ANNA SANTORO, SEVIM KAHRAMAN, GIORGIO BASILE, KHADIJA EL JELLAS, JIANG HU, RYAN TARPEY, BENTE B. JOHANSSON, ERCUMENT DIRICE, ISMAIL SYED, DIONICIO SIEGEL, ANDERS MOLVEN, BARBARA B. KAHN, ROHIT KULKARNI
Maturity onset diabetes of the young type 8 (MODY8) is caused by genetic mutations in the CEL gene which is expressed primarily in pancreatic acinar cells. MODY8 patients develop pancreatic exocrine and endocrine dysfunction. How the enzymatic function of mutant (MUT) CEL contributes to the development of diabetes in MODY8 is unknown. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are signaling lipids that augment glucose-stimulated insulin secretion (GSIS). CEL is the major PAHSA hydrolytic enzyme in the pancreas. Aim: To determine whether CEL regulates insulin secretion and whether the increased PAHSA hydrolytic activity of MUT CEL contributes to MODY8 pathogenesis. Methods: We overexpressed wildtype (WT) or MUT CEL in acinar cells in vitro and in vivo. In vivo, we used 2 approaches both with AAV8 driven by an acinar cell specific promoter: intraductal AAV injections in wildtype mice and intraperitoneal AAV injections in CEL KO mice. CEL overexpression was detected exclusively in acinar cells. Results: 9-PAHSA augments GSIS in human pancreatic beta cells. Recombinant CEL inhibits the PAHSA effect. MUT CEL overexpression in acinar cells increases 9-PAHSA hydrolytic activity compared to WT CEL. In vivo, MUT CEL expression in acinar cells of wildtype mice markedly impairs glucose tolerance. In CEL KO mice, expression of MUT CEL in acinar cells impairs GSIS. Both WT and MUT CEL reduce total pancreatic PAHSA levels in CEL KO mice. However, 12/13-PAHSAs were reduced only with MUT CEL expression. Conclusions: 1) CEL in acinar cells alters PAHSA hydrolysis and modulates insulin secretion. 2) MUT CEL potentially contributes to the development of diabetes by increasing PAHSA hydrolysis and thereby limiting the normal PAHSA-induced augmentation of GSIS. 3) These data highlight the critical role of acinar-beta cell interactions and the physiologic role of PAHSAs in insulin secretion and provide opportunities for developing strategies to treat MODY8 and other forms of diabetes. Disclosure A. Santoro: None. S. Kahraman: Employee; Boehringer-Ingelheim. G. Basile: None. K. El Jellas: None. J. Hu: None. R. Tarpey: None. B.B. Johansson: None. E. Dirice: None. I. Syed: None. D. Siegel: None. A. Molven: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc. R. Kulkarni: Advisory Panel; Novo Nordisk, Biomea Fusion, Inc. Consultant; Inversago Pharma. Advisory Panel; REDD Pharmaceutical. Funding K01 DK128075 (Anna Santoro), U01DK135095 (Rohit N. Kulkarni), R01DK067536 (Rohit N. Kulkarni), NIH R01 DK106210 (Barbara B. Kahn), JPB foundation (Barbara B. Kahn), and NIH P30 DK135043 (Barbara B. Kahn). Anna Santoro, Sevim Kahraman, Barbara B. Kahn and Rohit N. Kulkarni contributed equally.
成熟期发病的青年糖尿病 8 型（MODY8）是由 CEL 基因突变引起的，该基因主要在胰腺胰岛细胞中表达。MODY8 患者会出现胰腺外分泌和内分泌功能障碍。突变型（MUT）CEL 的酶功能如何导致 MODY8 型糖尿病的发生尚不清楚。棕榈酸羟基硬脂酸（Palmitic Acid Hydroxy Stearic Acids，PAHSAs）是一种信号脂质，可增强葡萄糖刺激的胰岛素分泌（GSIS）。CEL 是胰腺中主要的 PAHSA 水解酶。目的：确定 CEL 是否调节胰岛素分泌，以及 MUT CEL 的 PAHSA 水解活性增加是否导致 MODY8 发病。方法：我们在体外和体内的胰腺细胞中过表达野生型（WT）或 MUT CEL。在体内，我们使用了两种方法，一种是由针尖细胞特异性启动子驱动的 AAV8：在野生型小鼠的导管内注射 AAV，另一种是在 CEL KO 小鼠的腹腔内注射 AAV。CEL 的过表达只在尖突细胞中被检测到。结果9-PAHSA能增强人胰腺β细胞的GSIS。重组 CEL 可抑制 PAHSA 效应。与 WT CEL 相比，MUT CEL 在胰腺细胞中的过表达会增加 9-PAHSA 的水解活性。在体内，野生型小鼠胰腺细胞中 MUT CEL 的表达会明显影响葡萄糖耐量。在 CEL KO 小鼠中，MUT CEL 在胰腺细胞中的表达会损害 GSIS。在 CEL KO 小鼠中，WT 和 MUT CEL 都会降低胰腺 PAHSA 的总水平。然而，只有在表达 MUT CEL 的情况下，12/13-PAHSAs 才会减少。结论1）胰腺细胞中的 CEL 会改变 PAHSA 的水解并调节胰岛素分泌。2）MUT CEL 通过增加 PAHSA 的水解，从而限制正常 PAHSA 诱导的 GSIS 的增加，可能会导致糖尿病的发生。3）这些数据强调了尖塔-β细胞相互作用的关键作用以及 PAHSA 在胰岛素分泌中的生理作用，并为制定治疗 MODY8 和其他形式糖尿病的策略提供了机会。披露 A. Santoro：无。S. Kahraman：雇员；勃林格殷格翰公司。G. Basile：无：无。K. El Jellas：无。J. Hu：无。R. Tarpey：无。B.B. Johansson：无。E. Dirice：无。I. Syed：无。D. Siegel：无。A. Molven：无。B.B. Kahn：顾问团；Janssen Pharmaceuticals, Inc.顾问；Vida Ventures Advisors、Arrowhead Pharmaceuticals, Inc.R. Kulkarni：顾问团；诺和诺德、Biomea Fusion, Inc.顾问；Inversago Pharma.顾问团；REDD 制药公司。资金来源：K01 DK128075（Anna Santoro）、U01DK135095（Rohit N. Kulkarni）、R01DK067536（Rohit N. Kulkarni）、NIH R01 DK106210（Barbara B. Kahn）、JPB 基金会（Barbara B. Kahn）和 NIH P30 DK135043（Barbara B. Kahn）。Anna Santoro、Sevim Kahraman、Barbara B. Kahn 和 Rohit N. Kulkarni 的贡献相同。
{"title":"1557-P: Increased PAHSA Hydrolysis Driven by Mutant Carboxyl Ester Lipase (CEL) Contributes to Beta-Cell Dysfunction in MODY8","authors":"ANNA SANTORO, SEVIM KAHRAMAN, GIORGIO BASILE, KHADIJA EL JELLAS, JIANG HU, RYAN TARPEY, BENTE B. JOHANSSON, ERCUMENT DIRICE, ISMAIL SYED, DIONICIO SIEGEL, ANDERS MOLVEN, BARBARA B. KAHN, ROHIT KULKARNI","doi":"10.2337/db24-1557-p","DOIUrl":"https://doi.org/10.2337/db24-1557-p","url":null,"abstract":"Maturity onset diabetes of the young type 8 (MODY8) is caused by genetic mutations in the CEL gene which is expressed primarily in pancreatic acinar cells. MODY8 patients develop pancreatic exocrine and endocrine dysfunction. How the enzymatic function of mutant (MUT) CEL contributes to the development of diabetes in MODY8 is unknown. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are signaling lipids that augment glucose-stimulated insulin secretion (GSIS). CEL is the major PAHSA hydrolytic enzyme in the pancreas. Aim: To determine whether CEL regulates insulin secretion and whether the increased PAHSA hydrolytic activity of MUT CEL contributes to MODY8 pathogenesis. Methods: We overexpressed wildtype (WT) or MUT CEL in acinar cells in vitro and in vivo. In vivo, we used 2 approaches both with AAV8 driven by an acinar cell specific promoter: intraductal AAV injections in wildtype mice and intraperitoneal AAV injections in CEL KO mice. CEL overexpression was detected exclusively in acinar cells. Results: 9-PAHSA augments GSIS in human pancreatic beta cells. Recombinant CEL inhibits the PAHSA effect. MUT CEL overexpression in acinar cells increases 9-PAHSA hydrolytic activity compared to WT CEL. In vivo, MUT CEL expression in acinar cells of wildtype mice markedly impairs glucose tolerance. In CEL KO mice, expression of MUT CEL in acinar cells impairs GSIS. Both WT and MUT CEL reduce total pancreatic PAHSA levels in CEL KO mice. However, 12/13-PAHSAs were reduced only with MUT CEL expression. Conclusions: 1) CEL in acinar cells alters PAHSA hydrolysis and modulates insulin secretion. 2) MUT CEL potentially contributes to the development of diabetes by increasing PAHSA hydrolysis and thereby limiting the normal PAHSA-induced augmentation of GSIS. 3) These data highlight the critical role of acinar-beta cell interactions and the physiologic role of PAHSAs in insulin secretion and provide opportunities for developing strategies to treat MODY8 and other forms of diabetes. Disclosure A. Santoro: None. S. Kahraman: Employee; Boehringer-Ingelheim. G. Basile: None. K. El Jellas: None. J. Hu: None. R. Tarpey: None. B.B. Johansson: None. E. Dirice: None. I. Syed: None. D. Siegel: None. A. Molven: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc. R. Kulkarni: Advisory Panel; Novo Nordisk, Biomea Fusion, Inc. Consultant; Inversago Pharma. Advisory Panel; REDD Pharmaceutical. Funding K01 DK128075 (Anna Santoro), U01DK135095 (Rohit N. Kulkarni), R01DK067536 (Rohit N. Kulkarni), NIH R01 DK106210 (Barbara B. Kahn), JPB foundation (Barbara B. Kahn), and NIH P30 DK135043 (Barbara B. Kahn). Anna Santoro, Sevim Kahraman, Barbara B. Kahn and Rohit N. Kulkarni contributed equally.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730619","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}
LAURA SOLDOVIERI, GIANFRANCO DI GIUSEPPE, GEA CICCARELLI, MICHELA BRUNETTI, ANDREA MARI, GIUSEPPE QUERO, SERGIO ALFIERI, ANDREA GIACCARI, TERESA MEZZA
Introduction and Objectives: Diabetes typically develops when the endocrine pancreas fails to cope to insulin demand with adequate insulin secretion. Many studies have shown that diabetes appears when the loss of pancreatic β cell mass is approximately between 41% and 65% in humans. Near total pancreatectomy (NTP) is a surgical procedure that removes 80% of pancreatic mass.To investigate the metabolic effects of NTP in a cohort of nondiabetic subjects. Methods: We recruited 7 subjects who underwent an oral glucose tolerance test (OGTT) and a hyperglycemic clamp (HC) followed by arginine stimulation, before and 3 months after NTP. We calculated the area under the curve of glucose (AUC-Glu) and insulin (AUC-Ins) responses during OGTT. Therefore, we estimated the β cell glucose sensitivity (βCGS), an index of β cell function, and rate sensitivity (RS), an index of first phase insulin secretion. Further, we calculated the total area under the curve of insulin responses (AUC-Itot) and the area under the of the arginine-stimulated insulin secretion (AUC-Arg) during HC. Results: Compared to presurgical OGTT, we observed a 18% increase in the mean glucose levels during OGTT after surgery (AUC-Glu 19761 vs 23421 mg/dl·min) with a 57% reduction of the mean insulin concentration (AUC-Ins 6499 vs 2788 μU/ml·min p<0.05). Further, we observed a 36% reduction βCGS (61.2 vs 38.7 pmol min-1m-2mmol-1L) and a 82% reduction in the RS (763 vs 139 pmol m-2mmol-1L p<0.05) after surgery. Both total insulin secretion and arginine-stimulated insulin secretion during HC were reduced (AUC-Itot 15776 vs 6489 μU/ml·min) (AUC-Arg 7144 vs 2520 μU/ml·min), respectively by 58.8% and 64.7%. According to the ADA diagnostic criteria 3 of the 7 subjects developed diabetes. Conclusion: In conclusion, despite previous reports, 80% β cell mass loss is not always sufficient to develop hyperglycemia. Additional studies will be necessary to understand what mechanisms play a compensating role in the preservation of glucose tolerance in those patients. Disclosure L. Soldovieri: None. G. Di Giuseppe: None. G. Ciccarelli: None. M. Brunetti: None. A. Mari: Consultant; Lilly Diabetes. G. Quero: None. S. Alfieri: None. A. Giaccari: None. T. Mezza: None.
导言和目标：糖尿病通常是由于胰腺内分泌系统无法分泌足够的胰岛素来满足胰岛素需求而导致的。许多研究表明，当人类胰腺β细胞质量损失约为41%至65%时，就会出现糖尿病。近全胰切除术（NTP）是一种切除 80% 胰腺组织的外科手术。研究方法我们招募了 7 名受试者，他们在 NTP 之前和之后 3 个月接受了口服葡萄糖耐量试验 (OGTT) 和高血糖钳夹 (HC)，然后接受精氨酸刺激。我们计算了 OGTT 期间葡萄糖（AUC-Glu）和胰岛素（AUC-Ins）反应的曲线下面积。因此，我们估算了β细胞葡萄糖敏感性（βCGS）和速率敏感性（RS），前者是β细胞功能的指标，后者是第一阶段胰岛素分泌的指标。此外，我们还计算了 HC 期间胰岛素反应曲线下的总面积（AUC-Itot）和精氨酸刺激胰岛素分泌曲线下的面积（AUC-Arg）。结果：与术前 OGTT 相比，我们观察到术后 OGTT 期间的平均血糖水平增加了 18%（AUC-Glu 19761 vs 23421 mg/dl-min），平均胰岛素浓度降低了 57%（AUC-Ins 6499 vs 2788 μU/ml-min p<0.05）。此外，我们还观察到，手术后，βCGS 降低了 36%（61.2 vs 38.7 pmol min-1m-2mmol-1L），RS 降低了 82%（763 vs 139 pmol m-2mmol-1L p<0.05）。HC 期间的胰岛素总分泌量和精氨酸刺激的胰岛素分泌量分别减少了 58.8% 和 64.7%（AUC-Itot 15776 vs 6489 μU/ml-min）（AUC-Arg 7144 vs 2520 μU/ml-min）。根据 ADA 诊断标准，7 名受试者中有 3 人患上了糖尿病。结论总之，尽管之前有报道称，80% 的 β 细胞质量损失并不总是足以导致高血糖。有必要进行更多的研究，以了解是什么机制在这些患者的葡萄糖耐量保持过程中发挥了补偿作用。披露 L. Soldovieri：无。G. Di Giuseppe：无。G. Ciccarelli：无。M. 布鲁内蒂无。A. Mari：顾问；礼来糖尿病公司。G. Quero：无：无。S. Alfieri：无。A. Giaccari：无。T. Mezza：无。
{"title":"1555-P: Effects of 80% Pancreas Reduction on Beta-Cell Function and Glucose Metabolism","authors":"LAURA SOLDOVIERI, GIANFRANCO DI GIUSEPPE, GEA CICCARELLI, MICHELA BRUNETTI, ANDREA MARI, GIUSEPPE QUERO, SERGIO ALFIERI, ANDREA GIACCARI, TERESA MEZZA","doi":"10.2337/db24-1555-p","DOIUrl":"https://doi.org/10.2337/db24-1555-p","url":null,"abstract":"Introduction and Objectives: Diabetes typically develops when the endocrine pancreas fails to cope to insulin demand with adequate insulin secretion. Many studies have shown that diabetes appears when the loss of pancreatic β cell mass is approximately between 41% and 65% in humans. Near total pancreatectomy (NTP) is a surgical procedure that removes 80% of pancreatic mass.To investigate the metabolic effects of NTP in a cohort of nondiabetic subjects. Methods: We recruited 7 subjects who underwent an oral glucose tolerance test (OGTT) and a hyperglycemic clamp (HC) followed by arginine stimulation, before and 3 months after NTP. We calculated the area under the curve of glucose (AUC-Glu) and insulin (AUC-Ins) responses during OGTT. Therefore, we estimated the β cell glucose sensitivity (βCGS), an index of β cell function, and rate sensitivity (RS), an index of first phase insulin secretion. Further, we calculated the total area under the curve of insulin responses (AUC-Itot) and the area under the of the arginine-stimulated insulin secretion (AUC-Arg) during HC. Results: Compared to presurgical OGTT, we observed a 18% increase in the mean glucose levels during OGTT after surgery (AUC-Glu 19761 vs 23421 mg/dl·min) with a 57% reduction of the mean insulin concentration (AUC-Ins 6499 vs 2788 μU/ml·min p&lt;0.05). Further, we observed a 36% reduction βCGS (61.2 vs 38.7 pmol min-1m-2mmol-1L) and a 82% reduction in the RS (763 vs 139 pmol m-2mmol-1L p&lt;0.05) after surgery. Both total insulin secretion and arginine-stimulated insulin secretion during HC were reduced (AUC-Itot 15776 vs 6489 μU/ml·min) (AUC-Arg 7144 vs 2520 μU/ml·min), respectively by 58.8% and 64.7%. According to the ADA diagnostic criteria 3 of the 7 subjects developed diabetes. Conclusion: In conclusion, despite previous reports, 80% β cell mass loss is not always sufficient to develop hyperglycemia. Additional studies will be necessary to understand what mechanisms play a compensating role in the preservation of glucose tolerance in those patients. Disclosure L. Soldovieri: None. G. Di Giuseppe: None. G. Ciccarelli: None. M. Brunetti: None. A. Mari: Consultant; Lilly Diabetes. G. Quero: None. S. Alfieri: None. A. Giaccari: None. T. Mezza: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730620","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}
It is essential to decipher developmental features of each endocrine cell, which leads to exploring efficient methods for generating surrogate β cells. We previously developed three reporter mouse lines to quantify the genesis of endocrine progenitor cells, β cells, and α cells. Flow cytometry analysis revealed a significant decrease in the number of newly-generated endocrine progenitors and β cells after birth. Based on these findings, we hypothesized that environmental changes during parturition could affect endocrine genesis. The number of newly-generated endocrine cells was quantified with the reporter mouse lines at the following stages: (i) embryonic day 19.5 (E19.5) embryos, whose parturitions were prolonged by progesterone or COX-1 inhibitor SC-560 vs. newborn pups at postnatal day 0.5 (P0.5) (both were dissected at 19.5 days after coitus), and (ii) premature pups treated with anti-progesterone drug RU-486 (both were at 18.5 days after coitus) vs. E18.5 embryos. Flow cytometry with Neurog3-Timer pancreata demonstrated that the percentage of green-fluorescent progenitors was (i) significantly higher in E19.5 embryos than in P0.5 pups (0.80% vs. 0.22%, p<0.001), and (ii) significantly lower in premature pups than in E18.5 embryos (0.66% vs. 0.93%, p=0.0018). Likewise, flow cytometry with Ins1-Timer pancreata resulted in a significant increase in β-cell genesis at E19.5 than at P0.5 (0.36% vs. 0.16%, p<0.001). Surprisingly, flow cytometry with Gcg-Timer mice resulted in (i) a significant decrease in α-cell genesis at E19.5 than at P0.5 (2.1% vs. 2.4%, p=0.035), and (ii) a significant increase in premature pups 18.5 days after coitus than in E18.5 embryos (0.77% vs. 0.58%, p=0.022), which is in contrast with the findings in Neurog3-Timer and Ins1-Timer pancreata. Thus, parturition events suppress the generation of endocrine progenitors and β cells, but not α-cell genesis, which may reflect distinct molecular mechanisms in α-cell lineage during parturition. Disclosure A. Suzuki: None. T. Taguchi: None. S. Ito: None. H. Shimotatara: None. K. Kimura: None. N. Shimizu: None. R. Fujishima: None. M. Himuro: None. T. Miyatsuka: None.
{"title":"350-OR: Parturition Event Regulates Endocrine Genesis during Pancreas Differentiation","authors":"AGENA SUZUKI, TOMOMI TAGUCHI, SHIORI ITO, HIDEAKI SHIMOTATARA, KAORI KIMURA, NAOYA SHIMIZU, REI FUJISHIMA, MIWA HIMURO, TAKESHI MIYATSUKA","doi":"10.2337/db24-350-or","DOIUrl":"https://doi.org/10.2337/db24-350-or","url":null,"abstract":"It is essential to decipher developmental features of each endocrine cell, which leads to exploring efficient methods for generating surrogate β cells. We previously developed three reporter mouse lines to quantify the genesis of endocrine progenitor cells, β cells, and α cells. Flow cytometry analysis revealed a significant decrease in the number of newly-generated endocrine progenitors and β cells after birth. Based on these findings, we hypothesized that environmental changes during parturition could affect endocrine genesis. The number of newly-generated endocrine cells was quantified with the reporter mouse lines at the following stages: (i) embryonic day 19.5 (E19.5) embryos, whose parturitions were prolonged by progesterone or COX-1 inhibitor SC-560 vs. newborn pups at postnatal day 0.5 (P0.5) (both were dissected at 19.5 days after coitus), and (ii) premature pups treated with anti-progesterone drug RU-486 (both were at 18.5 days after coitus) vs. E18.5 embryos. Flow cytometry with Neurog3-Timer pancreata demonstrated that the percentage of green-fluorescent progenitors was (i) significantly higher in E19.5 embryos than in P0.5 pups (0.80% vs. 0.22%, p&lt;0.001), and (ii) significantly lower in premature pups than in E18.5 embryos (0.66% vs. 0.93%, p=0.0018). Likewise, flow cytometry with Ins1-Timer pancreata resulted in a significant increase in β-cell genesis at E19.5 than at P0.5 (0.36% vs. 0.16%, p&lt;0.001). Surprisingly, flow cytometry with Gcg-Timer mice resulted in (i) a significant decrease in α-cell genesis at E19.5 than at P0.5 (2.1% vs. 2.4%, p=0.035), and (ii) a significant increase in premature pups 18.5 days after coitus than in E18.5 embryos (0.77% vs. 0.58%, p=0.022), which is in contrast with the findings in Neurog3-Timer and Ins1-Timer pancreata. Thus, parturition events suppress the generation of endocrine progenitors and β cells, but not α-cell genesis, which may reflect distinct molecular mechanisms in α-cell lineage during parturition. Disclosure A. Suzuki: None. T. Taguchi: None. S. Ito: None. H. Shimotatara: None. K. Kimura: None. N. Shimizu: None. R. Fujishima: None. M. Himuro: None. T. Miyatsuka: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730472","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}
XIAOMENG HU, KATHY WHITE, CHI YOUNG, ARI G. OLROYD, PAUL KIEVIT, ANDREW CONNOLLY, TOBIAS DEUSE, SONJA SCHREPFER
Treatment of type 1 diabetes mellitus (T1DM) via allogeneic donor transplant has limited success due to morbidities from immunosuppression (IS) and a gradual loss of engrafted pancreatic islet function. We report that allogeneic transplantation of engineered, primary, hypoimmune, pseudo-islets (HIP p-islets) engraft into a fully immunocompetent, diabetic non-human primate (NHP), provide stable endocrine function, and enable insulin independence without inducing any detectable immune response in the absence of IS. NHP cadaveric islet cells were engineered to disrupt function of MHC class I and II and overexpress CD47 thus rendering them hypoimmune (HIP). Diabetes was induced in the NHP with streptozotocin and daily insulin injections started to re-establish glucose control. After 78 days, NHP underwent transplantation of HIP p-islets by intramuscular injection resulting in insulin independence. As early as one week after the transplantation, the NHP’s serum c-peptide level had normalized and remained stable throughout the follow-up period of 6 months. The NHP showed tightly controlled blood glucose levels for 6 months, was completely insulin-independent, and continuously healthy. Up to 6 months after HIP p-islet transplantation, PBMCs and serum were obtained for immune analyses. HIP PI showed no T cell recognition, no graft-specific antibodies, and were protected from NK cell and macrophage killing. To prove that the monkey’s insulin-independence was fully dependent on the HIP p-islets graft and there was no regeneration of his endogenous islet cell population, we triggered the destruction of the HIP p-islet transplant using a CD47-targeting strategy resulting in loss of glycemic control and return to exogenous insulin dependence. These data demonstrate evidence for immune evasion of HIP p-islets, graft mediated insulin-independence of the diabetic NHP, and a potential safety strategy. Disclosure X. Hu: Employee; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology. K. White: None. C. Young: Employee; Sana biotechnology. Stock/Shareholder; Sana biotechnology. A.G. Olroyd: Employee; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology. P. Kievit: Consultant; Alnylam Pharmaceuticals, Inc., Embark Bio. Research Support; Sana Biotechnology, Novo Nordisk A/S. A. Connolly: None. T. Deuse: Stock/Shareholder; Sana Biotechnology, Shinobi Therapeutics. S. Schrepfer: Stock/Shareholder; Sana Biotechnology. Employee; Sana Biotechnology.
通过异体供体移植治疗 1 型糖尿病（T1DM）的成功率有限，原因是免疫抑制（IS）和移植胰岛功能逐渐丧失造成的发病率。我们报告说，异体移植工程化、原发性、低免疫、假性胰岛细胞（HIP p-islets）可接种到完全免疫功能健全的糖尿病非人灵长类动物（NHP）体内，提供稳定的内分泌功能，并在无 IS 的情况下实现胰岛素独立，而不会诱发任何可检测到的免疫反应。对非人灵长类尸体胰岛细胞进行了改造，以破坏 MHC I 类和 II 类的功能，并过度表达 CD47，从而使其免疫力低下（HIP）。用链脲佐菌素诱导 NHP 患上糖尿病，并开始每天注射胰岛素以重建血糖控制。78 天后，通过肌肉注射移植 HIP p-islets 使 NHP 不再依赖胰岛素。早在移植后一周，NHP 的血清 c 肽水平就已恢复正常，并在 6 个月的随访期间保持稳定。在长达 6 个月的时间里，NHP 的血糖水平得到严格控制，完全不依赖胰岛素，身体持续健康。HIP p-islet移植6个月后，采集了PBMCs和血清进行免疫分析。HIP PI 没有出现 T 细胞识别，没有移植物特异性抗体，并且不会被 NK 细胞和巨噬细胞杀死。为了证明猴子的胰岛素依赖性完全依赖于 HIP p 型胰岛移植，其内源性胰岛细胞群没有再生，我们使用 CD47 靶向策略触发了对 HIP p 型胰岛移植的破坏，导致血糖失控，恢复了外源性胰岛素依赖性。这些数据证明了 HIP p-islet 的免疫逃避、糖尿病 NHP 移植介导的胰岛素依赖性以及潜在的安全策略。披露信息 X. Hu：员工；萨纳生物技术公司。萨纳生物技术公司股票/股东。K. White：无。C. Young：萨纳生物技术公司员工。萨纳生物技术公司股票/股东。A.G. Olroyd：员工；萨纳生物技术公司。萨纳生物技术公司股票/股东。P. Kievit：顾问; Alnylam Pharmaceuticals, Inc.研究支持；萨纳生物技术公司、诺和诺德公司。A. Connolly：无。T. Deuse：股票/股东；Sana 生物技术公司、Shinobi Therapeutics。S. Schrepfer：股票/股东；萨纳生物技术公司。萨纳生物技术公司员工。
{"title":"333-OR: Hypoimmune Islet Cells Mediate Insulin Independence after Allogeneic Transplantation in a Fully Immunocompetent Nonhuman Primate without Immunosuppression","authors":"XIAOMENG HU, KATHY WHITE, CHI YOUNG, ARI G. OLROYD, PAUL KIEVIT, ANDREW CONNOLLY, TOBIAS DEUSE, SONJA SCHREPFER","doi":"10.2337/db24-333-or","DOIUrl":"https://doi.org/10.2337/db24-333-or","url":null,"abstract":"Treatment of type 1 diabetes mellitus (T1DM) via allogeneic donor transplant has limited success due to morbidities from immunosuppression (IS) and a gradual loss of engrafted pancreatic islet function. We report that allogeneic transplantation of engineered, primary, hypoimmune, pseudo-islets (HIP p-islets) engraft into a fully immunocompetent, diabetic non-human primate (NHP), provide stable endocrine function, and enable insulin independence without inducing any detectable immune response in the absence of IS. NHP cadaveric islet cells were engineered to disrupt function of MHC class I and II and overexpress CD47 thus rendering them hypoimmune (HIP). Diabetes was induced in the NHP with streptozotocin and daily insulin injections started to re-establish glucose control. After 78 days, NHP underwent transplantation of HIP p-islets by intramuscular injection resulting in insulin independence. As early as one week after the transplantation, the NHP’s serum c-peptide level had normalized and remained stable throughout the follow-up period of 6 months. The NHP showed tightly controlled blood glucose levels for 6 months, was completely insulin-independent, and continuously healthy. Up to 6 months after HIP p-islet transplantation, PBMCs and serum were obtained for immune analyses. HIP PI showed no T cell recognition, no graft-specific antibodies, and were protected from NK cell and macrophage killing. To prove that the monkey’s insulin-independence was fully dependent on the HIP p-islets graft and there was no regeneration of his endogenous islet cell population, we triggered the destruction of the HIP p-islet transplant using a CD47-targeting strategy resulting in loss of glycemic control and return to exogenous insulin dependence. These data demonstrate evidence for immune evasion of HIP p-islets, graft mediated insulin-independence of the diabetic NHP, and a potential safety strategy. Disclosure X. Hu: Employee; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology. K. White: None. C. Young: Employee; Sana biotechnology. Stock/Shareholder; Sana biotechnology. A.G. Olroyd: Employee; Sana Biotechnology. Stock/Shareholder; Sana Biotechnology. P. Kievit: Consultant; Alnylam Pharmaceuticals, Inc., Embark Bio. Research Support; Sana Biotechnology, Novo Nordisk A/S. A. Connolly: None. T. Deuse: Stock/Shareholder; Sana Biotechnology, Shinobi Therapeutics. S. Schrepfer: Stock/Shareholder; Sana Biotechnology. Employee; Sana Biotechnology.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730476","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}
CRISTIAN LORETELLI, AHMED GOUDA ABDELRAHMAN ABDELSALAM, MOUFIDA BEN NASR, VERA USUELLI, EMMA ASSI, MONICA ZOCCHI, ADRIANA PETRAZZUOLO, AGNESE PETITTI, GIUSEPPE CANNALIRE, FRANCESCA D'ADDIO, CHIARA MAMELI, PAOLO FIORINA
Introduction & Objective: Approximately 50% of patients with new-onset Type 1 Diabetes (T1D) experience a temporary recovery in pancreatic β-cell function, termed the "honeymoon" (HM) phase, lasting approximately 7-9 months on average, and only rarely extending to years. This phase provides a crucial window for interventions to preserve insulin secretion, yet the factors contributing to its occurrence remain unclear. This study presents the first comprehensive multi-omic profiling of children with new-onset T1D in an extended honeymoon phase (ExMoon), revealing potential molecular targets for preserving β-cell mass and function. Methods: Patients in ExMoon were defined by insulin dose-adjusted HbA1c (IDAA1c) below 9 and C peptide >300 pmol/l, sustained for at least 9 months. We conducted analyses of PBMC immunophenotype, immunoreactivity to islet antigens, serum secretomics, proteomics/metabolomics/lipidomics, and PBMC transcriptomics using flow cytometry, ELISpot, immunomagnetic separation, mass spectrometry, and RNA sequencing, respectively. Profiles of ExMoon patients were compared to age- and gender-matched patients with T1D not in the HM phase (n=10 per group), with 10 matched nondiabetic patients included as additional controls. Results: Differential serum levels of immune factors (IP-10, IL-2, FGF2), proteins (TGM2, SIR4), metabolites (kynurenine), and lipids (myristic acid and monoarachidonic acid triglyceride 18:0_38:6) were observed in ExMoon compared to the T1D group. PBMCs obtained from patients of the two groups exhibited distinct expression patterns of ERAP2, TSKS mRNAs, and of miR-339-3p, miR-8087-3p miRNAs. No differences were found in the proportion of immune cell subpopulations and islet autoreactivity between the ExMoon and T1D patient cohorts. Conclusion: Our unbiased multiomic approach identified several immune and non-immune factors as potential molecular candidates for targeted therapies aimed at preserving β-cell mass and function. Disclosure C. Loretelli: None. A. Gouda Abdelrahman Abdelsalam: None. M. Ben Nasr: Research Support; Altheia Sciences. V. Usuelli: None. E. Assi: None. M. Zocchi: None. A. Petrazzuolo: None. A. Petitti: None. G. Cannalire: None. F. D'Addio: None. C. Mameli: None. P. Fiorina: None. Funding Fondazione "Romeo ed Enrica Invernizzi"
{"title":"332-OR: Multiomic Profiling of Extended Honeymoon Unveils New Therapeutic Targets","authors":"CRISTIAN LORETELLI, AHMED GOUDA ABDELRAHMAN ABDELSALAM, MOUFIDA BEN NASR, VERA USUELLI, EMMA ASSI, MONICA ZOCCHI, ADRIANA PETRAZZUOLO, AGNESE PETITTI, GIUSEPPE CANNALIRE, FRANCESCA D'ADDIO, CHIARA MAMELI, PAOLO FIORINA","doi":"10.2337/db24-332-or","DOIUrl":"https://doi.org/10.2337/db24-332-or","url":null,"abstract":"Introduction & Objective: Approximately 50% of patients with new-onset Type 1 Diabetes (T1D) experience a temporary recovery in pancreatic β-cell function, termed the \"honeymoon\" (HM) phase, lasting approximately 7-9 months on average, and only rarely extending to years. This phase provides a crucial window for interventions to preserve insulin secretion, yet the factors contributing to its occurrence remain unclear. This study presents the first comprehensive multi-omic profiling of children with new-onset T1D in an extended honeymoon phase (ExMoon), revealing potential molecular targets for preserving β-cell mass and function. Methods: Patients in ExMoon were defined by insulin dose-adjusted HbA1c (IDAA1c) below 9 and C peptide &gt;300 pmol/l, sustained for at least 9 months. We conducted analyses of PBMC immunophenotype, immunoreactivity to islet antigens, serum secretomics, proteomics/metabolomics/lipidomics, and PBMC transcriptomics using flow cytometry, ELISpot, immunomagnetic separation, mass spectrometry, and RNA sequencing, respectively. Profiles of ExMoon patients were compared to age- and gender-matched patients with T1D not in the HM phase (n=10 per group), with 10 matched nondiabetic patients included as additional controls. Results: Differential serum levels of immune factors (IP-10, IL-2, FGF2), proteins (TGM2, SIR4), metabolites (kynurenine), and lipids (myristic acid and monoarachidonic acid triglyceride 18:0_38:6) were observed in ExMoon compared to the T1D group. PBMCs obtained from patients of the two groups exhibited distinct expression patterns of ERAP2, TSKS mRNAs, and of miR-339-3p, miR-8087-3p miRNAs. No differences were found in the proportion of immune cell subpopulations and islet autoreactivity between the ExMoon and T1D patient cohorts. Conclusion: Our unbiased multiomic approach identified several immune and non-immune factors as potential molecular candidates for targeted therapies aimed at preserving β-cell mass and function. Disclosure C. Loretelli: None. A. Gouda Abdelrahman Abdelsalam: None. M. Ben Nasr: Research Support; Altheia Sciences. V. Usuelli: None. E. Assi: None. M. Zocchi: None. A. Petrazzuolo: None. A. Petitti: None. G. Cannalire: None. F. D'Addio: None. C. Mameli: None. P. Fiorina: None. Funding Fondazione \"Romeo ed Enrica Invernizzi\"","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730542","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}
THIM PRÆTORIUS, ANNE SOFIE B. LUNDBERG, ESKILD K. FREDSLUND, NIKLAS B. ROSSEN, SØREN GREGERSEN, ANDERS PRIOR, ESBEN SØNDERGAARD, SOREN T. KNUDSEN, ANNELLI SANDBÆK
Introduction and objective: To close treatment gaps in type 2 diabetes (T2D), a 2023 US National Clinical Care Commission calls for testing models of virtual collaboration. We examined the effect of video conferences between endocrinologists and family doctors on levels of recommended medication among persons with T2D seen in family practice. Methods: Two arm, pragmatic RCT with 25 family practices (mean no. of patients: 4,245) from Aarhus Municipality, Denmark (identified after inviting all 100), and one endocrinology department. Family practices were randomized 1:1 to usual phone-based hospital support or a sequence of four video conferences (45 min) with an endocrinologist over 12 months. Co-primary outcomes at months 12-15 were the proportion of persons with T2D and 1) ischemic heart disease and/or stroke receiving GLP1-RA and/or SGLT2 inhibitor; 2) micro/macro-albuminuria receiving ACE/AT2; and 3) LDL >2.5 mmol/L receiving statins. Secondary outcomes were the proportion below treatment cut-offs e.g.: HbA1c <58 mmol/L; systolic BP <140 mm Hg. Data were collected from electronic records and analyzed using t-tests. Results: Fourteen family practices were randomized to the intervention and 11 to usual support: no significant differences in practice characteristics. At the trial end, in the intervention and control groups: 65.2% and 47.6% of persons with T2D and ischemic heart disease and/or stroke received GLP1-RA and/or SGLT2 inhibitor (CI 4.6;30.7%); 94.7% and 95.8% of persons with T2D and micro/macro-albuminuria received ACE/AT2 (CI -2.8;0.6%); and 90.1% and 90.1% of persons with T2D and LDL>2.5 mmol/L received statins (CI -3.5;3.6%). We found no significant differences in secondary outcomes. Conclusion: Video conferences between endocrinologists and family doctors can close gaps in medication treatment for persons with T2D and CVD by accelerating knowledge diffusion and collaboration. Disclosure T. Prætorius: Research Support; Novo Nordisk Foundation. A.B. Lundberg: Other Relationship; Novo Nordisk Foundation. E.K. Fredslund: Consultant; Novartis Denmark. N.B. Rossen: None. S. Gregersen: None. A. Prior: None. E. Søndergaard: None. S.T. Knudsen: Other Relationship; Boehringer-Ingelheim, Sanofi, Mundipharma, Novo Nordisk A/S, Merck Sharp & Dohme Corp., Abbott, Bayer Inc. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. A. Sandbæk: Board Member; Boehringer-Ingelheim. Funding Quality and Training Committee of Central Denmark Region (1-30-72-404-21); Novo Nordisk Foundation (NNF17SA0031230-1)
{"title":"192-OR: Effect of Video Conferences between Endocrinologists and Family Doctors on Levels of Recommended Medication among Persons with Type 2 Diabetes—Pragmatic RCT","authors":"THIM PRÆTORIUS, ANNE SOFIE B. LUNDBERG, ESKILD K. FREDSLUND, NIKLAS B. ROSSEN, SØREN GREGERSEN, ANDERS PRIOR, ESBEN SØNDERGAARD, SOREN T. KNUDSEN, ANNELLI SANDBÆK","doi":"10.2337/db24-192-or","DOIUrl":"https://doi.org/10.2337/db24-192-or","url":null,"abstract":"Introduction and objective: To close treatment gaps in type 2 diabetes (T2D), a 2023 US National Clinical Care Commission calls for testing models of virtual collaboration. We examined the effect of video conferences between endocrinologists and family doctors on levels of recommended medication among persons with T2D seen in family practice. Methods: Two arm, pragmatic RCT with 25 family practices (mean no. of patients: 4,245) from Aarhus Municipality, Denmark (identified after inviting all 100), and one endocrinology department. Family practices were randomized 1:1 to usual phone-based hospital support or a sequence of four video conferences (45 min) with an endocrinologist over 12 months. Co-primary outcomes at months 12-15 were the proportion of persons with T2D and 1) ischemic heart disease and/or stroke receiving GLP1-RA and/or SGLT2 inhibitor; 2) micro/macro-albuminuria receiving ACE/AT2; and 3) LDL &gt;2.5 mmol/L receiving statins. Secondary outcomes were the proportion below treatment cut-offs e.g.: HbA1c &lt;58 mmol/L; systolic BP &lt;140 mm Hg. Data were collected from electronic records and analyzed using t-tests. Results: Fourteen family practices were randomized to the intervention and 11 to usual support: no significant differences in practice characteristics. At the trial end, in the intervention and control groups: 65.2% and 47.6% of persons with T2D and ischemic heart disease and/or stroke received GLP1-RA and/or SGLT2 inhibitor (CI 4.6;30.7%); 94.7% and 95.8% of persons with T2D and micro/macro-albuminuria received ACE/AT2 (CI -2.8;0.6%); and 90.1% and 90.1% of persons with T2D and LDL&gt;2.5 mmol/L received statins (CI -3.5;3.6%). We found no significant differences in secondary outcomes. Conclusion: Video conferences between endocrinologists and family doctors can close gaps in medication treatment for persons with T2D and CVD by accelerating knowledge diffusion and collaboration. Disclosure T. Prætorius: Research Support; Novo Nordisk Foundation. A.B. Lundberg: Other Relationship; Novo Nordisk Foundation. E.K. Fredslund: Consultant; Novartis Denmark. N.B. Rossen: None. S. Gregersen: None. A. Prior: None. E. Søndergaard: None. S.T. Knudsen: Other Relationship; Boehringer-Ingelheim, Sanofi, Mundipharma, Novo Nordisk A/S, Merck Sharp & Dohme Corp., Abbott, Bayer Inc. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. A. Sandbæk: Board Member; Boehringer-Ingelheim. Funding Quality and Training Committee of Central Denmark Region (1-30-72-404-21); Novo Nordisk Foundation (NNF17SA0031230-1)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730551","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}
IHSAN ALMARZOOQI, HALA ZAKARIA, MILENA CACCELLI, CIGDEM OZKAN, JESTONI BANGAYAN, MIRABELLE C. DANDAN, DIANNE JANE DIVINO, SOFIA ALEABOVA, YOUSEF SAID, ALI HASHEMI
Continuous monitoring in diabetes care enhances access, convenience, adherence, and glycemic control. Challenges in digital-only solutions include trust-building and limitations in face-to-face interactions, along with the lack of engagement by care teams outside the clinic setting. A hybrid model where providers incorporate both remote data monitoring and engagement with in-person visits would address these challenges. The aim of this study is to evaluate the impact of implementing the hybrid care approach on patients with T2D on glycemic control and clinical outcomes. A retrospective case-control observational study over 3 months by a hybrid provider (GluCare.Health) in the UAE included patients with T2D (n=262). The case group had both in-clinic visits and bi-weekly virtual engagements via an app that included a range of caregivers (physicians, dietitians, educators and coaches, n=162). The control group only conducted in-clinic visits without virtual engagement mimicking traditional, episodic care (n=100). Engagement data included dietary, lifestyle, medication, exercise and continuous glucose monitoring interactions. The case group (hybrid model) showed significant HbA1c improvements (-2.19%) (-25%) compared to the control group (-0.10%). Patients with higher baseline HbA1c (≥ 9.0%) experienced greater reductions (-3.67%) (-34%). The case group also showed improvements in weight (-6%), BMI (-6%), LDL (-21%), total cholesterol (-17%), and CVD risk (-41%). The control group had smaller improvements (p >0.05). Engagement strongly correlated with better outcomes; patients with ≥11 interactions (over 90 days) showed significant reductions in HbA1c (-2.38%) and weight (-6.00 kg) in comparison with those <11. The GluCare.Health hybrid model demonstrates promising outcomes in Type 2 diabetes management with a strong correlation between the number of remote engagement and outcomes in comparison to results seen in the physical-only (traditional-care like) control group. Disclosure I. Almarzooqi: None. H. Zakaria: None. M. Caccelli: None. C. Ozkan: None. J. Bangayan: None. M.C. Dandan: None. D. Divino: None. S. Aleabova: None. Y. Said: None. A. Hashemi: None.
{"title":"1092-P: Effectiveness of a Hybrid Care Model for Type 2 Diabetes —A Three-Month Evaluation","authors":"IHSAN ALMARZOOQI, HALA ZAKARIA, MILENA CACCELLI, CIGDEM OZKAN, JESTONI BANGAYAN, MIRABELLE C. DANDAN, DIANNE JANE DIVINO, SOFIA ALEABOVA, YOUSEF SAID, ALI HASHEMI","doi":"10.2337/db24-1092-p","DOIUrl":"https://doi.org/10.2337/db24-1092-p","url":null,"abstract":"Continuous monitoring in diabetes care enhances access, convenience, adherence, and glycemic control. Challenges in digital-only solutions include trust-building and limitations in face-to-face interactions, along with the lack of engagement by care teams outside the clinic setting. A hybrid model where providers incorporate both remote data monitoring and engagement with in-person visits would address these challenges. The aim of this study is to evaluate the impact of implementing the hybrid care approach on patients with T2D on glycemic control and clinical outcomes. A retrospective case-control observational study over 3 months by a hybrid provider (GluCare.Health) in the UAE included patients with T2D (n=262). The case group had both in-clinic visits and bi-weekly virtual engagements via an app that included a range of caregivers (physicians, dietitians, educators and coaches, n=162). The control group only conducted in-clinic visits without virtual engagement mimicking traditional, episodic care (n=100). Engagement data included dietary, lifestyle, medication, exercise and continuous glucose monitoring interactions. The case group (hybrid model) showed significant HbA1c improvements (-2.19%) (-25%) compared to the control group (-0.10%). Patients with higher baseline HbA1c (≥ 9.0%) experienced greater reductions (-3.67%) (-34%). The case group also showed improvements in weight (-6%), BMI (-6%), LDL (-21%), total cholesterol (-17%), and CVD risk (-41%). The control group had smaller improvements (p &gt;0.05). Engagement strongly correlated with better outcomes; patients with ≥11 interactions (over 90 days) showed significant reductions in HbA1c (-2.38%) and weight (-6.00 kg) in comparison with those &lt;11. The GluCare.Health hybrid model demonstrates promising outcomes in Type 2 diabetes management with a strong correlation between the number of remote engagement and outcomes in comparison to results seen in the physical-only (traditional-care like) control group. Disclosure I. Almarzooqi: None. H. Zakaria: None. M. Caccelli: None. C. Ozkan: None. J. Bangayan: None. M.C. Dandan: None. D. Divino: None. S. Aleabova: None. Y. Said: None. A. Hashemi: None.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730615","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}
ALICE L.J. CARR, BRAULIO A. MARFIL-GARZA, ANNA LAM, BLAIRE L. ANDERSON, DOUG O'GORMAN, TATSUYA KIN, DAVID BIGAM, A.M. JAMES SHAPIRO, PETER A. SENIOR
Islet transplantation (ITx) is an established treatment for recurrent, severe hypoglycemia in type 1 diabetes, however, requires lifelong immunosuppression (IS) which can be nephrotoxic. We conducted a risk regression to identify factors associated with progression to Stage 3 CKD (S3CKD) or worse post-ITx. We used data from adults undergoing ITx alone at the University of Alberta Hospital between March 11 1999 and Oct 1 2019 with >1 year follow up. IS included tacrolimus and sirolimus/mycophenolate. We identified episodes of irreversible S3CKD as eGFR <60 ml/min/1.73m2 for ≥90d in addition to a final 12m average eGFR below threshold. We conducted multivariable competing risk (death) regression with the covariates: baseline eGFR, age at first ITx, diabetes duration, total ITx count, mean tacrolimus trough levels in year 1 post-ITx, number of acute kidney injury (AKI) events in year 1 post-ITx, sex, baseline hypertension and sirolimus exposure. We identified 199 adults (41% M followed for a median 76.1m [IQR 38.0-131.6]), of which 47.7% progressed to S3CKD within a median 28m [IQR 9-57]. Female sex and more AKI events substantially increased the risk of progression to S3CKD (HR 1.50, [95% CI 1.31,1.80, p =0.004; HR 1.21, [95% CI 1.02, 1.45, p=0.028] respectively). Older age at first-ITx, lower baseline eGFR and longer diabetes duration had modest effect of significance on the risk of progression. Mean tacrolimus level in the first year post-ITx, number of ITx, baseline hypertension and exposure to sirolimus were not significant predictors for the risk of progression to S3CKD. No sex differences were found in risk for Stage 4 or 5 CKD. IS may put female ITx recipients at greater hazard of progressing to S3CKD, independently of other potential risk factors. Further study is required to elucidate this association, which could translate into sex-specific strategies to manage IS post-ITx. Effective IS regimens without nephrotoxicity remain an important goal. Disclosure A.L.J. Carr: None. B.A. Marfil-Garza: None. A. Lam: None. B.L. Anderson: None. D. O'Gorman: None. T. Kin: None. D. Bigam: None. A. Shapiro: Consultant; Vertex Pharmaceuticals Incorporated, Betalin Therapeutics, Hemostemix Inc, ViaCyte, Inc., Aspect Biosystems. P.A. Senior: Consultant; Abbott, Bayer Inc., Dexcom, Inc., Eli Lilly and Company, GlaxoSmithKline plc, Insulet Corporation, Novo Nordisk Canada Inc., Sanofi, Vertex Pharmaceuticals Incorporated. Speaker's Bureau; Abbott, Dexcom, Inc., Insulet Corporation, Novo Nordisk Canada Inc. Research Support; Novo Nordisk Canada Inc.
{"title":"336-OR: Females Undergoing Islet Transplantation with CNI-Based Immunosuppression May Be at Higher Risk of Renal Function Decline","authors":"ALICE L.J. CARR, BRAULIO A. MARFIL-GARZA, ANNA LAM, BLAIRE L. ANDERSON, DOUG O'GORMAN, TATSUYA KIN, DAVID BIGAM, A.M. JAMES SHAPIRO, PETER A. SENIOR","doi":"10.2337/db24-336-or","DOIUrl":"https://doi.org/10.2337/db24-336-or","url":null,"abstract":"Islet transplantation (ITx) is an established treatment for recurrent, severe hypoglycemia in type 1 diabetes, however, requires lifelong immunosuppression (IS) which can be nephrotoxic. We conducted a risk regression to identify factors associated with progression to Stage 3 CKD (S3CKD) or worse post-ITx. We used data from adults undergoing ITx alone at the University of Alberta Hospital between March 11 1999 and Oct 1 2019 with &gt;1 year follow up. IS included tacrolimus and sirolimus/mycophenolate. We identified episodes of irreversible S3CKD as eGFR &lt;60 ml/min/1.73m2 for ≥90d in addition to a final 12m average eGFR below threshold. We conducted multivariable competing risk (death) regression with the covariates: baseline eGFR, age at first ITx, diabetes duration, total ITx count, mean tacrolimus trough levels in year 1 post-ITx, number of acute kidney injury (AKI) events in year 1 post-ITx, sex, baseline hypertension and sirolimus exposure. We identified 199 adults (41% M followed for a median 76.1m [IQR 38.0-131.6]), of which 47.7% progressed to S3CKD within a median 28m [IQR 9-57]. Female sex and more AKI events substantially increased the risk of progression to S3CKD (HR 1.50, [95% CI 1.31,1.80, p =0.004; HR 1.21, [95% CI 1.02, 1.45, p=0.028] respectively). Older age at first-ITx, lower baseline eGFR and longer diabetes duration had modest effect of significance on the risk of progression. Mean tacrolimus level in the first year post-ITx, number of ITx, baseline hypertension and exposure to sirolimus were not significant predictors for the risk of progression to S3CKD. No sex differences were found in risk for Stage 4 or 5 CKD. IS may put female ITx recipients at greater hazard of progressing to S3CKD, independently of other potential risk factors. Further study is required to elucidate this association, which could translate into sex-specific strategies to manage IS post-ITx. Effective IS regimens without nephrotoxicity remain an important goal. Disclosure A.L.J. Carr: None. B.A. Marfil-Garza: None. A. Lam: None. B.L. Anderson: None. D. O'Gorman: None. T. Kin: None. D. Bigam: None. A. Shapiro: Consultant; Vertex Pharmaceuticals Incorporated, Betalin Therapeutics, Hemostemix Inc, ViaCyte, Inc., Aspect Biosystems. P.A. Senior: Consultant; Abbott, Bayer Inc., Dexcom, Inc., Eli Lilly and Company, GlaxoSmithKline plc, Insulet Corporation, Novo Nordisk Canada Inc., Sanofi, Vertex Pharmaceuticals Incorporated. Speaker's Bureau; Abbott, Dexcom, Inc., Insulet Corporation, Novo Nordisk Canada Inc. Research Support; Novo Nordisk Canada Inc.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730470","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}
JUSTIN LO, SUSAN J. MELHORN, KELSEY OLERICH, ALYSSA HUANG, SARAH KEE, ALEXA BEISER, SUDHA SESHADRI, CHARLES DECARLI, ELLEN SCHUR
Introduction: Hypothalamic gliosis is linked to obesity and insulin resistance in rodent models and humans. We tested associations between a radiologic measure of hypothalamic gliosis and clinically relevant cardiovascular disease (CVD) risk factors, as well as prevalent coronary heart disease (CHD). Methods: Using brain MRI images from FHS participants (n=867), T2 signal intensities were extracted bilaterally from the region of interest in the mediobasal hypothalamus (MBH) and reference regions in amygdala (AMY) and putamen (PUT). T2 signal ratios were created in which greater values suggest gliosis. The primary measure compared MBH to AMY (MBH/AMY); a positive control ratio (MBH/PUT) also assessed MBH whereas a negative control (PUT/AMY) did not. Outcomes were BMI, HDL-C, LDL-C, triglycerides, and the presence of hypertension (HTN; n=225), diabetes mellitus (DM; n=66), or metabolic syndrome (MetS; n=254). Prevalent CHD (n=22) was adjudicated by FHS. Linear and logistic regression models included age, sex, smoking, treatment status (e.g., lipids), and BMI (for outcomes except BMI and MetS). Results: Mean age was 54.9±8.8 y; 54.9% were female. Greater MBH/AMY ratios were associated with higher BMI (P<0.001). MBH/AMY ratios were associated with higher triglycerides, presence of HTN, and lower HDL-C, and the latter two were independent of BMI (both P<0.05). Results were consistent for the MBH/PUT ratios (all P<0.05). Findings for DM were mixed and attenuated by adjusting for BMI. MetS was strongly associated with MBH/AMY and MBH/PUT ratios (P<0.001). PUT/AMY ratios were unrelated to any outcome. No T2 signal ratio was associated with prevalent CHD (P>0.05), and confidence intervals were wide. Conclusion: Using a well-established study of CVD development, we found evidence linking hypothalamic gliosis to multiple CVD risk factors, independent of adiposity. Our results highlight the need to consider neurologic mechanisms in efforts to understand and improve cardiometabolic health. Disclosure J. Lo: None. S.J. Melhorn: None. K. Olerich: None. A. Huang: None. S. Kee: None. A. Beiser: None. S. Seshadri: None. C. DeCarli: None. E. Schur: Consultant; Amgen Inc. Funding National Institutes of Health (K24 HL144917; R01 DK089036; R01 DK117623; R01 DK098466; P30 DK035816)
{"title":"346-OR: Hypothalamic Gliosis Is Associated with CVD Risk Factors in the Framingham Heart Study (FHS)","authors":"JUSTIN LO, SUSAN J. MELHORN, KELSEY OLERICH, ALYSSA HUANG, SARAH KEE, ALEXA BEISER, SUDHA SESHADRI, CHARLES DECARLI, ELLEN SCHUR","doi":"10.2337/db24-346-or","DOIUrl":"https://doi.org/10.2337/db24-346-or","url":null,"abstract":"Introduction: Hypothalamic gliosis is linked to obesity and insulin resistance in rodent models and humans. We tested associations between a radiologic measure of hypothalamic gliosis and clinically relevant cardiovascular disease (CVD) risk factors, as well as prevalent coronary heart disease (CHD). Methods: Using brain MRI images from FHS participants (n=867), T2 signal intensities were extracted bilaterally from the region of interest in the mediobasal hypothalamus (MBH) and reference regions in amygdala (AMY) and putamen (PUT). T2 signal ratios were created in which greater values suggest gliosis. The primary measure compared MBH to AMY (MBH/AMY); a positive control ratio (MBH/PUT) also assessed MBH whereas a negative control (PUT/AMY) did not. Outcomes were BMI, HDL-C, LDL-C, triglycerides, and the presence of hypertension (HTN; n=225), diabetes mellitus (DM; n=66), or metabolic syndrome (MetS; n=254). Prevalent CHD (n=22) was adjudicated by FHS. Linear and logistic regression models included age, sex, smoking, treatment status (e.g., lipids), and BMI (for outcomes except BMI and MetS). Results: Mean age was 54.9±8.8 y; 54.9% were female. Greater MBH/AMY ratios were associated with higher BMI (P&lt;0.001). MBH/AMY ratios were associated with higher triglycerides, presence of HTN, and lower HDL-C, and the latter two were independent of BMI (both P&lt;0.05). Results were consistent for the MBH/PUT ratios (all P&lt;0.05). Findings for DM were mixed and attenuated by adjusting for BMI. MetS was strongly associated with MBH/AMY and MBH/PUT ratios (P&lt;0.001). PUT/AMY ratios were unrelated to any outcome. No T2 signal ratio was associated with prevalent CHD (P&gt;0.05), and confidence intervals were wide. Conclusion: Using a well-established study of CVD development, we found evidence linking hypothalamic gliosis to multiple CVD risk factors, independent of adiposity. Our results highlight the need to consider neurologic mechanisms in efforts to understand and improve cardiometabolic health. Disclosure J. Lo: None. S.J. Melhorn: None. K. Olerich: None. A. Huang: None. S. Kee: None. A. Beiser: None. S. Seshadri: None. C. DeCarli: None. E. Schur: Consultant; Amgen Inc. Funding National Institutes of Health (K24 HL144917; R01 DK089036; R01 DK117623; R01 DK098466; P30 DK035816)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730477","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}
JEAN-PIERRE RIVELINE, GAETAN PREVOST, ANAIS ANDRIEU, MICHAEL JOUBERT, PHILIPPE ORIOT, ALFRED PENFORNIS, JEAN-CHRISTOPHE PHILIPS, JEAN-BAPTISTE JULLA, EMMANUEL COSSON
A discrepancy between laboratory-measured HbA1c and Glucose Management Indicator (GMI), estimated from continuous glucose monitoring, is frequently encountered in clinical practice. However, its evolution over time is not yet known. Methodology: We conducted a multicenter retrospective study (9 centers) that collected pairs of HbA1c and GMI (calculated over 90 days) at T0, T1 year, T2 years of follow-up in patients with diabetes, all users of FreeStyleLibre®. The primary study endpoint was the analysis of the mean HbA1c-GMI differences at the 3 time points. Glucose data, clinical parameters, and complications were also analyzed. Patients were classified based on the HbA1c-GMI discrepancy: positive (PosD, HbA1c-GMI>+0.3%), neutral (NullD, HbA1c-GMI from -0.3 to +0.3%), negative (NegD, HbA1c-GMI< -0.3%) at each time point, and with the average differences over the 3 time points. Group comparisons were assessed using ANOVA. Result: We included 347 patients (82% type 1 diabetes), mean age of 51±17 years, diabetes duration 20±13 years, HbA1c 7.6±1.0%, 90±9% CGM data collected, Time in Range 70-180 mg/dl (TIR) 57±17%, GMI 7.4±0.8%. The mean HbA1c-GMI differed over time (T0: 0.27%, T1 year: 0.16%, T2 years: 0.04%, P<0.0001). Considering the mean HbA1c-GMI differences over the 3 time points for all patients, PosD individuals were statistically older, had higher BMI and HbA1c compared to NegD patients. At T0, the patients were distributed as follows: 168 PosD (48.4%), 129 NullD (37.2%), 50 NegD (14.4%). The 121 patients (only 34.8% of the cohort) who stayed in the same group at the three time-points were 44.6% PosD, 38% NullD and 17.4% NegD. Conclusion: In only 1/3 of patients does the difference between HbA1c and GMI appear to be stable over time. This should be taken into account when analyzing the supposed poor prognosis associated with PosD. Disclosure J. Riveline: Board Member; Abbott, Novo Nordisk A/S, Sanofi, Eli Lilly and Company, Medtronic, Dexcom, Inc., Insulet Corporation, Air Liquide, AstraZeneca. G. Prevost: Board Member; Abbott. A. Andrieu: None. M. Joubert: Consultant; Abbott, Medtronic, Dexcom, Inc. P. Oriot: Research Support; Abbott. A. Penfornis: Speaker's Bureau; Sanofi, Dexcom, Inc., Diabeloop SA. Board Member; AstraZeneca. Speaker's Bureau; Novo Nordisk, Lilly Diabetes. Board Member; Novo Nordisk, Bayer Inc. Advisory Panel; Abbott, Sanofi. J. Philips: Consultant; Sanofi, Novo Nordisk, Abbott, Avazzia, Boehringer-Ingelheim, Eli Lilly and Company. J. Julla: Speaker's Bureau; Lilly Diabetes, Novo Nordisk. Board Member; Sanofi. E. Cosson: Advisory Panel; Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk, Sanofi, Roche Diagnostics, Novartis AG, Amgen Inc. Funding Abbott Diabetes Care
{"title":"1020-P: Evolution over Time of the Discrepancy between HbA1c and Glucose Management Indicator—Findings from a Franco-Belgian Cohort of 347 Patients","authors":"JEAN-PIERRE RIVELINE, GAETAN PREVOST, ANAIS ANDRIEU, MICHAEL JOUBERT, PHILIPPE ORIOT, ALFRED PENFORNIS, JEAN-CHRISTOPHE PHILIPS, JEAN-BAPTISTE JULLA, EMMANUEL COSSON","doi":"10.2337/db24-1020-p","DOIUrl":"https://doi.org/10.2337/db24-1020-p","url":null,"abstract":"A discrepancy between laboratory-measured HbA1c and Glucose Management Indicator (GMI), estimated from continuous glucose monitoring, is frequently encountered in clinical practice. However, its evolution over time is not yet known. Methodology: We conducted a multicenter retrospective study (9 centers) that collected pairs of HbA1c and GMI (calculated over 90 days) at T0, T1 year, T2 years of follow-up in patients with diabetes, all users of FreeStyleLibre®. The primary study endpoint was the analysis of the mean HbA1c-GMI differences at the 3 time points. Glucose data, clinical parameters, and complications were also analyzed. Patients were classified based on the HbA1c-GMI discrepancy: positive (PosD, HbA1c-GMI&gt;+0.3%), neutral (NullD, HbA1c-GMI from -0.3 to +0.3%), negative (NegD, HbA1c-GMI&lt; -0.3%) at each time point, and with the average differences over the 3 time points. Group comparisons were assessed using ANOVA. Result: We included 347 patients (82% type 1 diabetes), mean age of 51±17 years, diabetes duration 20±13 years, HbA1c 7.6±1.0%, 90±9% CGM data collected, Time in Range 70-180 mg/dl (TIR) 57±17%, GMI 7.4±0.8%. The mean HbA1c-GMI differed over time (T0: 0.27%, T1 year: 0.16%, T2 years: 0.04%, P&lt;0.0001). Considering the mean HbA1c-GMI differences over the 3 time points for all patients, PosD individuals were statistically older, had higher BMI and HbA1c compared to NegD patients. At T0, the patients were distributed as follows: 168 PosD (48.4%), 129 NullD (37.2%), 50 NegD (14.4%). The 121 patients (only 34.8% of the cohort) who stayed in the same group at the three time-points were 44.6% PosD, 38% NullD and 17.4% NegD. Conclusion: In only 1/3 of patients does the difference between HbA1c and GMI appear to be stable over time. This should be taken into account when analyzing the supposed poor prognosis associated with PosD. Disclosure J. Riveline: Board Member; Abbott, Novo Nordisk A/S, Sanofi, Eli Lilly and Company, Medtronic, Dexcom, Inc., Insulet Corporation, Air Liquide, AstraZeneca. G. Prevost: Board Member; Abbott. A. Andrieu: None. M. Joubert: Consultant; Abbott, Medtronic, Dexcom, Inc. P. Oriot: Research Support; Abbott. A. Penfornis: Speaker's Bureau; Sanofi, Dexcom, Inc., Diabeloop SA. Board Member; AstraZeneca. Speaker's Bureau; Novo Nordisk, Lilly Diabetes. Board Member; Novo Nordisk, Bayer Inc. Advisory Panel; Abbott, Sanofi. J. Philips: Consultant; Sanofi, Novo Nordisk, Abbott, Avazzia, Boehringer-Ingelheim, Eli Lilly and Company. J. Julla: Speaker's Bureau; Lilly Diabetes, Novo Nordisk. Board Member; Sanofi. E. Cosson: Advisory Panel; Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk, Sanofi, Roche Diagnostics, Novartis AG, Amgen Inc. Funding Abbott Diabetes Care","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730479","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：