Sebastià Alcover, Sergi López, Lisaidy Ramos, Natàlia Muñoz-García, Alex Gallinat, Rosa Suades, Lina Badimon, Gemma Vilahur
Diabetic patients are at an increased risk of diabetic cardiomyopathy (DCM) and acute myocardial infarction (AMI). Protecting the heart against AMI is more challenging in DCM than non-diabetic hearts. We investigated whether intravenous atorvastatin administration during AMI exerts cardioprotection in DCM as seen in non-diabetic hearts. Sprague-Dawley rats were divided into streptozotocin-induced DCM and normoglycemic-control groups. Our model of DCM rats exhibited interstitial fibrosis and cardiac dysfunction at 5 weeks. At this time point, all animals underwent AMI-induction (coronary ligation for 45min), receiving intravenous atorvastatin or vehicle during ischemia. Animals were reperfused and sacrificed 24h later for myocardial infarct size analysis and cardiac tissue sampling. Echocardiography was performed. DCM vehicle rats had larger infarcts than normoglycemic vehicle-treated animals at comparable area-at-risk. Intravenous atorvastatin reduced infarct size and preserved systolic function in both groups. In comparison to vehicle animals, intravenous atorvastatin inhibited RhoA membrane translocation, induced AMPK phosphorylation, prevented apoptosis execution and improved cardiac remodelling in the infarcted heart of both groups whereas innate immune cell infiltration was further reduced in intravenous atorvastatin-treated DCM animals. The proven cardioprotective effectiveness of this intravenous statin formulation in the presence of DCM warrants its further development into a clinically therapeutic option.
{"title":"Cardioprotection during myocardial infarction in diabetic cardiomyopathy","authors":"Sebastià Alcover, Sergi López, Lisaidy Ramos, Natàlia Muñoz-García, Alex Gallinat, Rosa Suades, Lina Badimon, Gemma Vilahur","doi":"10.2337/db24-0510","DOIUrl":"https://doi.org/10.2337/db24-0510","url":null,"abstract":"Diabetic patients are at an increased risk of diabetic cardiomyopathy (DCM) and acute myocardial infarction (AMI). Protecting the heart against AMI is more challenging in DCM than non-diabetic hearts. We investigated whether intravenous atorvastatin administration during AMI exerts cardioprotection in DCM as seen in non-diabetic hearts. Sprague-Dawley rats were divided into streptozotocin-induced DCM and normoglycemic-control groups. Our model of DCM rats exhibited interstitial fibrosis and cardiac dysfunction at 5 weeks. At this time point, all animals underwent AMI-induction (coronary ligation for 45min), receiving intravenous atorvastatin or vehicle during ischemia. Animals were reperfused and sacrificed 24h later for myocardial infarct size analysis and cardiac tissue sampling. Echocardiography was performed. DCM vehicle rats had larger infarcts than normoglycemic vehicle-treated animals at comparable area-at-risk. Intravenous atorvastatin reduced infarct size and preserved systolic function in both groups. In comparison to vehicle animals, intravenous atorvastatin inhibited RhoA membrane translocation, induced AMPK phosphorylation, prevented apoptosis execution and improved cardiac remodelling in the infarcted heart of both groups whereas innate immune cell infiltration was further reduced in intravenous atorvastatin-treated DCM animals. The proven cardioprotective effectiveness of this intravenous statin formulation in the presence of DCM warrants its further development into a clinically therapeutic option.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"9 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618419","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}
Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular crosstalk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we employed single-cell analytical approaches to investigate cell-tocell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLSs), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported Lipid-associated macrophages (LAMs), we found a small subcluster expressing Macrophage-inducible C-type lectin (Mincle), specifically localizing to CLSs. Mincle signaling increased the expression of Oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm-deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, Osm expression was positively correlated with Mincle expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLSs.
{"title":"Novel cell-to-cell communications between macrophages and fibroblasts regulate obesity-induced adipose tissue fibrosis","authors":"Hiro Kohda, Miyako Tanaka, Shigeyuki Shichino, Satoko Arakawa, Tadasuke Komori, Ayaka Ito, Eri Wada, Kozue Ochi, Xunmei Yuan, Takehiko Takeda, Atsuhito Saiki, Ichiro Tatsuno, Kenji Ikeda, Yuki Miyai, Atsushi Enomoto, Yoshihiro Morikawa, Shigeomi Shimizu, Satoshi Ueha, Kouji Matsushima, Yoshihiro Ogawa, Takayoshi Suganami","doi":"10.2337/db24-0762","DOIUrl":"https://doi.org/10.2337/db24-0762","url":null,"abstract":"Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular crosstalk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we employed single-cell analytical approaches to investigate cell-tocell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLSs), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported Lipid-associated macrophages (LAMs), we found a small subcluster expressing Macrophage-inducible C-type lectin (Mincle), specifically localizing to CLSs. Mincle signaling increased the expression of Oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm-deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, Osm expression was positively correlated with Mincle expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLSs.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"14 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143590212","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}
Pouria Akhbari, Javier Perez-Hernandez, Mark A. Russell, Shalinee Dhayal, K. Afi Leslie, Stephanie L. Hunter, Kathryn Murrall, Alexia Carré, Noel G. Morgan, Roberto Mallone, Sarah J. Richardson
HLA class I (HLA-I) molecules present intracellular antigenic peptides to CD8+ T lymphocytes during immune surveillance. In donors with type 1 diabetes, hyperexpression of HLA-I occurs in islets with residual insulin-producing β-cells as a hallmark of the disease. HLA-I hyperexpression is frequently detected beyond the islet boundary, forming a ‘halo’. We hypothesized that this halo may reflect the diffusion of soluble forms of HLA-I (sHLA-I) from the islets to the surrounding pancreatic parenchyma. To verify this, we assessed the expression of total, cell surface and sHLA-I in β-cell lines and isolated human islets, following treatment with interferons (IFN)-α and IFN-γ. Consistent with the expression patterns of HLA-I in situ, both β-cell lines and cultured human islets dramatically upregulated total and surface HLA-I when exposed to IFNs. Concomitantly, sHLA-I release was significantly increased. HLA-I released within extracellular vesicles and cleaved forms of HLA-I did not significantly contribute to the sHLA-I pool. Rather, IFNs upregulated mRNA splice variants lacking the transmembrane domain. Our findings suggest that β-cells respond to IFNs by upregulating cellassociated and soluble forms of HLA-I. Soluble HLA-I may play a role in modulating islet inflammation during the autoimmune attack.
{"title":"Soluble HLA class I is released from human β-cells following exposure to interferons","authors":"Pouria Akhbari, Javier Perez-Hernandez, Mark A. Russell, Shalinee Dhayal, K. Afi Leslie, Stephanie L. Hunter, Kathryn Murrall, Alexia Carré, Noel G. Morgan, Roberto Mallone, Sarah J. Richardson","doi":"10.2337/db24-0827","DOIUrl":"https://doi.org/10.2337/db24-0827","url":null,"abstract":"HLA class I (HLA-I) molecules present intracellular antigenic peptides to CD8+ T lymphocytes during immune surveillance. In donors with type 1 diabetes, hyperexpression of HLA-I occurs in islets with residual insulin-producing β-cells as a hallmark of the disease. HLA-I hyperexpression is frequently detected beyond the islet boundary, forming a ‘halo’. We hypothesized that this halo may reflect the diffusion of soluble forms of HLA-I (sHLA-I) from the islets to the surrounding pancreatic parenchyma. To verify this, we assessed the expression of total, cell surface and sHLA-I in β-cell lines and isolated human islets, following treatment with interferons (IFN)-α and IFN-γ. Consistent with the expression patterns of HLA-I in situ, both β-cell lines and cultured human islets dramatically upregulated total and surface HLA-I when exposed to IFNs. Concomitantly, sHLA-I release was significantly increased. HLA-I released within extracellular vesicles and cleaved forms of HLA-I did not significantly contribute to the sHLA-I pool. Rather, IFNs upregulated mRNA splice variants lacking the transmembrane domain. Our findings suggest that β-cells respond to IFNs by upregulating cellassociated and soluble forms of HLA-I. Soluble HLA-I may play a role in modulating islet inflammation during the autoimmune attack.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"36 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143590276","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}
Taylor K. Watson, Aaron B.I. Rosen, Travis Drow, Jacob A. Medjo, Matthew A. MacQuivey, Yan Ge, H. Denny Liggitt, Dane A. Grosvenor, Kimberly A. Dill-McFarland, Matthew C. Altman, Patrick J. Concannon, Jane H. Buckner, David J. Rawlings, Eric J. Allenspach
Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D. Fine mapping has demonstrated the most credible causative variant is the single nucleotide rs3184504*T polymorphism in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cellintrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient naïve CD8+ T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival and reduced activation-induced cell death. Lastly, we created a spontaneous NOD.Sh2b3-/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens.
{"title":"Reduced function of the adaptor SH2B3 promotes T1D via altered cytokine-regulated, T cell intrinsic immune tolerance","authors":"Taylor K. Watson, Aaron B.I. Rosen, Travis Drow, Jacob A. Medjo, Matthew A. MacQuivey, Yan Ge, H. Denny Liggitt, Dane A. Grosvenor, Kimberly A. Dill-McFarland, Matthew C. Altman, Patrick J. Concannon, Jane H. Buckner, David J. Rawlings, Eric J. Allenspach","doi":"10.2337/db24-0655","DOIUrl":"https://doi.org/10.2337/db24-0655","url":null,"abstract":"Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D. Fine mapping has demonstrated the most credible causative variant is the single nucleotide rs3184504*T polymorphism in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cellintrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient naïve CD8+ T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival and reduced activation-induced cell death. Lastly, we created a spontaneous NOD.Sh2b3-/- mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"30 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143570350","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}
Jeongmin Lee, Alessandro Ustione, Emily M Wilkerson, Rekha Balakrishnan, Debbie C. Thurmond, Dennis Goldfarb, David W. Piston
Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrate the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D model, nonobese diabetic (NOD) mice, by suppressing glucagon secretion. This fraction promotes white adipocyte differentiation and browning, maintains healthy BAT, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. We identify nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. Secretions from a BAT cell line with siRNA knockdown of nidogen-2 fail to inhibit glucagon secretion and restore euglycemia. These findings demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2, beyond its traditional classification as an extracellular matrix protein.
{"title":"Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2","authors":"Jeongmin Lee, Alessandro Ustione, Emily M Wilkerson, Rekha Balakrishnan, Debbie C. Thurmond, Dennis Goldfarb, David W. Piston","doi":"10.2337/db24-1003","DOIUrl":"https://doi.org/10.2337/db24-1003","url":null,"abstract":"Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrate the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D model, nonobese diabetic (NOD) mice, by suppressing glucagon secretion. This fraction promotes white adipocyte differentiation and browning, maintains healthy BAT, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. We identify nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. Secretions from a BAT cell line with siRNA knockdown of nidogen-2 fail to inhibit glucagon secretion and restore euglycemia. These findings demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2, beyond its traditional classification as an extracellular matrix protein.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"40 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538392","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}
Ella A. Thomson, Sooyeon Lee, Haixia Xu, Hannah Moeller, Joanna Sands, Rayhan A. Lal, Justin P. Annes, Ada S. Y. Poon
Cadaveric islet and stem cell-derived transplantation hold promise as treatments for type 1 diabetes (T1D). To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques that utilize diffusion to transport insulin across an immunoisolating barrier have been developed. However, despite several devices progressing to human clinical trials, none have successfully attained physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with on-demand insulin delivery and physiologic glucose regulation, when solely reliant on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical evidence and experimental validation that applying pressure, at levels comparable to physiological diastolic blood pressure, significantly enhances insulin flux across immunoisolation membranes—increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pumpbased extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation.
{"title":"Intermittent Low-Magnitude Pressure Applied Across Macroencapsulation Devices Enables Physiological Insulin Delivery Dynamics","authors":"Ella A. Thomson, Sooyeon Lee, Haixia Xu, Hannah Moeller, Joanna Sands, Rayhan A. Lal, Justin P. Annes, Ada S. Y. Poon","doi":"10.2337/db24-0818","DOIUrl":"https://doi.org/10.2337/db24-0818","url":null,"abstract":"Cadaveric islet and stem cell-derived transplantation hold promise as treatments for type 1 diabetes (T1D). To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques that utilize diffusion to transport insulin across an immunoisolating barrier have been developed. However, despite several devices progressing to human clinical trials, none have successfully attained physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with on-demand insulin delivery and physiologic glucose regulation, when solely reliant on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical evidence and experimental validation that applying pressure, at levels comparable to physiological diastolic blood pressure, significantly enhances insulin flux across immunoisolation membranes—increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pumpbased extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"34 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538391","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}
Diabetic peripheral neuropathy (DPN) is a common diabetic complication with no currently available curative treatments. Here, we demonstrated that the protein level of G-protein-coupled receptor 40 (GPR40) is significantly repressed in the sciatic nerves (SN) of DPN patients, as well as in the peripheral nerves, including dorsal root ganglia (DRG) and SN, of streptozotocin (STZ)-induced type 1 diabetic mice and BKS Cg-m+/+Lepr db/J (db/db) type 2 diabetic mice. We identified that amlodipine besylate (AB), a first-line clinical antihypertensive drug, as a GPR40 agonist capable of alleviating DPN-like pathologies in mice. These pathologies include neurological damage, destruction of myelin sheath structures, vascular injury, loss of intraepidermal nerve fibers, and impaired neurite outgrowth in DRG neurons. To elucidate the underlying mechanisms, we generated the DPN mice with GPR40-specific knockdown in SN and DRG tissues using adeno associated virus 8-GPR40-RNAi. Mechanistically, AB attenuated inflammatory responses via the GPR40/β-arrestin2/NLRP3 pathway and ameliorated mitochondrial dysfunction through the GPR40/LKB1/AMPK/SIRT1/PGC-1α pathway in DPN mice, which were all further validated in primary human Schwann cells. Additionally, AB suppressed the crosstalk between Schwann cells and endothelial cells /DRG neurons in DPN mice. Collectively, our findings highlight the potential of AB for the treatment of DPN.
{"title":"Antihypertensive drug amlodipine besylate shows potential in alleviating diabetic peripheral neuropathy","authors":"Yuxi Wei, Yujie Huang, Runzhi Huang, Yuan Ruan, Tian Feng, Fan Zhou, Wei Zhang, Jianyu Lu, Sujie Xie, Yuntao Yao, Jiaying Wang, Shizhao Ji, Xu Shen","doi":"10.2337/db24-0403","DOIUrl":"https://doi.org/10.2337/db24-0403","url":null,"abstract":"Diabetic peripheral neuropathy (DPN) is a common diabetic complication with no currently available curative treatments. Here, we demonstrated that the protein level of G-protein-coupled receptor 40 (GPR40) is significantly repressed in the sciatic nerves (SN) of DPN patients, as well as in the peripheral nerves, including dorsal root ganglia (DRG) and SN, of streptozotocin (STZ)-induced type 1 diabetic mice and BKS Cg-m+/+Lepr db/J (db/db) type 2 diabetic mice. We identified that amlodipine besylate (AB), a first-line clinical antihypertensive drug, as a GPR40 agonist capable of alleviating DPN-like pathologies in mice. These pathologies include neurological damage, destruction of myelin sheath structures, vascular injury, loss of intraepidermal nerve fibers, and impaired neurite outgrowth in DRG neurons. To elucidate the underlying mechanisms, we generated the DPN mice with GPR40-specific knockdown in SN and DRG tissues using adeno associated virus 8-GPR40-RNAi. Mechanistically, AB attenuated inflammatory responses via the GPR40/β-arrestin2/NLRP3 pathway and ameliorated mitochondrial dysfunction through the GPR40/LKB1/AMPK/SIRT1/PGC-1α pathway in DPN mice, which were all further validated in primary human Schwann cells. Additionally, AB suppressed the crosstalk between Schwann cells and endothelial cells /DRG neurons in DPN mice. Collectively, our findings highlight the potential of AB for the treatment of DPN.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"26 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526430","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}
The discovery and development of the radioimmunoassay (RIA) for insulin by Berson and Yalow fundamentally changed biomedical science. The story of this accomplishment began with the pairing of brilliant scientists with complementary expertise who identified a key gap in knowledge they were able to bridge through a series of insightful experiments. Through a succession of important publications over 5 years of work, Berson and Yalow refined the approach to a novel method to measure insulin and demonstrated the power of this method in convincing clinical studies. This culminated in 1960, with three independent papers introducing the insulin RIA and demonstrating the utility in measuring circulating insulin in healthy and diseased states. Two of these papers were published in Diabetes—classics that are revisited here.
{"title":"Development of the Insulin Radioimmunoassay, the Watershed Moment in Diabetes Research: Revisiting 1960 Diabetes Classics by Berson and Yalow","authors":"David A. D’Alessio","doi":"10.2337/dbi24-0055","DOIUrl":"https://doi.org/10.2337/dbi24-0055","url":null,"abstract":"The discovery and development of the radioimmunoassay (RIA) for insulin by Berson and Yalow fundamentally changed biomedical science. The story of this accomplishment began with the pairing of brilliant scientists with complementary expertise who identified a key gap in knowledge they were able to bridge through a series of insightful experiments. Through a succession of important publications over 5 years of work, Berson and Yalow refined the approach to a novel method to measure insulin and demonstrated the power of this method in convincing clinical studies. This culminated in 1960, with three independent papers introducing the insulin RIA and demonstrating the utility in measuring circulating insulin in healthy and diseased states. Two of these papers were published in Diabetes—classics that are revisited here.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"50 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462808","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}
Yingying Yu, Guoxiao Wang, Wenqiang Chen, Xiangyu Liu, Vitor Rosetto Munoz, Weikang Cai, Antonio S. Gomes, C. Ronald Kahn
Insulin regulates glucose uptake and metabolism in muscle via the insulin receptor. Here we show that Lrtm1 (Leucine Rich Repeats and Transmembrane Domains 1), a protein of unknown function enriched in insulin-responsive metabolic tissues, senses changes in insulin signaling in muscle and serves as a regulator of metabolic response. Thus, whole-body Lrtm1 deficient mice exhibit a reduced the percentage of fat mass, increased percentage of lean mass, and enhanced glucose tolerance and insulin sensitivity compared to control mice, under both chow and high fat diet conditions. Lrtm1 whole-body deficiency also affects dopamine signaling in the brain leading to hyperactivity. The improvements in glucose and insulin tolerance, but not the behavioral or body composition changes, are also observed in skeletal muscle-specific Lrtm1 knockout mice. These effects occur with no change in classical insulin receptor-Akt signaling Thus, Lrtm1 senses changes in insulin receptor signaling and serves as a novel post-receptor regulator of metabolic and behavioral activity.
{"title":"Lrtm1 - A Novel Sensor of Insulin Signaling and Regulator of Metabolism and Activity","authors":"Yingying Yu, Guoxiao Wang, Wenqiang Chen, Xiangyu Liu, Vitor Rosetto Munoz, Weikang Cai, Antonio S. Gomes, C. Ronald Kahn","doi":"10.2337/db24-1031","DOIUrl":"https://doi.org/10.2337/db24-1031","url":null,"abstract":"Insulin regulates glucose uptake and metabolism in muscle via the insulin receptor. Here we show that Lrtm1 (Leucine Rich Repeats and Transmembrane Domains 1), a protein of unknown function enriched in insulin-responsive metabolic tissues, senses changes in insulin signaling in muscle and serves as a regulator of metabolic response. Thus, whole-body Lrtm1 deficient mice exhibit a reduced the percentage of fat mass, increased percentage of lean mass, and enhanced glucose tolerance and insulin sensitivity compared to control mice, under both chow and high fat diet conditions. Lrtm1 whole-body deficiency also affects dopamine signaling in the brain leading to hyperactivity. The improvements in glucose and insulin tolerance, but not the behavioral or body composition changes, are also observed in skeletal muscle-specific Lrtm1 knockout mice. These effects occur with no change in classical insulin receptor-Akt signaling Thus, Lrtm1 senses changes in insulin receptor signaling and serves as a novel post-receptor regulator of metabolic and behavioral activity.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"142 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367375","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}
Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J. Simmons, Roland Stein, Christopher M. Adams, David A. Jacobson, Ken S. Lau, Qi Liu, Guoqiang Gu
Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient β-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for β-cell identity. Atf4-deficient β-cells down-regulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for β-cell identity and function under high glucose. But Atf4 activation paradoxically induces β-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect β-cells from metabolic stress-induced failure.
{"title":"Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid","authors":"Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J. Simmons, Roland Stein, Christopher M. Adams, David A. Jacobson, Ken S. Lau, Qi Liu, Guoqiang Gu","doi":"10.2337/db24-0360","DOIUrl":"https://doi.org/10.2337/db24-0360","url":null,"abstract":"Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient β-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for β-cell identity. Atf4-deficient β-cells down-regulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for β-cell identity and function under high glucose. But Atf4 activation paradoxically induces β-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect β-cells from metabolic stress-induced failure.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083440","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}
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