Sky T. H. Ng, Michael J. Price, Naomi Richardson, Maher Nawaf, Alastair Copland, Heather B. Streeter, Parth Narendran, David C. Wraith
Dysregulation and loss of immune tolerance towards pancreatic β-cell autoantigens are features of type 1 diabetes (T1D). Until recently, life-long insulin injection was the only approved treatment for T1D, and this does not address the underlying disease pathology. Antigen-specific immunotherapy (ASI) seeks to restore tolerance and holds potential as a new therapeutic strategy for treating autoimmune diseases with well characterised antigens. Peptide ASI using processing independent CD4+ T-cell epitopes (PIPs) shows promising results in several autoimmune diseases. Here we successfully applied the principles of PIP design to the T1D autoantigen glutamate decarboxylase 65 (GAD65). Peptides spanning GAD65 predicted to be pan-HLA-DR binding were selected. Peptide P10 displayed enriched responses in peripheral blood mononuclear cells from people with T1D. The minimal epitope of the P10 peptide was fine mapped using T-cell hybridomas generated from HLA-DRB1*04:01 transgenic mice. This minimal epitope, P10Sol, was demonstrated to induce tolerance to the parent peptide in HLA-DRB1*04:01 transgenic mice using a novel activation-induced marker assay. Finally, we show that GAD65 P10Sol PIP is recognised by CD4+ T-cells from people with T1D who possess a range of HLA-DR alleles and can, therefore, be defined as a pan-DR binding peptide with therapeutic potential.
对胰腺β细胞自身抗原的调节失调和免疫耐受丧失是1型糖尿病（T1D）的特征。直到最近，终生注射胰岛素仍是唯一获准治疗 T1D 的方法，但这并不能从根本上解决疾病的病理问题。抗原特异性免疫疗法（ASI）旨在恢复患者的耐受性，有望成为治疗自身免疫性疾病的新疗法。使用独立于加工的 CD4+ T 细胞表位（PIPs）的多肽 ASI 在多种自身免疫性疾病中显示出良好的效果。在这里，我们成功地将 PIP 设计原理应用于 T1D 自身抗原谷氨酸脱羧酶 65（GAD65）。我们筛选出了跨越 GAD65 的肽段，这些肽段被预测为具有泛 HLA-DR 结合力。肽 P10 在 T1D 患者的外周血单核细胞中显示出丰富的反应。使用 HLA-DRB1*04:01 转基因小鼠产生的 T 细胞杂交瘤对 P10 肽的最小表位进行了精细绘制。使用一种新型活化诱导标记物测定法证明，这种最小表位 P10Sol 能诱导 HLA-DRB1*04:01 转基因小鼠对母肽产生耐受性。最后，我们证明了 GAD65 P10Sol PIP 可被拥有一系列 HLA-DR 等位基因的 T1D 患者的 CD4+ T 细胞识别，因此可被定义为具有治疗潜力的泛 DR 结合肽。
{"title":"Pre-clinical development of a tolerogenic peptide from glutamate decarboxylase as a candidate for antigen-specific immunotherapy in type 1 diabetes","authors":"Sky T. H. Ng, Michael J. Price, Naomi Richardson, Maher Nawaf, Alastair Copland, Heather B. Streeter, Parth Narendran, David C. Wraith","doi":"10.2337/db23-0996","DOIUrl":"https://doi.org/10.2337/db23-0996","url":null,"abstract":"Dysregulation and loss of immune tolerance towards pancreatic β-cell autoantigens are features of type 1 diabetes (T1D). Until recently, life-long insulin injection was the only approved treatment for T1D, and this does not address the underlying disease pathology. Antigen-specific immunotherapy (ASI) seeks to restore tolerance and holds potential as a new therapeutic strategy for treating autoimmune diseases with well characterised antigens. Peptide ASI using processing independent CD4+ T-cell epitopes (PIPs) shows promising results in several autoimmune diseases. Here we successfully applied the principles of PIP design to the T1D autoantigen glutamate decarboxylase 65 (GAD65). Peptides spanning GAD65 predicted to be pan-HLA-DR binding were selected. Peptide P10 displayed enriched responses in peripheral blood mononuclear cells from people with T1D. The minimal epitope of the P10 peptide was fine mapped using T-cell hybridomas generated from HLA-DRB1*04:01 transgenic mice. This minimal epitope, P10Sol, was demonstrated to induce tolerance to the parent peptide in HLA-DRB1*04:01 transgenic mice using a novel activation-induced marker assay. Finally, we show that GAD65 P10Sol PIP is recognised by CD4+ T-cells from people with T1D who possess a range of HLA-DR alleles and can, therefore, be defined as a pan-DR binding peptide with therapeutic potential.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"66 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684150","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}
Eric L. Waite, Mark Tigue, Ming Yu, Deeksha Lahori, Kai Kelly, Catherine Lee May, Ali Naji, Jeffrey Roman, Nicolai Doliba, Dana Avrahami, Kim-Vy Nguyen-Ngoc, Maike Sander, Benjamin Glaser, Klaus H. Kaestner
The gold standard for assessing the function of human islets or β-like cells derived from stem cells involves their engraftment under the kidney capsule of hyperglycemic, immunodeficient mice. Current models, such as Streptozotocin (STZ) treatment of severely immunodeficient mice or the NRG-Akita strain are limited due to unstable and variable hyperglycemia and/or high morbidity of these models. To address these limitations, we developed the IsletTester mouse via CRISPR-Cas9 mediated gene editing of glucokinase (Gck), the glucose sensor of the β-cells, directly in NSG zygotes. IsletTester mice are heterozygous for an Arg345->stop mutation in Gck and present with stable random hyperglycemia (∼250mg/dl; ∼14 mM), normal life span and fertility. We demonstrate the utility of this model through functional engraftment of both human islets and hESC-derived β-like cells. The IsletTester mouse will enable the study of human islet biology over time and under different physiological conditions and can provide a useful preclinical platform to determine the functionality of stem cell-derived islet products.
{"title":"The IsletTester mouse: an immunodeficient model with stable hyperglycemia for the study of human islets","authors":"Eric L. Waite, Mark Tigue, Ming Yu, Deeksha Lahori, Kai Kelly, Catherine Lee May, Ali Naji, Jeffrey Roman, Nicolai Doliba, Dana Avrahami, Kim-Vy Nguyen-Ngoc, Maike Sander, Benjamin Glaser, Klaus H. Kaestner","doi":"10.2337/db23-0887","DOIUrl":"https://doi.org/10.2337/db23-0887","url":null,"abstract":"The gold standard for assessing the function of human islets or β-like cells derived from stem cells involves their engraftment under the kidney capsule of hyperglycemic, immunodeficient mice. Current models, such as Streptozotocin (STZ) treatment of severely immunodeficient mice or the NRG-Akita strain are limited due to unstable and variable hyperglycemia and/or high morbidity of these models. To address these limitations, we developed the IsletTester mouse via CRISPR-Cas9 mediated gene editing of glucokinase (Gck), the glucose sensor of the β-cells, directly in NSG zygotes. IsletTester mice are heterozygous for an Arg345->stop mutation in Gck and present with stable random hyperglycemia (∼250mg/dl; ∼14 mM), normal life span and fertility. We demonstrate the utility of this model through functional engraftment of both human islets and hESC-derived β-like cells. The IsletTester mouse will enable the study of human islet biology over time and under different physiological conditions and can provide a useful preclinical platform to determine the functionality of stem cell-derived islet products.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"7 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684215","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}
Samantha Mar, Ekaterina Filatov, Shugo Sasaki, Majid Mojibian, Dahai Zhang, Angela Yang, Cuilan Nian, Francis C. Lynn
Human embryonic stem cell (hESC)-derived pancreatic alpha and beta cells can be used to develop cell replacement therapies to treat diabetes. However, recent published differentiation protocols yield varying amounts of alpha and beta cells amidst heterogeneous cell populations. To visualize and isolate hESC-derived alpha and beta cells, we generated a GLUCAGON-2AmScarlet and INSULIN-2A-EGFP dual fluorescent reporter (INSEGFPGCGmScarlet) hESC line using CRISPR/Cas9. We established robust expression of EGFP and mScarlet fluorescent proteins in insulin- and glucagon-expressing cells respectively without compromising the differentiation or function of these cells. We also showed the insulin- and glucagon-expressing bihormonal population at the maturing endocrine cell stage (Stage 6) of our pancreatic islet differentiation lose insulin expression over time, while maintaining an alpha-like expression profile, suggesting these bihormonal cells are cell autonomously fated to become alpha-like cells. We also demonstrated this cell line can be used to monitor hESC-derived insulin- and glucagonexpressing cells, and hESC-derived islet morphology in vivo by transplanting them into the anterior chamber of the eye in mice. Together, the INSEGFPGCGmScarlet hESC line provides an efficient strategy for tracking populations of hESC-derived beta- and alpha-like cells.
{"title":"Tracking insulin- and glucagon-expressing cells in vitro and in vivo using a double reporter human embryonic stem cell line","authors":"Samantha Mar, Ekaterina Filatov, Shugo Sasaki, Majid Mojibian, Dahai Zhang, Angela Yang, Cuilan Nian, Francis C. Lynn","doi":"10.2337/db24-0756","DOIUrl":"https://doi.org/10.2337/db24-0756","url":null,"abstract":"Human embryonic stem cell (hESC)-derived pancreatic alpha and beta cells can be used to develop cell replacement therapies to treat diabetes. However, recent published differentiation protocols yield varying amounts of alpha and beta cells amidst heterogeneous cell populations. To visualize and isolate hESC-derived alpha and beta cells, we generated a GLUCAGON-2AmScarlet and INSULIN-2A-EGFP dual fluorescent reporter (INSEGFPGCGmScarlet) hESC line using CRISPR/Cas9. We established robust expression of EGFP and mScarlet fluorescent proteins in insulin- and glucagon-expressing cells respectively without compromising the differentiation or function of these cells. We also showed the insulin- and glucagon-expressing bihormonal population at the maturing endocrine cell stage (Stage 6) of our pancreatic islet differentiation lose insulin expression over time, while maintaining an alpha-like expression profile, suggesting these bihormonal cells are cell autonomously fated to become alpha-like cells. We also demonstrated this cell line can be used to monitor hESC-derived insulin- and glucagonexpressing cells, and hESC-derived islet morphology in vivo by transplanting them into the anterior chamber of the eye in mice. Together, the INSEGFPGCGmScarlet hESC line provides an efficient strategy for tracking populations of hESC-derived beta- and alpha-like cells.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"3 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673899","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}
Sevilay Tokgöz, Marti Boss, Theodorus JP Jansen, Rick Meijer, Cathelijne Frielink, Arianne C van Bon, Cees J Tack, Bastiaan E de Galan, Martin Gotthardt
Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight and improve glucose control in a sizable minority of people with type 2 diabetes. We hypothesized that stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by GLP-1R agonists, thus inducing cortisol secretion, could explain this unresponsiveness to GLP-1R agonists. To assess the effects of GLP-1R agonist treatment on the HPA axis, we selected ten individuals with type 2 diabetes with (5 women/5 men) and nine without (4 women/5 men) an adequate response to GLP-1R agonists and used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) to quantify GLP-1R expression in the pituitary. Oral glucose tolerance and 24 h urinary cortisol excretion was measured in all participants. Pituitary tracer uptake was observed in all participants with no significant difference between responders and non-responders. Pituitary tracer uptake correlated with the area under the curve for ACTH, urinary cortisol to creatinine ratio and age. Interestingly, men had higher pituitary tracer uptake than women. In conclusion, this study does not indicate a role for pituitary GLP-1R expression and HPA axis stimulation to explain the difference in treatment response to GLP-1R agonists among individuals with type 2 diabetes. The findings of substantial pituitary GLP-1R expression and the significant sex differences require further research.
{"title":"Activation of the HPA axis does not explain non-responsiveness to GLP-1R agonist treatment in individuals with type 2 diabetes","authors":"Sevilay Tokgöz, Marti Boss, Theodorus JP Jansen, Rick Meijer, Cathelijne Frielink, Arianne C van Bon, Cees J Tack, Bastiaan E de Galan, Martin Gotthardt","doi":"10.2337/db24-0463","DOIUrl":"https://doi.org/10.2337/db24-0463","url":null,"abstract":"Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight and improve glucose control in a sizable minority of people with type 2 diabetes. We hypothesized that stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by GLP-1R agonists, thus inducing cortisol secretion, could explain this unresponsiveness to GLP-1R agonists. To assess the effects of GLP-1R agonist treatment on the HPA axis, we selected ten individuals with type 2 diabetes with (5 women/5 men) and nine without (4 women/5 men) an adequate response to GLP-1R agonists and used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) to quantify GLP-1R expression in the pituitary. Oral glucose tolerance and 24 h urinary cortisol excretion was measured in all participants. Pituitary tracer uptake was observed in all participants with no significant difference between responders and non-responders. Pituitary tracer uptake correlated with the area under the curve for ACTH, urinary cortisol to creatinine ratio and age. Interestingly, men had higher pituitary tracer uptake than women. In conclusion, this study does not indicate a role for pituitary GLP-1R expression and HPA axis stimulation to explain the difference in treatment response to GLP-1R agonists among individuals with type 2 diabetes. The findings of substantial pituitary GLP-1R expression and the significant sex differences require further research.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"8 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673903","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}
Xuan Wang, Hao Ma, Minghao Kou, Yoriko Heianza, Vivian Fonseca, Lu Qi
The obesity diagnosis by body mass index (BMI) exhibits considerable interindividual heterogeneity in metabolic phenotypes and risk of developing type 2 diabetes (T2D). We investigated the association of proteomic signature of BMI and T2D and examined whether the proteomic signature of BMI improves prediction of T2D risk. This study included 41,427 adults in the UK Biobank who were free of T2D at baseline and had complete data on proteomics metrics assessed by antibody based Olink assay. The main exposure was a proteomic BMI score (pro-BMI score) calculated from 67 pre-identified plasma proteins associated with BMI. During a median follow-up of 13.7 years, 2,030 incident events of T2D were documented. We observed that a higher proteomic BMI (pro-BMI) score was significantly associated with a higher risk of T2D independent of actual BMI, waist-to-hip ratio, and polygenic risk score for BMI (hazard ratio (HR) comparing the highest with the lowest quartiles was 3.81, 95% CI, 3.08 – 4.71). Pro- BMI score significantly increased the C index when added to a reference model with age, sex, and BMI (C index change, 0.023 [95%CI, 0.018 to 0.027]). Proteomic signature of BMI is significantly associated with the risk of T2D independent of BMI, WHR and genetic susceptibility to obesity. When added to actual BMI, the proteomic signature of BMI provides significant but modest improvement in discrimination.
{"title":"Proteomic Signature of Body Mass Index and Risk of Type 2 Diabetes","authors":"Xuan Wang, Hao Ma, Minghao Kou, Yoriko Heianza, Vivian Fonseca, Lu Qi","doi":"10.2337/db24-0329","DOIUrl":"https://doi.org/10.2337/db24-0329","url":null,"abstract":"The obesity diagnosis by body mass index (BMI) exhibits considerable interindividual heterogeneity in metabolic phenotypes and risk of developing type 2 diabetes (T2D). We investigated the association of proteomic signature of BMI and T2D and examined whether the proteomic signature of BMI improves prediction of T2D risk. This study included 41,427 adults in the UK Biobank who were free of T2D at baseline and had complete data on proteomics metrics assessed by antibody based Olink assay. The main exposure was a proteomic BMI score (pro-BMI score) calculated from 67 pre-identified plasma proteins associated with BMI. During a median follow-up of 13.7 years, 2,030 incident events of T2D were documented. We observed that a higher proteomic BMI (pro-BMI) score was significantly associated with a higher risk of T2D independent of actual BMI, waist-to-hip ratio, and polygenic risk score for BMI (hazard ratio (HR) comparing the highest with the lowest quartiles was 3.81, 95% CI, 3.08 – 4.71). Pro- BMI score significantly increased the C index when added to a reference model with age, sex, and BMI (C index change, 0.023 [95%CI, 0.018 to 0.027]). Proteomic signature of BMI is significantly associated with the risk of T2D independent of BMI, WHR and genetic susceptibility to obesity. When added to actual BMI, the proteomic signature of BMI provides significant but modest improvement in discrimination.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"46 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673900","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}
Shuangshuang Yuan, Qin Yu, Mao Luo, Jianbo Wu, Liqun Wang
MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes mellitus has been gradually elucidated but is still full of controversy. Some reports have indicated that MG53 is upregulated in animal models with metabolic disorders, and that muscle-specific MG53 upregulation is sufficient to induce whole-body insulin resistance and metabolic syndrome through targeting both the insulin receptor (IR) and IR substrate-1 (IRS-1) for ubiquitin-dependent degradation. Additionally, MG53 has been identified as a myokine/cardiokine that is secreted from striated muscles into the bloodstream and circulating MG53 has further been shown to trigger insulin resistance by binding to the extracellular domain of the IR, thereby allosterically inhibiting insulin signaling. Conversely, other studies have reported findings that contradict these results. Specifically, no significant change in MG53 expression in striated muscles or serum has been observed in diabetic models, and the MG53-mediated degradation of IRS-1 may be insufficient to induce insulin resistance due to the compensatory roles of other IRS subtypes. Furthermore, sustained elevation of MG53 levels in serum or systemic administration of recombinant human MG53 (rhMG53) has shown no impact on metabolic function. In this review, we will fully characterize these two disparate views, strive to provide critical insights into their contrasts and propose several specific experimental approaches that may yield additional evidence. Our goal is to encourage the scientific community to elucidate the effects of MG53 on metabolic diseases and the molecular mechanisms involved, thereby providing the theoretical basis for the treatment of metabolic diseases and the applications of rhMG53.
{"title":"Friend or foe: the paradoxical roles of MG53 in diabetes mellitus","authors":"Shuangshuang Yuan, Qin Yu, Mao Luo, Jianbo Wu, Liqun Wang","doi":"10.2337/db24-0556","DOIUrl":"https://doi.org/10.2337/db24-0556","url":null,"abstract":"MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes mellitus has been gradually elucidated but is still full of controversy. Some reports have indicated that MG53 is upregulated in animal models with metabolic disorders, and that muscle-specific MG53 upregulation is sufficient to induce whole-body insulin resistance and metabolic syndrome through targeting both the insulin receptor (IR) and IR substrate-1 (IRS-1) for ubiquitin-dependent degradation. Additionally, MG53 has been identified as a myokine/cardiokine that is secreted from striated muscles into the bloodstream and circulating MG53 has further been shown to trigger insulin resistance by binding to the extracellular domain of the IR, thereby allosterically inhibiting insulin signaling. Conversely, other studies have reported findings that contradict these results. Specifically, no significant change in MG53 expression in striated muscles or serum has been observed in diabetic models, and the MG53-mediated degradation of IRS-1 may be insufficient to induce insulin resistance due to the compensatory roles of other IRS subtypes. Furthermore, sustained elevation of MG53 levels in serum or systemic administration of recombinant human MG53 (rhMG53) has shown no impact on metabolic function. In this review, we will fully characterize these two disparate views, strive to provide critical insights into their contrasts and propose several specific experimental approaches that may yield additional evidence. Our goal is to encourage the scientific community to elucidate the effects of MG53 on metabolic diseases and the molecular mechanisms involved, thereby providing the theoretical basis for the treatment of metabolic diseases and the applications of rhMG53.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"98 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610131","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}
Shared medical appointments (SMAs) for diabetes and group prenatal care (GPC) for pregnant patients, have emerged as innovative care delivery models. They have the potential to transform diabetes care by overcoming many of the time limitations of traditional one-on-one clinical visits. There is compelling evidence that SMAs improve glycemic control for non-pregnant patients with diabetes, GPC reduces Black/White health disparities in preterm birth, and Diabetes Group Prenatal Care increase postpartum glucose tolerance test uptake among patients with gestational diabetes mellitus. GPC models standout as one of few interventions that reduce racial health disparities, which we hypothesize occurs because they inadvertently exert their effect on both the patient and clinician through a 20+ hour meaningful shared experience. This Perspective explores the evidence for SMA and GPC in diabetes and pregnancy, theoretical underpinnings of the models, their potential to promote more equitable care, and future directions from my Perspective, as a high-risk obstetrician and 2019 ADA Pathway Accelerator award recipient.
糖尿病患者的共享医疗预约（SMA）和孕妇的集体产前护理（GPC）已成为创新的医疗服务模式。它们克服了传统一对一临床就诊的许多时间限制，具有改变糖尿病护理的潜力。有令人信服的证据表明，SMA 改善了非孕期糖尿病患者的血糖控制，GPC 减少了早产中黑人/白人的健康差异，而糖尿病小组产前护理则提高了妊娠糖尿病患者的产后葡萄糖耐量测试接受率。GPC 模式是为数不多的能减少种族健康差异的干预措施之一，我们假设这是因为它们通过 20 多个小时有意义的共同体验，在不经意间对患者和临床医生产生了影响。作为一名高风险产科医生和 2019 ADA Pathway Accelerator 奖获得者，本视角从我的视角探讨了糖尿病和妊娠期 SMA 和 GPC 的证据、这些模式的理论基础、它们促进更公平护理的潜力以及未来发展方向。
{"title":"Innovating Diabetes Care in Pregnancy: Do group care models improve outcomes and equity?","authors":"Ebony B. Carter","doi":"10.2337/dbi24-0006","DOIUrl":"https://doi.org/10.2337/dbi24-0006","url":null,"abstract":"Shared medical appointments (SMAs) for diabetes and group prenatal care (GPC) for pregnant patients, have emerged as innovative care delivery models. They have the potential to transform diabetes care by overcoming many of the time limitations of traditional one-on-one clinical visits. There is compelling evidence that SMAs improve glycemic control for non-pregnant patients with diabetes, GPC reduces Black/White health disparities in preterm birth, and Diabetes Group Prenatal Care increase postpartum glucose tolerance test uptake among patients with gestational diabetes mellitus. GPC models standout as one of few interventions that reduce racial health disparities, which we hypothesize occurs because they inadvertently exert their effect on both the patient and clinician through a 20+ hour meaningful shared experience. This Perspective explores the evidence for SMA and GPC in diabetes and pregnancy, theoretical underpinnings of the models, their potential to promote more equitable care, and future directions from my Perspective, as a high-risk obstetrician and 2019 ADA Pathway Accelerator award recipient.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"5 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601205","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}
Clinton R. Bruce, Teddy Ang, Jason D. Toms, Giang M. Dao, Jean Liu, Glenn M. Ward, David N. O’Neal, Dale J. Morrison, Greg M. Kowalski
Small glycemic increments (≤0.5 mmol/L) can exert suppressive actions on endogenous glucose production (EGP) however it is unclear if this is an insulin dependent or independent process. Here, we performed a low-rate glucose infusion in control participants without diabetes and in people with type 1 diabetes (T1D) to better understand this phenomenon. Glucose kinetics, hormones and metabolites were measured during a 1 mg/kg/min glucose infusion (90 min) which rapidly increased glucose by ∼0.3 mmol/L in control participants. Insulin concentrations and secretion quickly increased by ∼20%, resulting in a ∼40% suppression of EGP, while glucose disposal remained unchanged. Free fatty acids (FFA) and glucagon were gradually suppressed to ∼30% below baseline at 60 min. When repeated under constant basal insulin concentrations in participants with T1D, glucose infusion caused only partial and transient EGP suppression, hence glucose increased in a near-linear manner, reaching levels ∼2 mmol/L above baseline at 90 min. FFAs and glucagon remained unchanged, while glucose disposal modestly increased. This demonstrates that small glycemic increments exert subtle stimulatory effects on insulin secretion that have potent metabolic actions on the liver and adipose tissue. It is conceivable that subtle increases in glucose could potentially serve as a signal for β-cell adaptation.
{"title":"The effect of small increases in blood glucose on insulin secretion and endogenous glucose production in humans","authors":"Clinton R. Bruce, Teddy Ang, Jason D. Toms, Giang M. Dao, Jean Liu, Glenn M. Ward, David N. O’Neal, Dale J. Morrison, Greg M. Kowalski","doi":"10.2337/db24-0388","DOIUrl":"https://doi.org/10.2337/db24-0388","url":null,"abstract":"Small glycemic increments (≤0.5 mmol/L) can exert suppressive actions on endogenous glucose production (EGP) however it is unclear if this is an insulin dependent or independent process. Here, we performed a low-rate glucose infusion in control participants without diabetes and in people with type 1 diabetes (T1D) to better understand this phenomenon. Glucose kinetics, hormones and metabolites were measured during a 1 mg/kg/min glucose infusion (90 min) which rapidly increased glucose by ∼0.3 mmol/L in control participants. Insulin concentrations and secretion quickly increased by ∼20%, resulting in a ∼40% suppression of EGP, while glucose disposal remained unchanged. Free fatty acids (FFA) and glucagon were gradually suppressed to ∼30% below baseline at 60 min. When repeated under constant basal insulin concentrations in participants with T1D, glucose infusion caused only partial and transient EGP suppression, hence glucose increased in a near-linear manner, reaching levels ∼2 mmol/L above baseline at 90 min. FFAs and glucagon remained unchanged, while glucose disposal modestly increased. This demonstrates that small glycemic increments exert subtle stimulatory effects on insulin secretion that have potent metabolic actions on the liver and adipose tissue. It is conceivable that subtle increases in glucose could potentially serve as a signal for β-cell adaptation.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597015","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}
Roberto Mallone, Emily Sims, Peter Achenbach, Chantal Mathieu, Alberto Pugliese, Mark Atkinson, Sanjoy Dutta, Carmella Evans-Molina, David Klatzmann, Anne Koralova, S. Alice Long, Lut Overbergh, Teresa Rodriguez-Calvo, Anette-Gabriele Ziegler, Sylvaine You
Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab to delay disease development. In this Perspective article, we discuss four major conceptual and practical issues that emerged as key to further advance type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the type 1 diabetes research and care community members are key to fostering innovation, know-how and translation into the clinical arena worldwide. Second, recent clinical trials in presymptomatic stage 2 and recent-onset stage 3 disease have shown the promise, and potential pitfalls, of using immunomodulatory and/or beta-cell protective agents to achieve sustained remission or prevention. Third, the increasingly appreciated heterogeneity of clinical, immunological, and metabolic phenotypes and disease trajectories is of critical importance to advance the decision-making process for tailored type 1 diabetes care and therapy. Fourth, the clinical benefits of early diagnosis of beta-cell autoimmunity warrant consideration of general population screening for islet autoantibodies, which requires further efforts to address the technical, organizational and ethical challenges inherent to a sustainable program. Efforts are underway to integrate these four concepts into the future directions of type 1 diabetes research and therapy.
{"title":"Emerging concepts and success stories in type 1 diabetes research: a roadmap for a bright future","authors":"Roberto Mallone, Emily Sims, Peter Achenbach, Chantal Mathieu, Alberto Pugliese, Mark Atkinson, Sanjoy Dutta, Carmella Evans-Molina, David Klatzmann, Anne Koralova, S. Alice Long, Lut Overbergh, Teresa Rodriguez-Calvo, Anette-Gabriele Ziegler, Sylvaine You","doi":"10.2337/db24-0439","DOIUrl":"https://doi.org/10.2337/db24-0439","url":null,"abstract":"Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab to delay disease development. In this Perspective article, we discuss four major conceptual and practical issues that emerged as key to further advance type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the type 1 diabetes research and care community members are key to fostering innovation, know-how and translation into the clinical arena worldwide. Second, recent clinical trials in presymptomatic stage 2 and recent-onset stage 3 disease have shown the promise, and potential pitfalls, of using immunomodulatory and/or beta-cell protective agents to achieve sustained remission or prevention. Third, the increasingly appreciated heterogeneity of clinical, immunological, and metabolic phenotypes and disease trajectories is of critical importance to advance the decision-making process for tailored type 1 diabetes care and therapy. Fourth, the clinical benefits of early diagnosis of beta-cell autoimmunity warrant consideration of general population screening for islet autoantibodies, which requires further efforts to address the technical, organizational and ethical challenges inherent to a sustainable program. Efforts are underway to integrate these four concepts into the future directions of type 1 diabetes research and therapy.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"194 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489448","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 vasculopathy, encompassing complications such as diabetic retinopathy, represents a significant source of morbidity, with inflammation playing a pivotal role in the progression of these complications. This study investigates the influence of m6A modification and the m6A demethylase FTO on macrophage polarization and its subsequent effects on diabetic microvasculopathy. We found that diabetes induces a shift in macrophage polarization towards a pro-inflammatory M1 phenotype, which is associated with a reduction in m6A modification levels. Notably, FTO emerges as a critical regulator of m6A under diabetic conditions. In vitro experiments reveal that FTO not only modulates macrophage polarization but also mediates their interactions with vascular endothelial cells. In vivo experiments demonstrate that FTO deficiency exacerbates retinal inflammation and microvascular dysfunction in diabetic retinas. Mechanistically, FTO stabilizes mRNA through an m6A-YTHDF2-dependent pathway, thereby activating the PI3K/AKT signaling cascade. Collectively, these findings position FTO as a promising therapeutic target for the management of diabetic vascular complications.
{"title":"N 6-Methyladenosine demethylase FTO controls macrophage homeostasis in diabetic vasculopathy","authors":"Siguo Feng, Qiuyang Zhang, Qing Liu, Chang Huang, Huiying Zhang, Fengsheng Wang, Yue Zhu, Qizhi Jian, Xue Chen, Qin Jiang, Biao Yan","doi":"10.2337/db24-0691","DOIUrl":"https://doi.org/10.2337/db24-0691","url":null,"abstract":"Diabetic vasculopathy, encompassing complications such as diabetic retinopathy, represents a significant source of morbidity, with inflammation playing a pivotal role in the progression of these complications. This study investigates the influence of m6A modification and the m6A demethylase FTO on macrophage polarization and its subsequent effects on diabetic microvasculopathy. We found that diabetes induces a shift in macrophage polarization towards a pro-inflammatory M1 phenotype, which is associated with a reduction in m6A modification levels. Notably, FTO emerges as a critical regulator of m6A under diabetic conditions. In vitro experiments reveal that FTO not only modulates macrophage polarization but also mediates their interactions with vascular endothelial cells. In vivo experiments demonstrate that FTO deficiency exacerbates retinal inflammation and microvascular dysfunction in diabetic retinas. Mechanistically, FTO stabilizes mRNA through an m6A-YTHDF2-dependent pathway, thereby activating the PI3K/AKT signaling cascade. Collectively, these findings position FTO as a promising therapeutic target for the management of diabetic vascular complications.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"58 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489445","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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