Carolina Solis-Herrera, Yuejuan Qin, Henri Honka, Eugenio Cersosimo, Curtis Triplitt, Sivaram Neppala, Jemena Rajan, Francisca M. Acosta, Alexander J. Moody, Patricio Iozzo, Peter Fox, Geoffrey Clarke, Ralph A. DeFronzo
We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction ≤50% received incremental infusions of β-OH-B for 3-6 hours to raise plasma β-OH-B concentration throughout the physiologic (Groups I and II) and pharmacologic (Group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, Group II also received NaHCO3 infusion, thus serving as their own control for time, volume, and pH. Additionally, Group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, III achieved plasma β-OH-B levels of 0.7±0.3, 1.6±0.2, 3.2±0.2 mmol/L, respectively. Cardiac output, LVEF, and stroke volume increased significantly during β-OH-B infusion in Groups II (CO, 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4) and did not change with NaHCO3 infusion in Group II. The increase in LVEF was greatest in Group III (p<0.001 vs Group II). MGU and MBF were not altered by β-OH-B. In T2DM patients with LVEF≤50%, increased plasma β-OH-B significantly increased LV function dose-dependently. Since MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU.
{"title":"Effect of Hyperketonemia on Myocardial Function in Patients with Heart Failure and Type 2 Diabetes","authors":"Carolina Solis-Herrera, Yuejuan Qin, Henri Honka, Eugenio Cersosimo, Curtis Triplitt, Sivaram Neppala, Jemena Rajan, Francisca M. Acosta, Alexander J. Moody, Patricio Iozzo, Peter Fox, Geoffrey Clarke, Ralph A. DeFronzo","doi":"10.2337/db24-0406","DOIUrl":"https://doi.org/10.2337/db24-0406","url":null,"abstract":"We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction ≤50% received incremental infusions of β-OH-B for 3-6 hours to raise plasma β-OH-B concentration throughout the physiologic (Groups I and II) and pharmacologic (Group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, Group II also received NaHCO3 infusion, thus serving as their own control for time, volume, and pH. Additionally, Group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, III achieved plasma β-OH-B levels of 0.7±0.3, 1.6±0.2, 3.2±0.2 mmol/L, respectively. Cardiac output, LVEF, and stroke volume increased significantly during β-OH-B infusion in Groups II (CO, 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4) and did not change with NaHCO3 infusion in Group II. The increase in LVEF was greatest in Group III (p&lt;0.001 vs Group II). MGU and MBF were not altered by β-OH-B. In T2DM patients with LVEF≤50%, increased plasma β-OH-B significantly increased LV function dose-dependently. Since MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"97 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489740","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}
Lin Cong, Benxiang Qi, Shijiu Chen, Ruiling Liu, Suxia Li, Qingjun Zhou, Yihai Cao, Bi Ning Zhang, Lixin Xie
Diabetic keratopathy (DK) is a common chronic metabolic disorder that causes ocular surface complications. Among various therapeutic approaches, local delivery of nerve growth factor (NGF) remains the most effective treatment for DK. However, achieving a sustained therapeutic effect with NGF and the frequent drug delivery burden remain challenging during clinical practice. Here, we developed a novel adeno-associated virus (AAV)-based NGF delivery system that achieved one-year-long-lasting effects by a single injection. We refined the corneal stromal injection technique, resulting in reduced corneal edema and improved AAV distribution homogeneity. AAV serotype AAV.rh10 exhibited high tropism and specificity to corneal nerves. A dose of 2×109 vector genomes (vg) was determined to achieve efficient Ngf gene expression without inducing corneal immune responses. Moreover, NGF protein was highly expressed in trigeminal ganglion (TG) through a retrograde transport mechanism, indicating the capacity for repairing corneal nerve damage both at the root and corneal nerve endings. In a mouse DK model, a single injection of AAV-Ngf into the corneal stroma led to marked corneal nerve regeneration for over 5 months. Together, we provide a novel therapeutic paradigm for long-term effective treatment of DK and this therapeutic approach is superior to current DK therapies.
{"title":"Long-term nerve regeneration in diabetic keratopathy mediated by a novel NGF delivery system","authors":"Lin Cong, Benxiang Qi, Shijiu Chen, Ruiling Liu, Suxia Li, Qingjun Zhou, Yihai Cao, Bi Ning Zhang, Lixin Xie","doi":"10.2337/db24-0393","DOIUrl":"https://doi.org/10.2337/db24-0393","url":null,"abstract":"Diabetic keratopathy (DK) is a common chronic metabolic disorder that causes ocular surface complications. Among various therapeutic approaches, local delivery of nerve growth factor (NGF) remains the most effective treatment for DK. However, achieving a sustained therapeutic effect with NGF and the frequent drug delivery burden remain challenging during clinical practice. Here, we developed a novel adeno-associated virus (AAV)-based NGF delivery system that achieved one-year-long-lasting effects by a single injection. We refined the corneal stromal injection technique, resulting in reduced corneal edema and improved AAV distribution homogeneity. AAV serotype AAV.rh10 exhibited high tropism and specificity to corneal nerves. A dose of 2×109 vector genomes (vg) was determined to achieve efficient Ngf gene expression without inducing corneal immune responses. Moreover, NGF protein was highly expressed in trigeminal ganglion (TG) through a retrograde transport mechanism, indicating the capacity for repairing corneal nerve damage both at the root and corneal nerve endings. In a mouse DK model, a single injection of AAV-Ngf into the corneal stroma led to marked corneal nerve regeneration for over 5 months. Together, we provide a novel therapeutic paradigm for long-term effective treatment of DK and this therapeutic approach is superior to current DK therapies.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"14 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489738","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}
Cheng-Hui Lin, Man-Ru Wu, Bogdan Tanasa, Praveen Prakhar, Boxiong Deng, Alexander E. Davis, Liang Li, Alexander Xia, Yang Shan, Patrice E. Fort, Sui Wang
Diabetes can lead to cell-type-specific responses in the retina, including vascular lesions, glial dysfunction and neurodegeneration, all of which contribute to retinopathy. However, the molecular mechanisms underlying these cell type-specific responses, and the cell types that are sensitive to diabetes have not been fully elucidated. Employing single cell transcriptomics, we profiled the transcriptional changes induced by diabetes in different retinal cell types in rat models as the disease progressed. Rod photoreceptors, a subtype of amacrine interneurons, and Müller glia exhibited rapid responses to diabetes at the transcript levels. Genes associated with ion regulation were upregulated in all three cell types, suggesting a common response to diabetes. Furthermore, focused studies revealed that while Müller glia initially increased the expression of genes playing protective roles, they cannot sustain this beneficial effect. We explored one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), and observed that depleting Zfp36 in rat Müller glial cells in vivo using AAV-based tools exacerbated diabetes-induced phenotypes, including glial reactivation, neurodegeneration, and vascular defects. Over-expression of Zfp36 slowed the development of these phenotypes. This work unveiled retinal cell types that are sensitive to diabetes and demonstrated that Müller glial cells can mount protective responses through Zfp36.
{"title":"Induction of a Müller glial-specific protective pathway safeguards the retina from diabetes induced damage","authors":"Cheng-Hui Lin, Man-Ru Wu, Bogdan Tanasa, Praveen Prakhar, Boxiong Deng, Alexander E. Davis, Liang Li, Alexander Xia, Yang Shan, Patrice E. Fort, Sui Wang","doi":"10.2337/db24-0199","DOIUrl":"https://doi.org/10.2337/db24-0199","url":null,"abstract":"Diabetes can lead to cell-type-specific responses in the retina, including vascular lesions, glial dysfunction and neurodegeneration, all of which contribute to retinopathy. However, the molecular mechanisms underlying these cell type-specific responses, and the cell types that are sensitive to diabetes have not been fully elucidated. Employing single cell transcriptomics, we profiled the transcriptional changes induced by diabetes in different retinal cell types in rat models as the disease progressed. Rod photoreceptors, a subtype of amacrine interneurons, and Müller glia exhibited rapid responses to diabetes at the transcript levels. Genes associated with ion regulation were upregulated in all three cell types, suggesting a common response to diabetes. Furthermore, focused studies revealed that while Müller glia initially increased the expression of genes playing protective roles, they cannot sustain this beneficial effect. We explored one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), and observed that depleting Zfp36 in rat Müller glial cells in vivo using AAV-based tools exacerbated diabetes-induced phenotypes, including glial reactivation, neurodegeneration, and vascular defects. Over-expression of Zfp36 slowed the development of these phenotypes. This work unveiled retinal cell types that are sensitive to diabetes and demonstrated that Müller glial cells can mount protective responses through Zfp36.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"1 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489449","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}
Hossam Montaser, Sonja Leppänen, Eliisa Vähäkangas, Nils Bäck, Alicia Grace, Solja Eurola, Hazem Ibrahim, Väinö Lithovius, Samuel B. Stephens, Tom Barsby, Diego Balboa, Jonna Saarimäki-Vire, Timo Otonkoski
Immediate early response 3 interacting-protein 1 (IER3IP1) is an endoplasmic reticulum resident protein, highly expressed in pancreatic cells and the developing brain cortex. Homozygous mutations in IER3IP1 have been found in individuals with microcephaly and neonatal diabetes, yet the underlying mechanism causing beta cell failure remains unclear. Here, we utilized differentiation of genome edited-stem cells into pancreatic islet cells to elucidate the molecular basis of IER3IP1 neonatal diabetes. Using CRISPR-Cas9, we generated two distinct IER3IP1-mutant human embryonic stem cell lines: a homozygous knock-in model of a patient mutation (IER3IP1V21G), and a knockout model (IER3IP1-/-). While these mutant stem cell lines differentiated normally into definitive endoderm and pancreatic progenitors, we observed that IER3IP1-KO stem cell derived-islets (SC-islets) presented a significant decrease in beta cell numbers and elevated ER stress. Retention Using Selective Hooks (RUSH) assay revealed three-fold reduction in ER-to-Golgi trafficking of proinsulin in IER3IP1 mutant beta cells. Additionally, IER3IP1 mutant SC-islets implanted into immunocompromised mice displayed defective human insulin secretion, indicating the deleterious impact of IER3IP1 mutations on beta cell function. Our study provides valuable insights into the role of IER3IP1 in human beta cell biology and establishes a useful model to investigate ER-to-Golgi trafficking defects within beta cells.
{"title":"IER3IP1 mutations cause neonatal diabetes due to impaired proinsulin trafficking","authors":"Hossam Montaser, Sonja Leppänen, Eliisa Vähäkangas, Nils Bäck, Alicia Grace, Solja Eurola, Hazem Ibrahim, Väinö Lithovius, Samuel B. Stephens, Tom Barsby, Diego Balboa, Jonna Saarimäki-Vire, Timo Otonkoski","doi":"10.2337/db24-0119","DOIUrl":"https://doi.org/10.2337/db24-0119","url":null,"abstract":"Immediate early response 3 interacting-protein 1 (IER3IP1) is an endoplasmic reticulum resident protein, highly expressed in pancreatic cells and the developing brain cortex. Homozygous mutations in IER3IP1 have been found in individuals with microcephaly and neonatal diabetes, yet the underlying mechanism causing beta cell failure remains unclear. Here, we utilized differentiation of genome edited-stem cells into pancreatic islet cells to elucidate the molecular basis of IER3IP1 neonatal diabetes. Using CRISPR-Cas9, we generated two distinct IER3IP1-mutant human embryonic stem cell lines: a homozygous knock-in model of a patient mutation (IER3IP1V21G), and a knockout model (IER3IP1-/-). While these mutant stem cell lines differentiated normally into definitive endoderm and pancreatic progenitors, we observed that IER3IP1-KO stem cell derived-islets (SC-islets) presented a significant decrease in beta cell numbers and elevated ER stress. Retention Using Selective Hooks (RUSH) assay revealed three-fold reduction in ER-to-Golgi trafficking of proinsulin in IER3IP1 mutant beta cells. Additionally, IER3IP1 mutant SC-islets implanted into immunocompromised mice displayed defective human insulin secretion, indicating the deleterious impact of IER3IP1 mutations on beta cell function. Our study provides valuable insights into the role of IER3IP1 in human beta cell biology and establishes a useful model to investigate ER-to-Golgi trafficking defects within beta cells.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488380","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}
Xing Xing, Siqi Xu, Yining Wang, Ziyuan Shen, Simin Wen, Yan Zhang, Guangfeng Ruan, Guoqi Cai
Exploring the mechanisms underlying abnormal glycemic traits is important for deciphering type 2 diabetes and characterizing novel drug targets. This study aimed to decipher the causal associations of circulating proteins with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) using large-scale proteome-wide Mendelian randomization (MR) analyses. Genetic data on plasma proteomes were obtained from ten proteomic genome-wide association studies (GWAS). Both cis- and cis+trans-protein quantitative trait loci (pQTLs) MR analyses were conducted. Bayesian colocalization, Steiger filtering analysis, assessment of protein-altering variants, and mapping expression quantitative trait loci to protein quantitative trait loci were performed to investigate the reliability of the MR findings. Protein-protein interaction, pathway enrichment analysis, and evaluation of drug targets were performed. Thirty-three proteins were identified with causal effects on FG, FI, or HbA1c but not 2hGlu in the cis-pQTLs analysis, and 93 proteins had causal effects on glycemic traits in the cis+trans-pQTLs analysis. Most proteins were either considered druggable or drug targets. In conclusion, many novel circulating protein biomarkers were identified to be causally associated with glycemic traits. These biomarkers enhance the understanding of molecular etiology and provide insights into the screening, monitoring, and treatment of diabetes.
{"title":"Evaluating the causal effect of circulating proteome on the glycemic traits: Evidence from Mendelian randomization","authors":"Xing Xing, Siqi Xu, Yining Wang, Ziyuan Shen, Simin Wen, Yan Zhang, Guangfeng Ruan, Guoqi Cai","doi":"10.2337/db24-0262","DOIUrl":"https://doi.org/10.2337/db24-0262","url":null,"abstract":"Exploring the mechanisms underlying abnormal glycemic traits is important for deciphering type 2 diabetes and characterizing novel drug targets. This study aimed to decipher the causal associations of circulating proteins with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) using large-scale proteome-wide Mendelian randomization (MR) analyses. Genetic data on plasma proteomes were obtained from ten proteomic genome-wide association studies (GWAS). Both cis- and cis+trans-protein quantitative trait loci (pQTLs) MR analyses were conducted. Bayesian colocalization, Steiger filtering analysis, assessment of protein-altering variants, and mapping expression quantitative trait loci to protein quantitative trait loci were performed to investigate the reliability of the MR findings. Protein-protein interaction, pathway enrichment analysis, and evaluation of drug targets were performed. Thirty-three proteins were identified with causal effects on FG, FI, or HbA1c but not 2hGlu in the cis-pQTLs analysis, and 93 proteins had causal effects on glycemic traits in the cis+trans-pQTLs analysis. Most proteins were either considered druggable or drug targets. In conclusion, many novel circulating protein biomarkers were identified to be causally associated with glycemic traits. These biomarkers enhance the understanding of molecular etiology and provide insights into the screening, monitoring, and treatment of diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"11 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448207","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}
Daniel B. Rosoff, Josephin Wagner, Jeesun Jung, Pal Pacher, Constantinos Christodoulides, George Davey Smith, David Ray, Falk W. Lohoff
The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10−12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10−10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10−4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.
{"title":"Multi-Omics Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations","authors":"Daniel B. Rosoff, Josephin Wagner, Jeesun Jung, Pal Pacher, Constantinos Christodoulides, George Davey Smith, David Ray, Falk W. Lohoff","doi":"10.2337/db24-0451","DOIUrl":"https://doi.org/10.2337/db24-0451","url":null,"abstract":"The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10−12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10−10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10−4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"232 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448158","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}
Daniel Schwarz, Maxime Le Marois, Volker Sturm, Andreas S. Peters, Rémi Longuespée, Dominic Helm, Martin Schneider, Bastian Eichmüller, Asa S. Hidmark, Manuel Fischer, Zoltan Kender, Constantin Schwab, Ingrid Hausser, Joachim Weis, Susanna Dihlmann, Dittmar Böckler, Martin Bendszus, Sabine Heiland, Stephan Herzig, Peter P. Nawroth, Julia Szendroedi, Thomas Fleming
Lesioned fascicles (LF) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging, and proteomic analysis. Lesions were only found in T2D donors and exhibited significant structural abnormalities, including axonal degeneration, demyelination, and impaired blood nerve barrier (BNB). While non-lesioned fascicles from T2D donors showed activation of neuroprotective pathways, lesioned fascicles lacked this response and instead displayed increased complement activation via the classical pathway. The detection of liver-derived acute-phase proteins suggests that BNB disruption facilitates harmful inter-organ communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention.
{"title":"Exploring Structural and Molecular Features of Sciatic Nerve Lesions in Diabetic Neuropathy: Unveiling Pathogenic Pathways and Targets","authors":"Daniel Schwarz, Maxime Le Marois, Volker Sturm, Andreas S. Peters, Rémi Longuespée, Dominic Helm, Martin Schneider, Bastian Eichmüller, Asa S. Hidmark, Manuel Fischer, Zoltan Kender, Constantin Schwab, Ingrid Hausser, Joachim Weis, Susanna Dihlmann, Dittmar Böckler, Martin Bendszus, Sabine Heiland, Stephan Herzig, Peter P. Nawroth, Julia Szendroedi, Thomas Fleming","doi":"10.2337/db24-0493","DOIUrl":"https://doi.org/10.2337/db24-0493","url":null,"abstract":"Lesioned fascicles (LF) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging, and proteomic analysis. Lesions were only found in T2D donors and exhibited significant structural abnormalities, including axonal degeneration, demyelination, and impaired blood nerve barrier (BNB). While non-lesioned fascicles from T2D donors showed activation of neuroprotective pathways, lesioned fascicles lacked this response and instead displayed increased complement activation via the classical pathway. The detection of liver-derived acute-phase proteins suggests that BNB disruption facilitates harmful inter-organ communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"232 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448106","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 Ventromedial hypothalamic nucleus (VMN) maintains healthy metabolic function through several important roles. Collectively, homeostasis is maintained via intermingled cells within the VMN that raise blood glucose, lower blood glucose, and stimulate energy expenditure when needed. This perspective discusses the defining factors for the VMN cell types that govern distinct functions induced by the VMN, particularly in relation to energy balance and blood glucose levels. Special attention is given to distinct features of VMN cells responsible for these processes. Finally, these topics are reviewed in the context of research funded by the Pathway to Stop Diabetes initiative, highlighting key findings and current unresolved questions for future investigations.
{"title":"Functionally Separate Populations of Ventromedial Hypothalamic Neurons in Obesity and Diabetes","authors":"Jonathan N. Flak","doi":"10.2337/dbi24-0011","DOIUrl":"https://doi.org/10.2337/dbi24-0011","url":null,"abstract":"The Ventromedial hypothalamic nucleus (VMN) maintains healthy metabolic function through several important roles. Collectively, homeostasis is maintained via intermingled cells within the VMN that raise blood glucose, lower blood glucose, and stimulate energy expenditure when needed. This perspective discusses the defining factors for the VMN cell types that govern distinct functions induced by the VMN, particularly in relation to energy balance and blood glucose levels. Special attention is given to distinct features of VMN cells responsible for these processes. Finally, these topics are reviewed in the context of research funded by the Pathway to Stop Diabetes initiative, highlighting key findings and current unresolved questions for future investigations.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"31 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448202","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}
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
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 < 5.7%, 5.7-6.4%, 6.5-7.0%, 7.1-8.0%, and >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 <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 >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 <5.7% is worthy for CVD prevention.
{"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":"2021 1","pages":""},"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}
Jingyi Lu, Jiaying Ni, Hang Su, Xingxing He, Wei Lu, Wei Zhu, Yufei Wang, Xiaojing Ma, Yuqian Bao, Jian Zhou
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 < 8.6 mmol/L and 2 h < 7.8 mmol/L (normal glucose tolerance [NGT] /1h-normal); 2) 1 h ≥ 8.6 mmol/L and 2 h < 7.8 mmol/L (NGT/1h-high); 3) 1 h < 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
{"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":"24 1","pages":""},"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}
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