mice. Podocyte-specific REDD1 expression was required for diabetes-induced reduction in slit diaphragm (SD) proteins podocin and nephrin. Notably, podocyte-specific REDD1 deletion protected against podocytopenia and preserved glomerular basement membrane and foot process architecture in diabetic mice. In the kidneys of diabetic mice and in human podocyte cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the transient receptor potential canonical 6 (TRPC6) channel. More specifically, REDD1 promoted NF-κB-dependent transcription of TRPC6, intracellular calcium entry, and cytoskeletal remodeling under hyperglycemic conditions. Overall, the findings provide new insight into the role of podocyte-specific REDD1 expression in renal pathology and support the possibility that therapeutics targeting REDD1 in podocytes could be beneficial for DN.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321252","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