Diabetes最新文献

{"title":"1563-P: High Fat and Fructose Feeding Severely Impairs Hepatic Glucose Effectiveness but Not Insulin Action Under Euglycemic Conditions","authors":"DALE S. EDGERTON, GUILLAUME KRAFT, HANNAH L. WATERMAN, BEN FARMER, KALISHA YANKEY, MARTA S. SMITH, JON R. HASTINGS, MELANIE SCOTT, ALAN D. CHERRINGTON","doi":"10.2337/db24-1563-p","DOIUrl":"https://doi.org/10.2337/db24-1563-p","url":null,"abstract":"Diets high in fat and fructose (HFHF) disrupt glucose metabolism. This study compared the effects of a HFHF diet on liver insulin action vs glucose effectiveness. Dogs were fed either a chow or HFHF diet for 1 month. At the start of each study, 3-3H-glucose was infused and after a basal sampling period, somatostatin and basal glucagon were given. During the experimental period (4h) either insulin was infused into the hepatic portal vein at 4 fold basal, while glucose was delivered to maintain euglycemia (CHOW-INS and HFHF-INS), or glucose was infused to increase its level 2.5 fold, while insulin was maintained at basal (CHOW-GLC and HFHF-GLC) (n=6/grp). Plasma insulin, glucagon, glucose, and hepatic glucose load were matched within the respective groups. In response to selective hyperinsulinemia, net hepatic glucose balance (NHGB) was suppressed from output to uptake (basal period to last h; 1.2±0.1 to -1.0±0.2 vs 1.7±0.2 to 0.0±0.1; deltas of 2.2±0.2 vs 1.6±0.3 mg/kg/min in CHOW-INS vs HFHF-INS, respectively; p=0.2). Selective hyperglycemia, on the other hand, caused changes in NHGB of 1.1±0.2 to -2.5±0.4 vs 1.4±0.1 to 1.7±0.6; deltas of 3.6±0.4 vs -0.3±0.6 mg/kg/min in CHOW-GLC vs HFHF-GLC, respectively (p<0.001). Glucose turnover (Ra) was suppressed (basal period to last h) by 1.7±0.3 vs 1.3±0.1 mg/kg/min (p=0.4) in CHOW-INS vs HFHF-INS, and by 1.9±0.2 vs 0.5±0.1 mg/kg/min (p<0.001) in CHOW-GLC vs HFHF-GLC, respectively. Thus, the HFHF diet had a small, non-significant effect on liver insulin action under euglycemic conditions, whereas it severely impaired the effect of hyperglycemia in the presence of basal insulin (i.e. hepatic glucose effectiveness). These data demonstrate that the “gold standard” hyperinsulinemic euglycemic clamp may overlook substantial diet induced liver dysfunction. Furthermore, Ra accounts for glucose production but not liver uptake, thus has the potential to miss critical and substantial changes in liver glucose metabolism. Disclosure D.S. Edgerton: None. G. Kraft: None. H.L. Waterman: None. B. Farmer: None. K. Yankey: None. M.S. Smith: None. J.R. Hastings: None. M. Scott: None. A.D. Cherrington: Consultant; Abvance Therapeutics. Research Support; Abvance Therapeutics. Advisory Panel; AdipoPharma. Research Support; Cellular Longevity, Inc. dba Loyal. Advisory Panel; Fractyl Health, Inc. Consultant; Fractyl Health, Inc. Research Support; Fractyl Health, Inc. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Consultant; Paratus, Portal Insulin. Advisory Panel; Sekkei Bio, Sensulin Labs, LLC. Consultant; Thetis Pharmaceuticals, LLC. Funding R01DK18243","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"24 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730471","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}

{"title":"1971-LB: Contributions of Fasting and Postprandial Glucose Increments to Overall Hyperglycemia in Pregnant Women with Type 1 Diabetes","authors":"PING LING, DAIZHI YANG, CHAOFAN WANG, XUEYING ZHENG, SIHUI LUO, XUBIN YANG, HONGRONG DENG, WEN XU, JINHUA YAN, JIANPING WENG","doi":"10.2337/db24-1971-lb","DOIUrl":"https://doi.org/10.2337/db24-1971-lb","url":null,"abstract":"Aims: To evaluate the relative contribution of fasting hyperglycemia (FHG) and postprandial hyperglycemia (PHG) to overall hyperglycemia across time in range (TIR) and glycated hemoglobin (HbA1c) categories in pregnant women with type 1 diabetes mellitus (T1DM). Materials and Methods: This observational study included 112 pregnant women with T1DM from the CARNATION study who wore continuous glucose monitoring (CGM) devices during pregnancy. The data from CGM were analyzed for TIR, AUC of PHG, AUC of FHG, FHG and PHG contribution rates. The levels of HbA1c (<6.0, 6.0-8.0, ≥8.0%) and TIR(<60, 60-78,≥78%) were categorized according to the guidelines, and the contribution of FHG and PHG to the overall hyperglycemia were compared. Results: A total of 295 CGM-HbA1c profiles were analyzed in this study. All women experienced a mean TIR of 75.6±19.0% and a mean HbA1c of 6.2±1.1% during pregnancy. The FHG contribution rates increased gradually with TIR decreasing [74.9(36.8, 100) vs. 69.1(13.4, 100) vs. 66.5 (10.0, 100), P<0.001] or with HbA1c increasing [57.8% (0, 100) vs. 72.7% (36.8, 100) vs. 80.7% (31.4, 100), P<0.001], whereas the contribution of PHG decreased progressively with diabetes worsening. Conclusions: FHG was the major contributor to hyperglycemia during pregnancy. Along with controlling the postprandial hyperglycemia, pregnant women with T1DM who did not reach the target of TIR or HbA1c may benefit more from the optimization of insulin regimens focusing on reducing the fasting hyperglycemia. Disclosure P. Ling: None. D. Yang: None. C. Wang: None. X. Zheng: None. S. Luo: None. X. Yang: None. H. Deng: None. W. Xu: None. J. Yan: None. J. Weng: None. Funding Science and Technology Planning Project of Guangzhou (grant/award number: 202102010154), Diabetes mellitus research fund program from Shanghai Medical and Health Development Foundation (grant/award number: DMRFP_II_14 from SHMHDF).","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"160 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730481","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}

{"title":"138-OR: Pioglitazone Amplifies the Decrease in HbA1c and Prevents the Increase in Plasma Ketone Caused by Dapagliflozin in Type 1 Diabetes Mellitus Patients","authors":"MUHAMMAD ABDUL-GHANI, GOZDE BASKOY, AFIF NAKHLEH, SIHAM ABDELGANI, FAHD AL-MULLA, MOHAMED ABU-FARHA, FAHAD ALAJMI, THAMER ALESSA, RALPH A. DEFRONZO, NAIM SHEHADEH","doi":"10.2337/db24-138-or","DOIUrl":"https://doi.org/10.2337/db24-138-or","url":null,"abstract":"Introduction and Objectives: SGLT2 inhibitors (SGLT2i) lower the plasma glucose concentration in T1DM patients. However, they cause an increase in plasma ketone concentration and risk of ketoacidosis. The aim of the present study is to examine whether pioglitazone amplifies the decrease in HbA1c and prevents the increase in plasma ketone concentration caused by dapagliflozin in T1DM patients. Methods: After a 4-week run in period, 60 T1DM patients received dapagliflozin 10 mg for 12 weeks. At week 16 patients were randomized to receive in double blind fashion pioglitazone (45 mg) or matching placebo for an additional 16 weeks. Results: T1DM patients were 42±3 years of age, 30% female, BMI=26.8±0.7, HbA1c=8.5±0.2%, insulin dose= 63±4 units, and eGFR=114±6 ml/min. Dapagliflozin caused -0.63±0.18%, and -0.56±0.11% decrease from baseline in HbA1c at week 16 in subjects receiving pioglitazone and placebo, respectively (both p<0.001). At week 32, the decrease from baseline in HbA1c was -0.86±0.3 and -0.44±0.17 in subjects receiving pioglitazone and placebo, respectively. Thus, the HbA1c was -0.42±0.12 lower in subjects receiving pioglitazone versus placebo (p<0.05). Plasma ketone concentration increased above baseline by 0.12±0.03 mM and 0.14±0.03 mM at week 16 in subjects receiving pioglitazone and placebo, respectively (both p<0.05). At week 32 plasma ketone concentration remained elevated above baseline in subjects receiving placebo (0.15±0.03 mM, p<0.05), and decreased below baseline (-0.06±0.02mM, p<0.05) in subjects receiving pioglitazone. Thus, the difference in plasma ketone concentration between subjects receiving pioglitazone and placebo at week 32 was -0.19±0.3, p<0.001. Conclusion: Addition of pioglitazone to SGLT2i in T1DM patients amplifies the decrease in HbA1c and prevents the increase in plasma ketone caused by SGLT2i, allowing long-term cardiovascular and renal outcome studies to be carried out safely in T1DM patients. Disclosure M. Abdul-Ghani: None. G. Baskoy: None. A. Nakhleh: None. S. Abdelgani: None. F. Al-Mulla: None. M. Abu-farha: None. F. Alajmi: Consultant; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. T. Alessa: None. R.A. DeFronzo: Advisory Panel; AstraZeneca, Novo Nordisk, Boehringer-Ingelheim, Intarcia Therapeutics, Inc., Aardvark, Renalytix, Corcept Therapeutics, Alnylam Pharmaceuticals, Inc. Research Support; Boehringer-Ingelheim, AstraZeneca, 89bio, Inc., Amgen Inc., Medality, Corcept Therapeutics. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Renalytix. N. Shehadeh: Research Support; Abbott. Advisory Panel; AstraZeneca, Eli Lilly and Company, Boehringer-Ingelheim. Research Support; Novo Nordisk Foundation. Funding The study was funded by JDRF grant to MAG. Astrazeneca provided dapagliflozin.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"35 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730473","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}

{"title":"1666-P: Effect of Obesity in Family History (FH) on the Prevalence of Type 2 Diabetes Mellitus (T2DM), Hypertension (HT), and Dyslipidemia (DL)","authors":"IZUMI IKEDA, KAZUYA FUJIHARA, YASUNAGA TAKEDA, CHIKA HORIKAWA, SATORU KODAMA, EFREM D. FERREIRA, YASUMICHI MORI, TAKASHI KADOWAKI, RITSUKO YAMAMOTO-HONDA, YASUJI ARASE, HIROHITO SONE","doi":"10.2337/db24-1666-p","DOIUrl":"https://doi.org/10.2337/db24-1666-p","url":null,"abstract":"Heritability and obesity are strongly associated with the prevalence of T2DM, HT, and DL. We compared the effects of an FH of T2DM, HT, and DL combined with obesity on the prevalence of each in the same population. Of 41931 participants who underwent health checkups, the effects of an FH and BMI on the prevalence of those conditions were analyzed cross-sectionally. Prevalences of T2DM, HT, and DL were 5%, 20%, and 48%, respectively. Logistic regression analysis showed that ORs increased for all three as the number of FH positive cases increased and was most pronounced for T2DM. An FH of obesity and increased BMI were additively associated with the prevalence of the three diseases compared to BMI 20.0-21.9 and no positive FH (Fig. A). In addition, the combination of the number of family members with FH positivity (0,1, 2, ≥3) and obesity was additively associated with an increased FH of the three diseases compared to non-obesity and no FH of any of these diseases (Fig. B). For T2DM, the OR increased sharply in non-obese participants when the number of those with an FH of T2DM was ≥3 (14.4 [8.88-23.5]), but in obese participants the OR increased sharply when the number of those with an FH of T2DM was 2 (12.2 [8.85-16.9]) (Fig. B). Results suggest that, especially for T2DM, avoidance of obesity may be effective in reducing the prevalence of these disorders in those with many FH-positive family members. Disclosure I. Ikeda: None. K. Fujihara: None. Y. Takeda: None. C. Horikawa: None. S. Kodama: None. E.D. Ferreira: None. Y. Mori: None. T. Kadowaki: None. R. Yamamoto-Honda: None. Y. Arase: None. H. Sone: Research Support; Novo Nordisk, Astellas Pharma Inc., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Eisai Inc., Sumitomo Dainippon Pharma Co., Ltd.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"26 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730616","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}

{"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":"79 1","pages":""},"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}

{"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<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.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"79 1","pages":""},"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}

{"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<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.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"2013 1","pages":""},"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}

{"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":"10034 1","pages":""},"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}

{"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 >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":"17 1","pages":""},"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}

{"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 >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)","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"38 1","pages":""},"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}