NICHOLETTE ALLRED, CHINMAY RAUT, YANHUA CHEN, ANTONINO OLIVERI, JEFFREY O'CONNELL, KATHLEEN RYAN, JEROME I. ROTTER, STEPHEN S. RICH, AARON HAKIM, PATRICIA PEYSER, LAWRENCE F. BIELAK, CHING-TI LIU, JAMES G. TERRY, MYRIAM FORNAGE, LYNNE E. WAGENKNECHT, ELIZABETH K. SPELIOTES, NHLBI TRANS-OMICS FOR PRECISION MEDICINE (TOPMED)PROGRAM, GOLD CONSORTIUM
Introduction and Objective: Steatotic liver disease, formerly called non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease worldwide; yet, few effective methods for prevention/treatment exist making it one of the biggest unmet public health needs of our time. To date, genetic studies have been limited to identifying common variants in predominantly European-ancestry populations or focused on surrogate phenotypes, e.g. liver enzymes, identifying association with comorbidities. Here we present a multi-ancestry whole genome sequencing (WGS) association study to discover rare variants associated with imaging-measured hepatic steatosis. Methods: Study-, ancestry- and sex-stratified association analyses were conducted using SAIGEgds in nine studies with imaging-measured hepatic steatosis adjusted for age, sex, alcoholic drinks per week and principal component estimates of admixture. Stratified results were meta-analyzed using a fixed-effects model. Cochran’s Q-test and the I2 metric were used to estimate heterogeneity. Results: Meta-analyses included 23,156 European, African, Hispanic and Chinese ancestry individuals and identified five significant loci (P<5x10-08): PNPLA3, PPP1R3B, HAPLN4, intergenic region on chr14 and F11-AS1. Nine additional variants trended toward association (P<5x10-07). Sex-stratified meta-analyses revealed additional associations in an intergenic region on chr10, RP11-115J16.1 and UBE3B. Variants in RP11-115J16.1 remained significant in European ancestry samples. Significantly associated variants in SLC2A1-AS1 and LINC01684 were novel loci in African Americans. Conclusion: Taken together, multi-ancestry analysis of imaging-measured hepatic steatosis using WGS replicated previously associated loci and identified novel sex- and ancestry-specific loci. Functional studies are underway to determine the biological impact of these findings. Disclosure N. Allred: None. C. Raut: None. Y. Chen: None. A. Oliveri: None. J. O'Connell: None. K. Ryan: None. J.I. Rotter: None. S.S. Rich: None. A. Hakim: None. P. Peyser: None. L.F. Bielak: None. C. Liu: None. J.G. Terry: None. M. Fornage: None. L.E. Wagenknecht: None. E.K. Speliotes: Other Relationship; University of Michigan. Funding National Institute of Diabetes and Digestive Kidney Disease (R01 DK128871)
{"title":"348-OR: Multiancestry Whole Genome Sequencing (WGS) Meta-analysis to Identify Loci Associated with Imaging-Measured Hepatic Steatosis","authors":"NICHOLETTE ALLRED, CHINMAY RAUT, YANHUA CHEN, ANTONINO OLIVERI, JEFFREY O'CONNELL, KATHLEEN RYAN, JEROME I. ROTTER, STEPHEN S. RICH, AARON HAKIM, PATRICIA PEYSER, LAWRENCE F. BIELAK, CHING-TI LIU, JAMES G. TERRY, MYRIAM FORNAGE, LYNNE E. WAGENKNECHT, ELIZABETH K. SPELIOTES, NHLBI TRANS-OMICS FOR PRECISION MEDICINE (TOPMED)PROGRAM, GOLD CONSORTIUM","doi":"10.2337/db24-348-or","DOIUrl":"https://doi.org/10.2337/db24-348-or","url":null,"abstract":"Introduction and Objective: Steatotic liver disease, formerly called non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease worldwide; yet, few effective methods for prevention/treatment exist making it one of the biggest unmet public health needs of our time. To date, genetic studies have been limited to identifying common variants in predominantly European-ancestry populations or focused on surrogate phenotypes, e.g. liver enzymes, identifying association with comorbidities. Here we present a multi-ancestry whole genome sequencing (WGS) association study to discover rare variants associated with imaging-measured hepatic steatosis. Methods: Study-, ancestry- and sex-stratified association analyses were conducted using SAIGEgds in nine studies with imaging-measured hepatic steatosis adjusted for age, sex, alcoholic drinks per week and principal component estimates of admixture. Stratified results were meta-analyzed using a fixed-effects model. Cochran’s Q-test and the I2 metric were used to estimate heterogeneity. Results: Meta-analyses included 23,156 European, African, Hispanic and Chinese ancestry individuals and identified five significant loci (P&lt;5x10-08): PNPLA3, PPP1R3B, HAPLN4, intergenic region on chr14 and F11-AS1. Nine additional variants trended toward association (P&lt;5x10-07). Sex-stratified meta-analyses revealed additional associations in an intergenic region on chr10, RP11-115J16.1 and UBE3B. Variants in RP11-115J16.1 remained significant in European ancestry samples. Significantly associated variants in SLC2A1-AS1 and LINC01684 were novel loci in African Americans. Conclusion: Taken together, multi-ancestry analysis of imaging-measured hepatic steatosis using WGS replicated previously associated loci and identified novel sex- and ancestry-specific loci. Functional studies are underway to determine the biological impact of these findings. Disclosure N. Allred: None. C. Raut: None. Y. Chen: None. A. Oliveri: None. J. O'Connell: None. K. Ryan: None. J.I. Rotter: None. S.S. Rich: None. A. Hakim: None. P. Peyser: None. L.F. Bielak: None. C. Liu: None. J.G. Terry: None. M. Fornage: None. L.E. Wagenknecht: None. E.K. Speliotes: Other Relationship; University of Michigan. Funding National Institute of Diabetes and Digestive Kidney Disease (R01 DK128871)","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":"141730547","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}
ANANTA ADDALA, SUSANNE M. CABRERA, DAVID D. CUTHBERTSON, INGRID LIBMAN, MUSTAFA TOSUR, ALEJANDRO F. SILLER, LINDA A. DIMEGLIO, KEVAN C. HEROLD, MARIA J. REDONDO, HEBA M. ISMAIL
Introduction & Objective: The diversity of individuals living with T1D has increased, driven by Hispanic (H) and non-Hispanic Black (NHB) populations. Yet, whether H and NHB populations have different rates of SAB+ than other groups, which can impact clinical care and research opportunities, has not been well characterized. Area deprivation and race/ethnicity are strongly associated with each other and have compounding and adverse effects on diabetes-related health outcomes. We examined TrialNet data from relatives of persons with T1D screened for pancreatic autoantibodies and evaluated the frequency of SAB+ by race/ethnicity and area deprivation. Methods: Persons (n=28330) screened between 4/9/19-12/31/22 were included. Race/ethnicity was categorized as non-Hispanic white (NHW), H, NHB, and non-Hispanic other (NHO). Home address zip codes were used to assign an Area Deprivation Index, a Health and Human Services Administration index incorporating neighborhood income, education, employment, and housing that ranges from 1 (least deprived) to 100 (most deprived). Deprivation was analyzed in quintiles. Results: A majority (80.7%) self-identified as NHW; fewer as H (9.8%), NHB (2.5%), and NHO (7.0%). Deprivation differed by race/ethnicity (NHW 46±23, H: 45±24, NHB: 53±23, and NHO: 39±25, p<0.001). SAB+ was more common in NHB and H than NHO and NHW individuals (Overall: 3.0%, NHB: 4.7%, H: 3.8%, NHO: 3.1%, NWH: 3.0%; χ2 p=0.02). Logistic regression identified a linear relationship between SAB+ and deprivation (Deprivation quintiles 1 to 5: 2.9%, 2.7%, 3.1%, 3.1%, 3.5%; p=0.04). Conclusion: These data suggest SAB+ status varies by both race/ethnicity and deprivation which warrants further investigation. Understanding patterns of autoantibody positivity that occur in diverse populations at risk for T1D is foundational to identifying persons who are SAB+ or in early stages of T1D who may now be eligible for preventive therapies. Disclosure A. Addala: None. S.M. Cabrera: Research Support; Abbott. D.D. Cuthbertson: None. I. Libman: None. M. Tosur: None. A.F. Siller: None. L.A. DiMeglio: Research Support; Dompé, Lilly Diabetes, MannKind Corporation, Medtronic, Provention Bio, Inc., Sanofi, Zealand Pharma A/S, Amgen Inc. Advisory Panel; Vertex Pharmaceuticals Incorporated, Abata Therapeutics. K.C. Herold: Consultant; Sanofi. M.J. Redondo: None. H.M. Ismail: Consultant; Sanofi, Rise Therapeutics.
{"title":"1301-P: Frequency of Single Autoantibody Positivity (SAB+) Varies by Race/Ethnicity and Area Deprivation Index in Individuals at Risk for Type 1 Diabetes (T1D)","authors":"ANANTA ADDALA, SUSANNE M. CABRERA, DAVID D. CUTHBERTSON, INGRID LIBMAN, MUSTAFA TOSUR, ALEJANDRO F. SILLER, LINDA A. DIMEGLIO, KEVAN C. HEROLD, MARIA J. REDONDO, HEBA M. ISMAIL","doi":"10.2337/db24-1301-p","DOIUrl":"https://doi.org/10.2337/db24-1301-p","url":null,"abstract":"Introduction & Objective: The diversity of individuals living with T1D has increased, driven by Hispanic (H) and non-Hispanic Black (NHB) populations. Yet, whether H and NHB populations have different rates of SAB+ than other groups, which can impact clinical care and research opportunities, has not been well characterized. Area deprivation and race/ethnicity are strongly associated with each other and have compounding and adverse effects on diabetes-related health outcomes. We examined TrialNet data from relatives of persons with T1D screened for pancreatic autoantibodies and evaluated the frequency of SAB+ by race/ethnicity and area deprivation. Methods: Persons (n=28330) screened between 4/9/19-12/31/22 were included. Race/ethnicity was categorized as non-Hispanic white (NHW), H, NHB, and non-Hispanic other (NHO). Home address zip codes were used to assign an Area Deprivation Index, a Health and Human Services Administration index incorporating neighborhood income, education, employment, and housing that ranges from 1 (least deprived) to 100 (most deprived). Deprivation was analyzed in quintiles. Results: A majority (80.7%) self-identified as NHW; fewer as H (9.8%), NHB (2.5%), and NHO (7.0%). Deprivation differed by race/ethnicity (NHW 46±23, H: 45±24, NHB: 53±23, and NHO: 39±25, p&lt;0.001). SAB+ was more common in NHB and H than NHO and NHW individuals (Overall: 3.0%, NHB: 4.7%, H: 3.8%, NHO: 3.1%, NWH: 3.0%; χ2 p=0.02). Logistic regression identified a linear relationship between SAB+ and deprivation (Deprivation quintiles 1 to 5: 2.9%, 2.7%, 3.1%, 3.1%, 3.5%; p=0.04). Conclusion: These data suggest SAB+ status varies by both race/ethnicity and deprivation which warrants further investigation. Understanding patterns of autoantibody positivity that occur in diverse populations at risk for T1D is foundational to identifying persons who are SAB+ or in early stages of T1D who may now be eligible for preventive therapies. Disclosure A. Addala: None. S.M. Cabrera: Research Support; Abbott. D.D. Cuthbertson: None. I. Libman: None. M. Tosur: None. A.F. Siller: None. L.A. DiMeglio: Research Support; Dompé, Lilly Diabetes, MannKind Corporation, Medtronic, Provention Bio, Inc., Sanofi, Zealand Pharma A/S, Amgen Inc. Advisory Panel; Vertex Pharmaceuticals Incorporated, Abata Therapeutics. K.C. Herold: Consultant; Sanofi. M.J. Redondo: None. H.M. Ismail: Consultant; Sanofi, Rise Therapeutics.","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":"141730475","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}
DONALD C. SIMONSON, WILLIAM F. GOURASH, DAVID ARTERBURN, BO HU, SANGEETA R. KASHYAP, MARY-ELIZABETH PATTI, PHILIP SCHAUER, DAVID E. CUMMINGS, ANITA COURCOULAS, ALI AMINIAN, JOHN M. JAKICIC, ASHLEY H. VERNON, JOHN P. KIRWAN
Introduction & Objective: T2D and obesity are associated with reduced quality of life (QoL) and health utility (HU), but long-term effects of metabolic/bariatric surgery (MBS) vs. a medical/lifestyle intervention (MLI) on these outcomes are not known. Methods: We studied 228 patients with T2D and obesity who were randomized to MBS (RYGB, gastric band, or sleeve gastrectomy; n = 152) vs. MLI (n = 76) in the ARMMS-T2D study. QoL (SF-36; including Physical Component Score [PCS], Mental Component Score [MCS], and 8 scale scores) and HU (SF-6D) were measured annually for 12 yrs. Results: At baseline, age = 49.2 ± 8.0 yrs., 68% were female, 68% White, BMI = 36.3 ± 3.4 kg/m², HbA1c = 8.7 ± 1.6%. PCS improved significantly in MBS at year 1, remained higher vs. MLI over 12 yrs. (p < 0.001), and was associated with better general health (p < 0.001), physical function (p = 0.001), energy (p = 0.003), and reduced pain (p = 0.03). Change in BMI was greater after MBS vs. MLI (-18.6 ± 12.4% vs. -11.4 ± 10.9%, p < 0.001), and significantly correlated with change in PCS (r = -0.43, p < 0.001). In contrast, MCS (p = 0.14), emotional well-being (p = 0.53), role emotional (p = 0.43), and social functioning (p = 0.11) did not change from baseline and were similar between groups over 12 yrs. Changes in PCS and MCS were not associated with change in HbA1c. Among patients taking insulin at baseline, those who discontinued insulin had higher PCS (p < 0.001) over time. HU was moderately low at baseline (0.69 ± 0.08) and did not change significantly in either group during 12 yrs. Conclusions: MBS produced sustained weight loss that correlated with improved PCS, including better general health, physical function, energy, and less pain. PCS improved more in patients who discontinued insulin. There were no significant differences between groups over time in MCS or in HU. These differences may help patients with T2D and obesity make informed decisions about their best treatment options. Disclosure D.C. Simonson: Stock/Shareholder; Phase V Technologies, Inc. Advisory Panel; GI Windows. W.F. Gourash: None. D. Arterburn: None. B. Hu: None. S.R. Kashyap: Research Support; Fractyl Health, Inc. Advisory Panel; GI Dynamics. Research Support; Janssen Pharmaceuticals, Inc. M. Patti: Research Support; Dexcom, Inc. Consultant; Hanmi Pharm. Co., Ltd., MBX Biosciences. Other Relationship; Fractyl Health, Inc. Consultant; AstraZeneca, Spruce Biosciences. P. Schauer: Research Support; Ethicon, Inc. Other Relationship; Ethicon, Inc. Research Support; Medtronic. Other Relationship; Medtronic, Novo Nordisk. Advisory Panel; Lilly Diabetes, GI Dynamics, Heron. Stock/Shareholder; Mediflix, SE Healthcare. Other Relationship; Klens. Advisory Panel; Persona, Keyron. Stock/Shareholder; Metabolic Health International LTD. D.E. Cummings: None. A. Courcoulas: Research Support; Allurion, Eli Lilly and Company. A. Aminian: Research Support; Medtronic. Consultant; Medt
{"title":"235-OR: Quality of Life and Health Utility 12 Years after Randomization to Bariatric Surgery vs. Medical Therapy in Patients with Type 2 Diabetes and Obesity—The ARMMS-T2D Study","authors":"DONALD C. SIMONSON, WILLIAM F. GOURASH, DAVID ARTERBURN, BO HU, SANGEETA R. KASHYAP, MARY-ELIZABETH PATTI, PHILIP SCHAUER, DAVID E. CUMMINGS, ANITA COURCOULAS, ALI AMINIAN, JOHN M. JAKICIC, ASHLEY H. VERNON, JOHN P. KIRWAN","doi":"10.2337/db24-235-or","DOIUrl":"https://doi.org/10.2337/db24-235-or","url":null,"abstract":"Introduction & Objective: T2D and obesity are associated with reduced quality of life (QoL) and health utility (HU), but long-term effects of metabolic/bariatric surgery (MBS) vs. a medical/lifestyle intervention (MLI) on these outcomes are not known. Methods: We studied 228 patients with T2D and obesity who were randomized to MBS (RYGB, gastric band, or sleeve gastrectomy; n = 152) vs. MLI (n = 76) in the ARMMS-T2D study. QoL (SF-36; including Physical Component Score [PCS], Mental Component Score [MCS], and 8 scale scores) and HU (SF-6D) were measured annually for 12 yrs. Results: At baseline, age = 49.2 ± 8.0 yrs., 68% were female, 68% White, BMI = 36.3 ± 3.4 kg/m², HbA1c = 8.7 ± 1.6%. PCS improved significantly in MBS at year 1, remained higher vs. MLI over 12 yrs. (p &lt; 0.001), and was associated with better general health (p &lt; 0.001), physical function (p = 0.001), energy (p = 0.003), and reduced pain (p = 0.03). Change in BMI was greater after MBS vs. MLI (-18.6 ± 12.4% vs. -11.4 ± 10.9%, p &lt; 0.001), and significantly correlated with change in PCS (r = -0.43, p &lt; 0.001). In contrast, MCS (p = 0.14), emotional well-being (p = 0.53), role emotional (p = 0.43), and social functioning (p = 0.11) did not change from baseline and were similar between groups over 12 yrs. Changes in PCS and MCS were not associated with change in HbA1c. Among patients taking insulin at baseline, those who discontinued insulin had higher PCS (p &lt; 0.001) over time. HU was moderately low at baseline (0.69 ± 0.08) and did not change significantly in either group during 12 yrs. Conclusions: MBS produced sustained weight loss that correlated with improved PCS, including better general health, physical function, energy, and less pain. PCS improved more in patients who discontinued insulin. There were no significant differences between groups over time in MCS or in HU. These differences may help patients with T2D and obesity make informed decisions about their best treatment options. Disclosure D.C. Simonson: Stock/Shareholder; Phase V Technologies, Inc. Advisory Panel; GI Windows. W.F. Gourash: None. D. Arterburn: None. B. Hu: None. S.R. Kashyap: Research Support; Fractyl Health, Inc. Advisory Panel; GI Dynamics. Research Support; Janssen Pharmaceuticals, Inc. M. Patti: Research Support; Dexcom, Inc. Consultant; Hanmi Pharm. Co., Ltd., MBX Biosciences. Other Relationship; Fractyl Health, Inc. Consultant; AstraZeneca, Spruce Biosciences. P. Schauer: Research Support; Ethicon, Inc. Other Relationship; Ethicon, Inc. Research Support; Medtronic. Other Relationship; Medtronic, Novo Nordisk. Advisory Panel; Lilly Diabetes, GI Dynamics, Heron. Stock/Shareholder; Mediflix, SE Healthcare. Other Relationship; Klens. Advisory Panel; Persona, Keyron. Stock/Shareholder; Metabolic Health International LTD. D.E. Cummings: None. A. Courcoulas: Research Support; Allurion, Eli Lilly and Company. A. Aminian: Research Support; Medtronic. Consultant; Medt","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":"141730484","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}
CHUNHUA DAI, AJAY K. SINGH, REBEKAH BRANTLEY, AMBER BRADLEY, REGINA JENKINS, DIANE C. SAUNDERS, MARCELA BRISSOVA, EREZ LEVANON, AGNES KLOCHENDLER, YUVAL DOR, ALVIN C. POWERS
Introduction & Objective: It is thought that viral infection triggers islet inflammation, an interferon signature, and autoimmunity resulting in type 1 diabetes. Despite extensive research, an inciting virus has not been identified. We hypothesized that impaired RNA editing and accumulation of double-stranded RNA in beta cells triggers an interferon response, causing islet inflammation, autoimmunity, and beta cell destruction. While RNA editing regulated by adenosine deaminases acting on RNA (ADAR) has been studied in some organs and in cancer, little is known about the role of ADAR in human islets. Method: To elucidate the role of ADAR1 in human islets, we first studied ADAR expression and distribution in human pancreas across postnatal developmental timeline (1 day, 4 months, 2, 6, 10, 35 years). Then we transduced human pseudoislets with a shRNA for ADAR and examined their function and gene expression. The transduced pseudoislets were also transplanted into NSG mice. Insulin secretion was measured and grafts were studied. Results: We found that ADAR1 expression at all ages was greater in endocrine cells than acinar cells. Using the shRNA approach, ADAR mRNA levels were reduced by 70% (n=11 donors). After 7-day culture, expression of dsRNA sensors, IFNB1, IRF7, IRF9, and interferon-stimulated genes was increased while INS and MAFA expression was reduced in ADAR knockdown islets without changes in insulin secretion. However, 3 weeks post transplantation, glucose/arginine-stimulated human insulin secretion was significantly decreased in mice with the ADAR shRNA graft compared with scrambled shRNA control graft (0.117 vs 0.300 ng/mL, p=0.0001, n=3 donors). Analysis of pseudoislet grafts 4 weeks after transplantation showed marked accumulation of mouse CD45+ cells around ADAR-knockdown islet grafts. Conclusion: Interruption of RNA editing in human islets activates the interferon signaling pathway leading to islet inflammation and beta cell dysfunction. Disclosure C. Dai: None. A.K. Singh: None. R. Brantley: None. A. Bradley: None. R. Jenkins: None. D.C. Saunders: None. M. Brissova: None. E. Levanon: Advisory Panel; ADARX, Exsilio. A. Klochendler: None. Y. Dor: None. A.C. Powers: None.
{"title":"349-OR: Reduction of RNA-Editing Enzyme ADAR1 in Human Islets Triggers an Interferon Response and Impairs Beta-Cell Function","authors":"CHUNHUA DAI, AJAY K. SINGH, REBEKAH BRANTLEY, AMBER BRADLEY, REGINA JENKINS, DIANE C. SAUNDERS, MARCELA BRISSOVA, EREZ LEVANON, AGNES KLOCHENDLER, YUVAL DOR, ALVIN C. POWERS","doi":"10.2337/db24-349-or","DOIUrl":"https://doi.org/10.2337/db24-349-or","url":null,"abstract":"Introduction & Objective: It is thought that viral infection triggers islet inflammation, an interferon signature, and autoimmunity resulting in type 1 diabetes. Despite extensive research, an inciting virus has not been identified. We hypothesized that impaired RNA editing and accumulation of double-stranded RNA in beta cells triggers an interferon response, causing islet inflammation, autoimmunity, and beta cell destruction. While RNA editing regulated by adenosine deaminases acting on RNA (ADAR) has been studied in some organs and in cancer, little is known about the role of ADAR in human islets. Method: To elucidate the role of ADAR1 in human islets, we first studied ADAR expression and distribution in human pancreas across postnatal developmental timeline (1 day, 4 months, 2, 6, 10, 35 years). Then we transduced human pseudoislets with a shRNA for ADAR and examined their function and gene expression. The transduced pseudoislets were also transplanted into NSG mice. Insulin secretion was measured and grafts were studied. Results: We found that ADAR1 expression at all ages was greater in endocrine cells than acinar cells. Using the shRNA approach, ADAR mRNA levels were reduced by 70% (n=11 donors). After 7-day culture, expression of dsRNA sensors, IFNB1, IRF7, IRF9, and interferon-stimulated genes was increased while INS and MAFA expression was reduced in ADAR knockdown islets without changes in insulin secretion. However, 3 weeks post transplantation, glucose/arginine-stimulated human insulin secretion was significantly decreased in mice with the ADAR shRNA graft compared with scrambled shRNA control graft (0.117 vs 0.300 ng/mL, p=0.0001, n=3 donors). Analysis of pseudoislet grafts 4 weeks after transplantation showed marked accumulation of mouse CD45+ cells around ADAR-knockdown islet grafts. Conclusion: Interruption of RNA editing in human islets activates the interferon signaling pathway leading to islet inflammation and beta cell dysfunction. Disclosure C. Dai: None. A.K. Singh: None. R. Brantley: None. A. Bradley: None. R. Jenkins: None. D.C. Saunders: None. M. Brissova: None. E. Levanon: Advisory Panel; ADARX, Exsilio. A. Klochendler: None. Y. Dor: None. A.C. Powers: 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":"141730622","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}
PHOOM NARONGKIATIKHUN, YE JI CHOI, NHUNG NGUYEN, KELLY NASH, KALIE L. TOMMERDAHL, MATTHIAS KRETZLER, THOMAS INGE, JUSTIN R. RYDER, LAURA PYLE, PETTER BJORNSTAD
Introduction & Objective: This study aims to explore the effects of metabolic bariatric surgery (MBS) on plasma proteins linked to diabetic kidney disease and hypertension in youth with type 2 diabetes (T2D). Methods: We measured 7604 proteins in 326 plasma samples from severely obese youth, both with and without T2D, in the Teen-LABS study, examining pre- and post-MBS changes (6 month, 1, 2-, 3-, 4-, and 5-year follow-up). This analysis focused on proteins identified in the TODAY cohort as predictors of severe albuminuria (ACR ≥300 mg/g) and hypertension (SBP≥130/80 mm Hg), in youth with T2D (n=374), using Cox proportional hazard models adjusted for age, sex, HbA1c, log-transformed triglycerides and estimated insulin sensitivity. A mixed model evaluated proteomic changes post-MBS, maintaining a 5% false discovery rate with reported q-values. Results: In Teen-LABS, several proteins associated with a higher risk of severe albuminuria and hypertension in TODAY showed notable post-surgical downregulation. Higher pigment epithelium-derived factor (PEDF) at baseline predicted onset to severe albuminuria (HR: 1.63, 95% CI 1.12, 2.37, per 1 SD increment) and hypertension (HR: 1.41, 95% CI 1.22, 1.63, per 1 SD increment) over 15 years in TODAY after multivariable adjustments. In Teen-LABS, PEDF decreased post-MBS compared to baseline at 6 months follow-up (logFC: -0.30, q-value=1.24x10-31), year 1 (logFC: -0.28, q-value=2.35x10-29), year 2 (logFC: -0.32, q-value=1.85x10-34), year 3 (logFC: -0.28, q-value=6.95x10-29), year 4 (logFC: -0.30, q-value=4.13x10-28) and year 5 (logFC: -0.30, q-value=2.78x10-26). Conclusion: These analyses show durable attenuation of plasma PEDF after MBS, a protein strongly associated with risk of severe albuminuria and hypertension in youth with T2D. PEDF is implicated in endothelial dysfunction and vascular damage through impaired angiogenesis and endothelial repair mechanisms. Disclosure P. Narongkiatikhun: None. Y. Choi: None. N. Nguyen: None. K. Nash: None. K.L. Tommerdahl: None. M. Kretzler: Research Support; Boehringer-Ingelheim, Certa, Traveere Pharmaceuticals, Maze Therapeutics, Roche Pharmaceuticals, AstraZeneca, Novo Nordisk, Moderna, Inc., Chinook Therapeutics Inc., angion, Lilly Diabetes, Renalytix, Gilead Sciences, Inc., Regeneron Pharmaceuticals Inc., Janssen Pharmaceuticals, Inc. T. Inge: Consultant; Medtronic, Eli Lilly and Company, Brainstorm Therapeutics. Stock/Shareholder; Standard Bariatrics. Consultant; Teleflex. J.R. Ryder: None. L. Pyle: None. P. Bjornstad: Consultant; AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Lilly Diabetes, Novo Nordisk, Bayer Inc., Horizon Therapeutics plc. Funding National Institutes of Health
{"title":"1135-P: Pigment Epithelium–Derived Factor, Diabetic Kidney Disease, and Hypertension—Deciphering the Proteomic Response to Metabolic Bariatric Surgery in Adolescents","authors":"PHOOM NARONGKIATIKHUN, YE JI CHOI, NHUNG NGUYEN, KELLY NASH, KALIE L. TOMMERDAHL, MATTHIAS KRETZLER, THOMAS INGE, JUSTIN R. RYDER, LAURA PYLE, PETTER BJORNSTAD","doi":"10.2337/db24-1135-p","DOIUrl":"https://doi.org/10.2337/db24-1135-p","url":null,"abstract":"Introduction & Objective: This study aims to explore the effects of metabolic bariatric surgery (MBS) on plasma proteins linked to diabetic kidney disease and hypertension in youth with type 2 diabetes (T2D). Methods: We measured 7604 proteins in 326 plasma samples from severely obese youth, both with and without T2D, in the Teen-LABS study, examining pre- and post-MBS changes (6 month, 1, 2-, 3-, 4-, and 5-year follow-up). This analysis focused on proteins identified in the TODAY cohort as predictors of severe albuminuria (ACR ≥300 mg/g) and hypertension (SBP≥130/80 mm Hg), in youth with T2D (n=374), using Cox proportional hazard models adjusted for age, sex, HbA1c, log-transformed triglycerides and estimated insulin sensitivity. A mixed model evaluated proteomic changes post-MBS, maintaining a 5% false discovery rate with reported q-values. Results: In Teen-LABS, several proteins associated with a higher risk of severe albuminuria and hypertension in TODAY showed notable post-surgical downregulation. Higher pigment epithelium-derived factor (PEDF) at baseline predicted onset to severe albuminuria (HR: 1.63, 95% CI 1.12, 2.37, per 1 SD increment) and hypertension (HR: 1.41, 95% CI 1.22, 1.63, per 1 SD increment) over 15 years in TODAY after multivariable adjustments. In Teen-LABS, PEDF decreased post-MBS compared to baseline at 6 months follow-up (logFC: -0.30, q-value=1.24x10-31), year 1 (logFC: -0.28, q-value=2.35x10-29), year 2 (logFC: -0.32, q-value=1.85x10-34), year 3 (logFC: -0.28, q-value=6.95x10-29), year 4 (logFC: -0.30, q-value=4.13x10-28) and year 5 (logFC: -0.30, q-value=2.78x10-26). Conclusion: These analyses show durable attenuation of plasma PEDF after MBS, a protein strongly associated with risk of severe albuminuria and hypertension in youth with T2D. PEDF is implicated in endothelial dysfunction and vascular damage through impaired angiogenesis and endothelial repair mechanisms. Disclosure P. Narongkiatikhun: None. Y. Choi: None. N. Nguyen: None. K. Nash: None. K.L. Tommerdahl: None. M. Kretzler: Research Support; Boehringer-Ingelheim, Certa, Traveere Pharmaceuticals, Maze Therapeutics, Roche Pharmaceuticals, AstraZeneca, Novo Nordisk, Moderna, Inc., Chinook Therapeutics Inc., angion, Lilly Diabetes, Renalytix, Gilead Sciences, Inc., Regeneron Pharmaceuticals Inc., Janssen Pharmaceuticals, Inc. T. Inge: Consultant; Medtronic, Eli Lilly and Company, Brainstorm Therapeutics. Stock/Shareholder; Standard Bariatrics. Consultant; Teleflex. J.R. Ryder: None. L. Pyle: None. P. Bjornstad: Consultant; AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Lilly Diabetes, Novo Nordisk, Bayer Inc., Horizon Therapeutics plc. Funding National Institutes of Health","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":"141730485","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}
CATHERINE MAHONEY, CHRISTINE SLYNE, MEDHA MUNSHI, COLIN D. CONERY, HALEY BRABANT, NOA KRAKOFF, JANE D. BULGER, RUTH S. WEINSTOCK, ELENA TOSCHI
Background & Objective: Initiation of continuous glucose monitoring (CGM) remotely in adults with diabetes (DM) has been shown beneficial. However, this model has not been evaluated in older adults. The objective of this study was to assess the benefit and challenges encountered by older patients on multiple daily insulin injections (MDI) initiating CGM using a virtual platform. Methods: Older adults with DM who are participating in an ongoing study on initiation CGM remotely between January-December 2023 were interviewed. Interviews were transcribed, de-identified, coded, and qualitatively analyzed. Baseline demographic characteristics were collected. Results: Interim analysis of 24 interviews was conducted: age 72 ± 4 years, duration of diabetes 30 ± 15 years, 52% female, 76% white, 52% having type 1 diabetes (T1DM), 72% CGM naïve, HbA1C 8.1 ± 1.6, 92% on MDI, and 84% utilizing Medicare as primary insurance. Overarching themes were the use of remote education, initiation of CGM remotely, and ongoing use of CGM. All 100% surveyed participants favorably rated the remote education and its ease of scheduling as well as the overall value of CGM. All participants were able to initiate and maintained CGM use successfully with remote education assistance, with 95% of participants planning to continue to use CGM after study completion. The challenges reported with the CGM use included difficulty with mobile application (33%), annoyance with alarms (50%), and concerns for Medicare coverage (42%). Conclusions: The results of this qualitative analysis show that in our cohort, remote initiation of CGM in older adults was perceived positively, despite some challenges. Disclosure C. Mahoney: None. C. Slyne: None. M. Munshi: Consultant; Sanofi. C.D. Conery: None. H. Brabant: None. N. Krakoff: None. J.D. Bulger: None. R.S. Weinstock: Research Support; Eli Lilly and Company, Tandem Diabetes Care, Inc., Diasome, Amgen Inc., MannKind Corporation, Insulet Corporation, Novo Nordisk. Other Relationship; Dexcom, Inc. E. Toschi: Consultant; Vertex Pharmaceuticals Incorporated, Sanofi. Funding The Leona M. and Harry B. Helmsley Charitable Trust
{"title":"1004-P: Remote Initiation of Continuous Glucose Monitoring in Older Adults Using Insulin","authors":"CATHERINE MAHONEY, CHRISTINE SLYNE, MEDHA MUNSHI, COLIN D. CONERY, HALEY BRABANT, NOA KRAKOFF, JANE D. BULGER, RUTH S. WEINSTOCK, ELENA TOSCHI","doi":"10.2337/db24-1004-p","DOIUrl":"https://doi.org/10.2337/db24-1004-p","url":null,"abstract":"Background & Objective: Initiation of continuous glucose monitoring (CGM) remotely in adults with diabetes (DM) has been shown beneficial. However, this model has not been evaluated in older adults. The objective of this study was to assess the benefit and challenges encountered by older patients on multiple daily insulin injections (MDI) initiating CGM using a virtual platform. Methods: Older adults with DM who are participating in an ongoing study on initiation CGM remotely between January-December 2023 were interviewed. Interviews were transcribed, de-identified, coded, and qualitatively analyzed. Baseline demographic characteristics were collected. Results: Interim analysis of 24 interviews was conducted: age 72 ± 4 years, duration of diabetes 30 ± 15 years, 52% female, 76% white, 52% having type 1 diabetes (T1DM), 72% CGM naïve, HbA1C 8.1 ± 1.6, 92% on MDI, and 84% utilizing Medicare as primary insurance. Overarching themes were the use of remote education, initiation of CGM remotely, and ongoing use of CGM. All 100% surveyed participants favorably rated the remote education and its ease of scheduling as well as the overall value of CGM. All participants were able to initiate and maintained CGM use successfully with remote education assistance, with 95% of participants planning to continue to use CGM after study completion. The challenges reported with the CGM use included difficulty with mobile application (33%), annoyance with alarms (50%), and concerns for Medicare coverage (42%). Conclusions: The results of this qualitative analysis show that in our cohort, remote initiation of CGM in older adults was perceived positively, despite some challenges. Disclosure C. Mahoney: None. C. Slyne: None. M. Munshi: Consultant; Sanofi. C.D. Conery: None. H. Brabant: None. N. Krakoff: None. J.D. Bulger: None. R.S. Weinstock: Research Support; Eli Lilly and Company, Tandem Diabetes Care, Inc., Diasome, Amgen Inc., MannKind Corporation, Insulet Corporation, Novo Nordisk. Other Relationship; Dexcom, Inc. E. Toschi: Consultant; Vertex Pharmaceuticals Incorporated, Sanofi. Funding The Leona M. and Harry B. Helmsley Charitable Trust","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":"141730543","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}
MIGUEL DURAN, SONJA VIRKUS, KYLIE A. MCMICHEN, YASLLE ANDRADE CAVALCANTE MORAES, ESHITA YADAV, JAGJOT K. SINGH, ZOE FOKAKIS, SAMANTHA Q. STOCKING, SAMUEL O. POOLE, CHAD S. HUNTER, KIRK M. HABEGGER, JAMES A. HARDAWAY
Introduction: Glucagon-like peptide 1 (GLP-1) therapeutics have experienced a meteoric rise in adoption, but our understanding of the endogenous systems that produce GLP-1 and how they regulate behavior remain incomplete. Preproglucagon neurons in the nucleus of the solitary tract (GcgNTS neurons) are the primary source of GLP-1 in the brain. In this study, we examined the neurophysiological and causal contributions of GcgNTS neurons to consummatory and valence behavior. Methods: electrophysiology, in vivo optogenetics, fiber photometry. Results: Using electrophysiology, we observed that GcgNTS neuron neural firing and excitability is reduced in response to 24-hour food deprivation that varied by sex. Conversely, GcgNTS neurons significantly increase their firing rate after a brief 1-hour chow refeed after food deprivation. Consistent with this, GcgNTS neurons display elevated Fos levels following binge-like consumption of palatable high-fat diet. Using in vivo optogenetics, we observed that optogenetic activation of GcgNTS neurons produced anxiety and negative valence that varied by sex. High-frequency activation of GcgNTS neurons also reduced feeding and appetitive behavior. Interestingly, high-frequency activation of GcgNTS neurons produced lasting effects that persisted after cessation of laser illumination. Using a novel transgenic mouse, Gcg-IRES-FlpO, crossed to Glp1r-Cre mice combined with viral and transgenic reporters, we found that GcgNTS neurons and Glp1r neurons in the hypothalamus and amygdala make reciprocal connections. Currently, we are measuring functional connections between GcgNTS neurons and Glp1r neurons in the paraventricular nucleus of the hypothalamus and amygdala. Conclusions: GcgNTS neurons control valence and consumption, interacting with an interconnected GLP-1R-expressing network in the hypothalamus and amygdala. Disclosure M. Duran: None. S. Virkus: None. K.A. McMichen: None. Y. Andrade Cavalcante Moraes: None. E. Yadav: None. J.K. Singh: None. Z. Fokakis: None. S.Q. Stocking: None. S.O. Poole: None. C.S. Hunter: None. K.M. Habegger: Research Support; Eli Lilly and Company. Consultant; Glyscend Inc. Stock/Shareholder; Glyscend Inc. Consultant; Merck & Co., Inc. Research Support; Novo Nordisk. Advisory Panel; Abvance Therapeutics. J.A. Hardaway: None. Funding K01DK115902R03DK129561P30DK079626P30DK056336
{"title":"104-OR: State-Dependent Activity in Hindbrain Glucagon-Like Peptide 1—Producing Neurons Regulates Consummatory and Valence Behavior through Functionally Interconnected Hypothalamic and Limbic Circuits","authors":"MIGUEL DURAN, SONJA VIRKUS, KYLIE A. MCMICHEN, YASLLE ANDRADE CAVALCANTE MORAES, ESHITA YADAV, JAGJOT K. SINGH, ZOE FOKAKIS, SAMANTHA Q. STOCKING, SAMUEL O. POOLE, CHAD S. HUNTER, KIRK M. HABEGGER, JAMES A. HARDAWAY","doi":"10.2337/db24-104-or","DOIUrl":"https://doi.org/10.2337/db24-104-or","url":null,"abstract":"Introduction: Glucagon-like peptide 1 (GLP-1) therapeutics have experienced a meteoric rise in adoption, but our understanding of the endogenous systems that produce GLP-1 and how they regulate behavior remain incomplete. Preproglucagon neurons in the nucleus of the solitary tract (GcgNTS neurons) are the primary source of GLP-1 in the brain. In this study, we examined the neurophysiological and causal contributions of GcgNTS neurons to consummatory and valence behavior. Methods: electrophysiology, in vivo optogenetics, fiber photometry. Results: Using electrophysiology, we observed that GcgNTS neuron neural firing and excitability is reduced in response to 24-hour food deprivation that varied by sex. Conversely, GcgNTS neurons significantly increase their firing rate after a brief 1-hour chow refeed after food deprivation. Consistent with this, GcgNTS neurons display elevated Fos levels following binge-like consumption of palatable high-fat diet. Using in vivo optogenetics, we observed that optogenetic activation of GcgNTS neurons produced anxiety and negative valence that varied by sex. High-frequency activation of GcgNTS neurons also reduced feeding and appetitive behavior. Interestingly, high-frequency activation of GcgNTS neurons produced lasting effects that persisted after cessation of laser illumination. Using a novel transgenic mouse, Gcg-IRES-FlpO, crossed to Glp1r-Cre mice combined with viral and transgenic reporters, we found that GcgNTS neurons and Glp1r neurons in the hypothalamus and amygdala make reciprocal connections. Currently, we are measuring functional connections between GcgNTS neurons and Glp1r neurons in the paraventricular nucleus of the hypothalamus and amygdala. Conclusions: GcgNTS neurons control valence and consumption, interacting with an interconnected GLP-1R-expressing network in the hypothalamus and amygdala. Disclosure M. Duran: None. S. Virkus: None. K.A. McMichen: None. Y. Andrade Cavalcante Moraes: None. E. Yadav: None. J.K. Singh: None. Z. Fokakis: None. S.Q. Stocking: None. S.O. Poole: None. C.S. Hunter: None. K.M. Habegger: Research Support; Eli Lilly and Company. Consultant; Glyscend Inc. Stock/Shareholder; Glyscend Inc. Consultant; Merck & Co., Inc. Research Support; Novo Nordisk. Advisory Panel; Abvance Therapeutics. J.A. Hardaway: None. Funding K01DK115902R03DK129561P30DK079626P30DK056336","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":"141730550","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}
ANDREA FOPPIANI, FABIANA CICIRIELLO, FEDERICO ALGHISI, VINCENZINA LUCIDI, FEDERICA SILEO, MARIA CRISTINA LUCANTO, FABIOLA CORTI, CARLA COLOMBO, ALBERTO BATTEZZATI
People with Cystic Fibrosis (pwCF) exhibit a defect of insulin secretion[1], potentially leading to Cystic Fibrosis Related Diabetes. Little information exists about the molecular mechanism that links the defect of insulin secretion to the CF-causing variants of the CFTR gene[2,3]. We sought to describe the relationship between the CFTR function and β-cell function in pwCF. We studied 341 patients (193 (57%) females, 271 (79%) pancreatic insufficient, median (IQR) age 19 (15, 24) years) with the oral glucose tolerance test (OGTT), sampling glucose, insulin, and C-peptide before and every 30 minutes over the 2 hour OGTT, modeling β-cell function expressed by the β-cell glucose sensitivity[4]. Each patient was characterized by either having at least one allele with a residual function mutation (group 1, 85 (25%)), or a minimal function mutation on both alleles (group 2, 255 (75%) ). After adjusting for sex, pancreatic insufficiency (PI), and age, patients in group 1 displayed better glucose tolerance at all OGTT timepoint (all p=<0.05), and better β-cell glucose sensitivity (22 pmol×min⁻¹×m⁻²×mM⁻¹; 95% CI 9.6, 34; p=<0.001).Within the whole sample, 162 patients (82 (51%) females, 136 (84%) of group 2, 139 (86%) pancreatic insufficient, median (IQR) age 20 (15, 25) years) carried variants on both alleles that had been tested for chloride conductance in the Fischer Rat Thyroid cell line (http://cftr2.org). The mean chloride conductance of the most functional allele was positively related to β-cell glucose sensitivity (0.96; 95% CI 0.13, 1.8; p=0.025), with no PI interaction (interaction term -0.63; 95% CI -3.7, 2.4; p=0.7), and adjusting for differences in sex and age. In conclusion, we have shown that CFTR function is quantitatively related to β-cell function in pwCF. Even though exocrine PI is associated with worse β-cell function, the association of CFTR residual function and β-cell glucose sensitivity is not necessarily mediated by exocrine PI. Disclosure A. Foppiani: None. F. Ciciriello: None. F. Alghisi: None. V. Lucidi: None. F. Sileo: None. M. Lucanto: None. F. Corti: None. C. Colombo: None. A. Battezzati: None. Funding Cystic Fibrosis Research Foundation FFC#16/2005, FFC#21/2013, FFC#20/2016, and FFC#24/2019
{"title":"1552-P: Mutations with Residual CFTR Function Are Associated to Better Glucose Tolerance and Insulin Secretion in Patients with Cystic Fibrosis","authors":"ANDREA FOPPIANI, FABIANA CICIRIELLO, FEDERICO ALGHISI, VINCENZINA LUCIDI, FEDERICA SILEO, MARIA CRISTINA LUCANTO, FABIOLA CORTI, CARLA COLOMBO, ALBERTO BATTEZZATI","doi":"10.2337/db24-1552-p","DOIUrl":"https://doi.org/10.2337/db24-1552-p","url":null,"abstract":"People with Cystic Fibrosis (pwCF) exhibit a defect of insulin secretion[1], potentially leading to Cystic Fibrosis Related Diabetes. Little information exists about the molecular mechanism that links the defect of insulin secretion to the CF-causing variants of the CFTR gene[2,3]. We sought to describe the relationship between the CFTR function and β-cell function in pwCF. We studied 341 patients (193 (57%) females, 271 (79%) pancreatic insufficient, median (IQR) age 19 (15, 24) years) with the oral glucose tolerance test (OGTT), sampling glucose, insulin, and C-peptide before and every 30 minutes over the 2 hour OGTT, modeling β-cell function expressed by the β-cell glucose sensitivity[4]. Each patient was characterized by either having at least one allele with a residual function mutation (group 1, 85 (25%)), or a minimal function mutation on both alleles (group 2, 255 (75%) ). After adjusting for sex, pancreatic insufficiency (PI), and age, patients in group 1 displayed better glucose tolerance at all OGTT timepoint (all p=&lt;0.05), and better β-cell glucose sensitivity (22 pmol×min⁻¹×m⁻²×mM⁻¹; 95% CI 9.6, 34; p=&lt;0.001).Within the whole sample, 162 patients (82 (51%) females, 136 (84%) of group 2, 139 (86%) pancreatic insufficient, median (IQR) age 20 (15, 25) years) carried variants on both alleles that had been tested for chloride conductance in the Fischer Rat Thyroid cell line (http://cftr2.org). The mean chloride conductance of the most functional allele was positively related to β-cell glucose sensitivity (0.96; 95% CI 0.13, 1.8; p=0.025), with no PI interaction (interaction term -0.63; 95% CI -3.7, 2.4; p=0.7), and adjusting for differences in sex and age. In conclusion, we have shown that CFTR function is quantitatively related to β-cell function in pwCF. Even though exocrine PI is associated with worse β-cell function, the association of CFTR residual function and β-cell glucose sensitivity is not necessarily mediated by exocrine PI. Disclosure A. Foppiani: None. F. Ciciriello: None. F. Alghisi: None. V. Lucidi: None. F. Sileo: None. M. Lucanto: None. F. Corti: None. C. Colombo: None. A. Battezzati: None. Funding Cystic Fibrosis Research Foundation FFC#16/2005, FFC#21/2013, FFC#20/2016, and FFC#24/2019","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":"141730555","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}
SATISH K. GARG, IRL B. HIRSCH, ENRICO REPETTO, JANET K. SNELL-BERGEON, BRIAN ULMER, CHRISTOPHER PERKINS, RICHARD M. BERGENSTAL
Introduction & Objective: The increasing prevalence of diabetes in the US continues to drive a steady rise in healthcare resource utilization. The real-world impact of continuous glucose monitoring (CGM) on hospitalizations in a broad type 2 diabetes population is not completely understood. Methods: In this retrospective analysis, we used Optum's de-identified Market Clarity data of >79 million people to evaluate CGM use in 74,264 people with type 2 diabetes who were treated with non-insulin (NIT; n=25,788), basal insulin (BIT; n=25,292), and prandial insulin therapy (PIT; n=23,184). The primary outcomes were changes in all-cause hospitalizations (ACH), acute diabetes-related hospitalizations (ADH), and acute diabetes-related emergency room visits (ADER) during the 6- and 12-months post-index period. Results: ACH, ADH, and ADER were significantly reduced in the first 6 months (post-index) in all three groups: NIT (14%, 32%, 30%), BIT (25%, 57%, 37%), PIT (25%, 54%, 36%) respectively. (Figure 1) The reductions were sustained during 6-12 months in NIT (10%, 31%, 30%), BIT (23%, 56%, 34%), and PIT (19%, 49%, 36%) respectively (all p<0.0001). Conclusion: The use of CGM in real-world across different therapeutic regimes in people with type 2 diabetes was associated with significant reductions in all-cause hospitalizations, acute diabetes-related hospitalizations and ER visits. Disclosure S.K. Garg: Research Support; Eli Lilly and Company. Advisory Panel; Medtronic. Research Support; Medtronic. Advisory Panel; Novo Nordisk. Research Support; DarioHealth Corp., Dexcom, Inc., Diasome. Advisory Panel; Roche Diabetes Care. I.B. Hirsch: Advisory Panel; Abbott. Research Support; Dexcom, Inc. Advisory Panel; Roche Diabetes Care. Research Support; MannKind Corporation, Tandem Diabetes Care, Inc. Advisory Panel; embecta. Research Support; Tandem Diabetes Care, Inc. Advisory Panel; Vertex Pharmaceuticals Incorporated. E. Repetto: Employee; Roche Diabetes Care. J.K. Snell-Bergeon: None. B. Ulmer: Employee; Roche Diabetes Care. C. Perkins: Employee; Roche Diabetes Care. R.M. Bergenstal: Other Relationship; Abbott. Research Support; Arkray Marketing. Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur. Other Relationship; Dexcom, Inc., Eli Lilly and Company. Consultant; embecta, Hygieia. Research Support; Insulet Corporation. Consultant; MannKind Corporation. Other Relationship; Medtronic, Novo Nordisk. Consultant; Onduo LLC, Roche Diabetes Care. Other Relationship; Sanofi. Research Support; Tandem Diabetes Care, Inc. Other Relationship; UnitedHealth Group. Consultant; Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S. Funding Roche Diagnostics, Diabetes Care
{"title":"1927-LB: Impact of Continuous Glucose Monitoring Use on Hospitalizations in People with Type 2 Diabetes—Real-World Analysis","authors":"SATISH K. GARG, IRL B. HIRSCH, ENRICO REPETTO, JANET K. SNELL-BERGEON, BRIAN ULMER, CHRISTOPHER PERKINS, RICHARD M. BERGENSTAL","doi":"10.2337/db24-1927-lb","DOIUrl":"https://doi.org/10.2337/db24-1927-lb","url":null,"abstract":"Introduction & Objective: The increasing prevalence of diabetes in the US continues to drive a steady rise in healthcare resource utilization. The real-world impact of continuous glucose monitoring (CGM) on hospitalizations in a broad type 2 diabetes population is not completely understood. Methods: In this retrospective analysis, we used Optum's de-identified Market Clarity data of &gt;79 million people to evaluate CGM use in 74,264 people with type 2 diabetes who were treated with non-insulin (NIT; n=25,788), basal insulin (BIT; n=25,292), and prandial insulin therapy (PIT; n=23,184). The primary outcomes were changes in all-cause hospitalizations (ACH), acute diabetes-related hospitalizations (ADH), and acute diabetes-related emergency room visits (ADER) during the 6- and 12-months post-index period. Results: ACH, ADH, and ADER were significantly reduced in the first 6 months (post-index) in all three groups: NIT (14%, 32%, 30%), BIT (25%, 57%, 37%), PIT (25%, 54%, 36%) respectively. (Figure 1) The reductions were sustained during 6-12 months in NIT (10%, 31%, 30%), BIT (23%, 56%, 34%), and PIT (19%, 49%, 36%) respectively (all p&lt;0.0001). Conclusion: The use of CGM in real-world across different therapeutic regimes in people with type 2 diabetes was associated with significant reductions in all-cause hospitalizations, acute diabetes-related hospitalizations and ER visits. Disclosure S.K. Garg: Research Support; Eli Lilly and Company. Advisory Panel; Medtronic. Research Support; Medtronic. Advisory Panel; Novo Nordisk. Research Support; DarioHealth Corp., Dexcom, Inc., Diasome. Advisory Panel; Roche Diabetes Care. I.B. Hirsch: Advisory Panel; Abbott. Research Support; Dexcom, Inc. Advisory Panel; Roche Diabetes Care. Research Support; MannKind Corporation, Tandem Diabetes Care, Inc. Advisory Panel; embecta. Research Support; Tandem Diabetes Care, Inc. Advisory Panel; Vertex Pharmaceuticals Incorporated. E. Repetto: Employee; Roche Diabetes Care. J.K. Snell-Bergeon: None. B. Ulmer: Employee; Roche Diabetes Care. C. Perkins: Employee; Roche Diabetes Care. R.M. Bergenstal: Other Relationship; Abbott. Research Support; Arkray Marketing. Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur. Other Relationship; Dexcom, Inc., Eli Lilly and Company. Consultant; embecta, Hygieia. Research Support; Insulet Corporation. Consultant; MannKind Corporation. Other Relationship; Medtronic, Novo Nordisk. Consultant; Onduo LLC, Roche Diabetes Care. Other Relationship; Sanofi. Research Support; Tandem Diabetes Care, Inc. Other Relationship; UnitedHealth Group. Consultant; Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S. Funding Roche Diagnostics, 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":"141730556","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}
JULIA K. MADER, GUIDO FRECKMANN, THOMAS FORST, GERHARD VOGT, MICHAEL ANGSTMANN, SANDRA MOCERI, DANIEL MILITZ
Introduction and Objective: The use of continuous glucose monitoring (CGM) improves glycemic control in people with diabetes (PwD). The availability of multiple systems with high accuracy allows PwD and their health care professionals to choose the best option for each individual based on respective needs. This study aimed to evaluate the clinical performance of a novel CGM system, the Accu-Chek® SmartGuide device, in PwD on insulin therapy. Methods: An open label, single-arm, prospective, non-randomized, multi-center clinical study was performed to evaluate the performance of the Accu-Chek® SmartGuide device in adults aged ≥18 years with type 1 or type 2 diabetes on insulin therapy. Participants wore 3 sensors at the back of the upper arms for 14 days and CGM data was compared with capillary glucose measurements (Accu-Chek® Guide) in in-clinic sessions throughout the wear time of the device. The study included glucose manipulations into hypo- and hyperglycemic ranges and the 20/20 agreement rate (percentage of values within ±20 mg/dL (< 100 mg/dL) as well as ±20% (≥ 100 mg/dL)) was evaluated as primary endpoint. In addition, secondary endpoints included the evaluation of the mean absolute relative difference (MARD) e.g. overall, for different time points and for dynamic (absolute rate-of-change ≥1 mg/dL/min) and stable glucose phases as well as safety endpoints. Results: In total, 48 participants (20 females, 28 males; 40 type 1, 8 type 2) were included into the study. The 20/20 agreement rate was 90.5 % (CI: 0.90 - 0.91). The overall MARD was 9.2 % over the entire run-time, 8.3 % for the beginning, 9.0 % for the middle and 10.8 % for the end of the wearing time as well as 8.8 % and 10.6 % for stable and dynamic glucose periods. No serious adverse events were reported during the study. A total of 15 device-related adverse events were reported, all due to application site reactions. Conclusion: In this study, the Accu-Chek® SmartGuide device has been proven to be safe and demonstrated a robust accuracy over a 14-day wear period including glucose manipulations. Disclosure J.K. Mader: Advisory Panel; Becton, Dickinson and Company. Speaker's Bureau; Becton, Dickinson and Company, A. Menarini Diagnostics, Boehringer-Ingelheim, diaTribe. Other Relationship; Diabetes UK. Stock/Shareholder; decide Clinical Software GmbH. Advisory Panel; embecta. Speaker's Bureau; embecta, Viatris Inc., Eli Lilly and Company. Advisory Panel; Eli Lilly and Company, Medtronic. Speaker's Bureau; Medtrust. Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Advisory Panel; PharmaSens, Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care. Board Member; Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Sanofi, Dexcom, Inc., Viatris Inc. Advisory Panel; Viatris Inc. Speaker's Bureau; Ypsomed AG. Research Support; European Union. Stock/Shareholder; elyte Diagnostics GmbH. Other Relationship; elyte Diagnostics GmbH.
{"title":"1924-LB: Clinical Performance of a Novel CGM System","authors":"JULIA K. MADER, GUIDO FRECKMANN, THOMAS FORST, GERHARD VOGT, MICHAEL ANGSTMANN, SANDRA MOCERI, DANIEL MILITZ","doi":"10.2337/db24-1924-lb","DOIUrl":"https://doi.org/10.2337/db24-1924-lb","url":null,"abstract":"Introduction and Objective: The use of continuous glucose monitoring (CGM) improves glycemic control in people with diabetes (PwD). The availability of multiple systems with high accuracy allows PwD and their health care professionals to choose the best option for each individual based on respective needs. This study aimed to evaluate the clinical performance of a novel CGM system, the Accu-Chek® SmartGuide device, in PwD on insulin therapy. Methods: An open label, single-arm, prospective, non-randomized, multi-center clinical study was performed to evaluate the performance of the Accu-Chek® SmartGuide device in adults aged ≥18 years with type 1 or type 2 diabetes on insulin therapy. Participants wore 3 sensors at the back of the upper arms for 14 days and CGM data was compared with capillary glucose measurements (Accu-Chek® Guide) in in-clinic sessions throughout the wear time of the device. The study included glucose manipulations into hypo- and hyperglycemic ranges and the 20/20 agreement rate (percentage of values within ±20 mg/dL (&lt; 100 mg/dL) as well as ±20% (≥ 100 mg/dL)) was evaluated as primary endpoint. In addition, secondary endpoints included the evaluation of the mean absolute relative difference (MARD) e.g. overall, for different time points and for dynamic (absolute rate-of-change ≥1 mg/dL/min) and stable glucose phases as well as safety endpoints. Results: In total, 48 participants (20 females, 28 males; 40 type 1, 8 type 2) were included into the study. The 20/20 agreement rate was 90.5 % (CI: 0.90 - 0.91). The overall MARD was 9.2 % over the entire run-time, 8.3 % for the beginning, 9.0 % for the middle and 10.8 % for the end of the wearing time as well as 8.8 % and 10.6 % for stable and dynamic glucose periods. No serious adverse events were reported during the study. A total of 15 device-related adverse events were reported, all due to application site reactions. Conclusion: In this study, the Accu-Chek® SmartGuide device has been proven to be safe and demonstrated a robust accuracy over a 14-day wear period including glucose manipulations. Disclosure J.K. Mader: Advisory Panel; Becton, Dickinson and Company. Speaker's Bureau; Becton, Dickinson and Company, A. Menarini Diagnostics, Boehringer-Ingelheim, diaTribe. Other Relationship; Diabetes UK. Stock/Shareholder; decide Clinical Software GmbH. Advisory Panel; embecta. Speaker's Bureau; embecta, Viatris Inc., Eli Lilly and Company. Advisory Panel; Eli Lilly and Company, Medtronic. Speaker's Bureau; Medtrust. Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Advisory Panel; PharmaSens, Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care. Board Member; Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Sanofi, Dexcom, Inc., Viatris Inc. Advisory Panel; Viatris Inc. Speaker's Bureau; Ypsomed AG. Research Support; European Union. Stock/Shareholder; elyte Diagnostics GmbH. Other Relationship; elyte Diagnostics GmbH.","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":"141730468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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