bluuebunny/crossref_metadata_2025_split huggingface dataset:
27-OR: Residual Beta-Cell Function Associates with Lower Glycaemic Variability and More Time in Range in Individuals with Type 1 Diabetes
Authors: FUHRI SNETHAGE COCO , MCDONALD TIMOTHY J. , RAMPANELLI ELENA , DE GROEN PLEUN , SCHIMMEL ALINDA W.M. , VAN RAALTE DANIËL , BROUWER CATHERINE B. , ORAM RICHARD A. , ROEP BART O. , NIEUWDORP MAX , HANSSEN NORDIN 
Published: June 2023

Introduction: A significant proportion of individuals with type 1 diabetes (T1D) have long-term preservation of beta-cell function. Residual beta-cell function (RBCF) is associated with fewer long-term complications and hypoglycemic events. Yet, little is known about the influence of RBCF on daily glycemic control. Therefore, we investigated the associations between RBCF and daily markers of glycemic control in individuals with T1D.
Methods: In this cross-sectional study 500 individuals with T1D were included (41.0 ±14years), 64% female, HbA1c 55.6 ±12mmol/mol, median T1D duration 14 years [IQR: 6-29years]. As a validated marker of RBCF, postprandial urinary C-peptide/creatinine ratios (UCPCR) were measured. Time in euglycemic range (TIR) (3.9-10mmol/L) and hypoglycemic range (TUR) (&lt;3.9-10mmol/L) were monitored 14 days prior to the study visit, with a continuous glucose monitoring device. Spearman correlations were calculated in Rstudio.
Results: The median UCPCR was 0.03 (IQR: 0.00-0.88) nmol/mmol and strongly correlated with duration of T1D (r = -0.651, p &lt; 0.001). Higher UCPCR correlated with longer TIR (r = 0.330, p &lt; 0.001), lower mean glucose levels (r =-0.318, p=0.005) and shorter TUR (r= -0.237, p &lt;0.001) and lower glucose variation (-0.356, p &lt;0.001). In line, higher UCPCR associated with lower HbA1c levels (r= -0.183, p&lt;0.001) and less 24-hour insulin use (r = -0.183, p = &lt;0.001). The associations remained significant in linear regression models when adjusted for sex, age, plasma glucose and duration of diabetes.
Conclusion: UCPCR correlates with more time in range, shorter time under range, and lower HbA1c levels in individuals with T1D. Beneficial effects of beta-cell preservation in T1D may therefore be attributable to less intermittent glucotoxicity and hypoglycaemic episodes.

Disclosure
C.Fuhri snethage: None. M.Nieuwdorp: Advisory Panel; caelus health. N.Hanssen: Consultant; Novo Nordisk, Research Support; Novo Nordisk. T.J.Mcdonald: None. E.Rampanelli: None. P.De groen: None. A.W.M.Schimmel: None. D.Van raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc., Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. C.B.Brouwer: None. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. B.O.Roep: None.

Funding
DNF DON Grant 2020 (2020.10.002)
276-LB: STR-Mediated Glucose Sensing and GLUT2-Regulated Glucose Absorption Are Repaired by DJB Surgery in Diabetic Rats
Authors: WANG ANPING , KOU RONGGUAN , ZHAO XIANGYU , SUN SIPENG , WANG YI , GAO ZHIQIN 
Published: June 2023

Abstract: Our previous study demonstrated that duodenal-jejunal bypass (DJB) ameliorated glycemic control in a diabetic rat model but the underlying mechanisms are still unclear. This study aimed to identify the regulatory function of sweet taste receptors and glucose transporters within the DJB-remodeled small intestine and gut peptide secretion. DJB or sham surgeries were performed in streptozotocin (STZ)-induced diabetic rats. The blood GLP-1 and GLP-2 levels were evaluated under feeding and fasting conditions. The effects of sweet taste receptors (STR) inhibition on glucose control were measured in vivo with lactisole (STR inhibitor). The results showed that the glucose tolerance was improved in DJB-operated rats compared with Sham group, similar to that of normal control rats without significant differences in food intake and body weight. The plasma levels of insulin were increased after DJB in both feeding and fasting conditions. The plasma GLP-1 levels of DJB rats were increased under diet-fed condition, and GLP-2 levels of DJB rats were increased after fasting. The villus height and crypt depth were significantly increased in the intestinal alimentary limb (A limb) of DJB-operated rats, while decreased in the biliopancreatic limb (BP limb). The expression levels of T1R2, T1R3, sweet taste signaling effector Gα-gustducin and glucose transporters SGLT1, GLUT2 was downregulated in the BP and common limbs, but was elevated in the A limb after DJB. However, the beneficial effects of DJB on glood control was abolished in the presence of lactisole. Furthermore, the immunofluorescence results displayed that GLUT2 localization was normalized after DJB.
In conclusion, these findings indicate that DJB ameliorates glycemic control probably via repairing sweet taste receptor-mediated glucose sensing and absorption with the responses of GLP-1 and GLP-2 to dietary carbohydrate.
Keywords: Sweet taste receptor; Lactisole; GLUT2; SGLT1; GLP-1; GLP-2; DJB;

Disclosure
A. Wang: None. R. Kou: None. X. Zhao: None. S. Sun: None. Y. Wang: None. Z. Gao: None.

Funding
National Natural Science Foundation of China (82070856, 82100842); Natural Science Foundation of Shandong Province (ZR201807090175, ZR2020QH084)
276-OR: Postprandial Hyper- and Hypoglycemia Are Related to Injection Time—An Insulclock Connected Insulin Cap–Based Real-World Study
Authors: GOMEZ-PERALTA FERNANDO , VALLEDOR XOÁN , LOPEZ-PICADO AMANDA , ABREU CRISTINA , FERNÁNDEZ-RUBIO ELSA , PUJANTE ALARCÓN PEDRO , GARCÍA ELENA , AZRIEL SHARONA , CORCOY ROSA , CERQUEIRA CRISTINA , PÉREZ JESUS , RUIZ-VALDEPEÑAS LUIS 
Published: June 2023

Background: Reaching the optimal postprandial glucose dynamics is a daily challenge for people with T1D. The study aimed to analyze postprandial hyperglycemia excursion (PHE) and late postprandial hypoglycemia (LPH) risk according to insulin injection time.
Methods: Real-world, retrospective study in T1D using multiple daily injection (MDI) insulin. Five hours of paired CGM and automatically tracked insulin injections were collected with the Insulclock® connected cap. Meal events were identified using the ROC detection methodology. Postprandial glucometrics and LPH (glucose &lt;70 mg/dL 2-5 hours after a meal) were evaluated according to insulin injection time.
Results: Meal glycemic excursions (n=2784) were analyzed in 82 people. In 63% insulin was injected after the meal started. The best balance between PHE control and LPH risk is obtained by injecting -15 to 0 minutes before meals. Higher PHE (glucose peak-baseline; mg/dL) was observed in delayed injections (mean±SD): Early (-45-15 min) (n=348) 101.8 ± 34.0; Optimal (-15-0 min)(n=612) 98.3± 29.8; Delayed (0-+45 min) (n=1528) 114.8±40,2 (n=348), (p &lt;0.001). LPH risk also increased with delayed injections, n (%): Early 31 (8.9); Optimal 47 (7.7); Delayed 171 (11.2), (p 0.038).
Conclusion: The correct timing of insulin injection is crucial to reduce postprandial hyper- and hypoglycemia.

Disclosure
F.Gomez-peralta: Advisory Panel; Abbott Diabetes, Insulcloud S.L., Speaker's Bureau; A. Menarini Diagnostics, Boehringer Ingelheim and Eli Lilly Alliance, Lilly Diabetes, Novartis, Novo Nordisk. C.Cerqueira: Employee; Insulcloud S.L. J.Pérez: Employee; Insulcloud S.L. L.Ruiz-valdepeñas: Employee; Insulcloud S.L., Stock/Shareholder; Insulcloud S.L. X.Valledor: Employee; Insulcloud S.L. A.Lopez-picado: Employee; Insulcloud S.L.. C.Abreu: Speaker's Bureau; Lilly, Novo Nordisk. E.Fernández-rubio: Speaker's Bureau; Lilly Diabetes, Novo Nordisk, AstraZeneca. P.Pujante alarcón: None. E.García: Advisory Panel; Airliquide, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Boehringer Ingelheim and Eli Lilly Alliance, Novo Nordisk, Sanofi, Airliquide. S.Azriel: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Medtronic, Speaker's Bureau; Dexcom, Inc., Lilly Diabetes, AstraZeneca, Sanofi. R.Corcoy: Advisory Panel; Novo Nordisk, Other Relationship; Novo Nordisk, Lilly, Sanofi, Abbott, Speaker's Bureau; Sanofi, Roche Diabetes Care.
277-LB: Weight Cycling Is Associated with ICU Admission and Mechanical Ventilation in Adults with Diabetes Hospitalized with COVID-19
Authors: MI KANG YU , SIMONSON DONALD C. , CHAUGULE AKSHATA S. , GARG RAJESH K. , GOPALAKRISHNAN GEETHA , HOWARD KYRA , LEBASTCHI JASMIN , MITRI JOANNA , PALERMO NADINE E. , WEINSTOCK RUTH S. , MCDONNELL MARIE E. 
Published: June 2023

Weight variability in diabetes is an emerging risk factor for macrovascular complications and mortality, potentially via increased inflammation. We examined the impact of pre-admission weight cycling (WC) on COVID-19-related outcomes, including in-hospital mortality, ICU admission, and mechanical ventilation (MV), using a large multicenter cohort. This study included 277 adults with diabetes hospitalized with COVID-19 (March 2020-February 2021) at 5 university hospitals in the eastern US (COVIDEastDM Consortium) with body weight measurements at 0, 6, and 12 months before admission. Weight change was considered significant if it exceeded 5% in each 6-month interval. The cohort was grouped into four weight categories: unchanged (n=57; reference group), weight loss (WL; n=88), weight gain (WG; n=50) and WC (n=32), and was 54.6% male, 58.6% White, 24.2% Black, 18.5% Hispanic, with mean (SD) age 65.1 (12.6) years and HbA1c 7.7 (2.0)%. During hospitalization, 41.9% subjects were admitted to the ICU, 25.1% received MV, and 15.0% died. Age was the strongest risk factor for mortality (OR = 1.08 [95% CI: 1.03-1.13), and the presence of pre-existing comorbidity for both ICU admission (OR = 2.58 [1.13-5.90]) and MV (OR = 3.89 [1.30-11.64]). In an adjusted model, WC, but not WL or WG, was associated with ICU admission (OR = 3.09 [1.11-8.59]) and MV ((OR = 4.59 [1.48-14.19]), but not with mortality (OR = 3.19 [0.76-13.32]). The glycemic gap, shown previously to be associated with increased MV and mortality, did not change the relationship between WC and outcomes. The WC group trended toward higher peak ESR (94.3±23.1 ml/h vs. 62.2±33.5 ml/h, P=0.044) and hsCRP levels (150.0±133.9 mg/L vs. 104.1±105.3 mg/L, P=0.142).
Conclusion: Weight cycling is associated with ICU admission and mechanical ventilation in adults with diabetes and COVID-19. Our findings identify a unique vulnerability of individuals with diabetes and recent weight cycling.

Disclosure
Y. Kang: None. R. S. Weinstock: Consultant; Jaeb Center for Health Research, Other Relationship; Wolters Kluwer Health, Research Support; Insulet Corporation, Medtronic, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim Inc., Hemsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Tandem Diabetes Care, Inc., Kowa Pharmaceuticals America, Inc. M. E. Mcdonnell: None. D. C. Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows. A. S. Chaugule: None. R. K. Garg: None. G. Gopalakrishnan: Research Support; Spruce Biosciences, Sparrow Pharmaceuticals Inc, Medtronic. K. Howard: None. J. Lebastchi: None. J. Mitri: Other Relationship; Novo Nordisk, Research Support; Kowa Company, Ltd. N. E. Palermo: Research Support; Dexcom, Inc.
28-LB: Role of Glycine N-methyltransferase in Electronegative Lipoproteins-Induced Vascular Dysfunction in a Diabetic Rodent Model
Authors: LEE AN-SHENG , CHEN YUN-FANG , CHEN WEI-YU 
Published: June 2023

Several studies showed low-density lipoprotein (LDL) is associated with high risk of atherosclerosis in patients with diabetes. However, aggressively decreasing total LDL does not prevent all vascular complications. A novel culprit electronegative LDL (L5) was significantly increased in diabetic patients and could induce vascular damage according to our previous studies. However, the mechanism of L5 formation and how to reduce plasma L5 level are still unclear. In the present study, we found both aqueous and ethylacetate extracts of a traditional Chinese remedy Artemisia capillaris (AC) could decrease plasma L5 level in western diet-fed hamster (22.45 and 28.64 vs. 56.83%, respectively), while clinical remedies Simvastatin and Niacin could not. AC could also reverse western diet-induced vascular senescence (b-gal staining) and relaxation dysfunction in aortic rings (63.66±2.14 vs 40.13±1.48% of maximum contraction when compared to western diet hamsters; P&lt;0.01). To further determine the underlying mechanism, we have found that AC reversed western diet-reduced Glycine N-methyltransferase (GNMT) protein abundance and altered several microRNA expression by analyzing the microarray heatmap in liver tissue.
In conclusion, AC could significantly reverse western diet-induced vascular injury by lowering plasma L5 level through restore the liver enzyme GNMT activity.

Disclosure
A. Lee: None. Y. Chen: None. W. Chen: None.
28-OR: Characterising a Novel Peptide That Inhibits and Reverses Type 1 Diabetes
Authors: KING THOMAS W. , TAY SZUN S. , COLAKOGLU FEYZA , DEVALARAJA MATT , REMALEY ALAN , BIRO MATÉ , COCHRAN BLAKE , ANNE RYE KERRY 
Published: June 2023

Aims: Interventions that regenerate functional pancreatic β-cells are a potential treatment option for type 1 diabetes. D6PV is a small peptide that lowers plasma triglyceride levels. We have found that it also enhances expression of the β-cell survival gene Pdx1 and stimulates insulin production in INS-1E insulinoma cells. This study asks whether D6PV delays diabetes onset and preserves β-cell mass in mice with autoimmune β-cell loss.
Methods: Female 8-week-old NOD/ShiLtJ (NOD) mice (n=10-20/group) were treated twice/week for 16 weeks with D6PV (40 mg/kg i.p) or PBS. Diabetes onset was evaluated by measuring blood glucose levels. A separate cohort of female NOD mice were treated with D6PV or PBS twice/week for 4 weeks after they developed diabetes. Glycaemic control was evaluated by glucose tolerance test (1 g/kg i.p). Islet insulin content was quantified by immunostaining of paraffin-embedded, formalin-fixed pancreatic tissue. Expansion of CD8+ T-cells was analysed ex vivo from OTI-TCR transgenic mouse splenocytes and healthy human donors following stimulation via IL-7/15 and incubation ± D6PV.
Results: D6PV treatment for 16 weeks decreased fed and fasted blood glucose levels (p&lt;0.05 for both) and delayed diabetes onset in NOD mice (p&lt;0.01). This was accompanied by increased insulin +ve islet area in the D6PV treated, but not the PBS treated animals (p&lt;0.05). D6PV treatment also reduced lymphocyte infiltration into islets but increased lymphocytic migration to the basement membrane (0.2 ± 0.1% vs 1.8 ± 1.7%, p&lt;0.05). When NOD mice with diabetes were treated with D6PV, glucose tolerance improved (AUC 1167±341 vs 543±328, p&lt;0.01). Treatment of both mouse and human cytokine-activated isolated CD8+ T-cells with D6PV suppressed T-cell expansion (p&lt;0.001).
Conclusions: D6PV treatment delays diabetes onset, improves glycaemic control in mice with established disease, increases pancreatic insulin expression and inhibits T-cell expansion in NOD mice. D6PV is a potential treatment option for type 1 diabetes.

Disclosure
T.W.King: None. S.S.Tay: None. F.Colakoglu: None. M.Devalaraja: None. A.Remaley: None. M.Biro: None. B.Cochran: None. K.Rye: None.

Funding
National Health and Medical Research Council of Australia (RG201951)
282-OR: Closed-Loop Insulin Delivery Postpartum in Type 1 Diabetes
Authors: DONOVAN LOIS E. , FEIG DENICE , LEMIEUX PATRICIA , MURPHY HELEN R. , BELL RHONDA C. , SIGAL RONALD J. , HO JOSEPHINE , YAMAMOTO JENNIFER M. 
Published: June 2023

Background: Postpartum demands of caring for a newborn, breastfeeding, and sleep deprivation result in little time for self care of type 1 diabetes (T1D). Data are limited on the efficacy, safety and feasibility of closed loop insulin delivery postpartum.
Methods: We performed an open label, controlled pilot trial randomizing women to hybrid closed loop insulin delivery Medtronic MiniMed™ 670G/770G in auto mode or sensor augmented insulin pump (SAP) therapy in the first 12 twelve postpartum weeks. The primary outcome was the percent time in target glucose range of 70-180 mg/dL (3.9-10.0 mmol/L). Mixed models analysis assessed between group differences in glucose measures from median start time of closed loop (8 days) to 12wks postpartum.
Results: Twenty women were recruited. Two withdrew prior to randomization. The remaining 18 women completed 12 weeks of postpartum follow up in their assigned randomization group. Overall baseline mean age, duration of T1D and first pregnancy A1c was 32 years, 22 years and 6.9% respectively. Analyses adjusted for first pregnancy A1c and was intention to treat. Time in range did not differ between groups (79 ± 8.0% versus 80 ± 6.4% p =.079). Time below 70mg/dL (3.9 mmol/L) and 54mg/dL (3.0 mmol/L) was less for women randomized to closed loop versus SAP (1.6 ± .72 % vs 5.3 ± 3.3 % p &lt;0.001 and .23 ± .16 % vs .95 ± .82 % p = 0.002 respectively). Time above 180 mg/dL (10 mmol/L) was not different between groups 19.5 ±8.7% vs 15.9 ±7.8% p = .823. Mean glucose was 146 ± 13 and 133 ± 14 mg/dL p &lt;.001 for closed loop and SAP groups respectively. No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either group.
Conclusions: Closed loop insulin delivery postpartum was associated with less hypoglycemia than SAP and slightly higher mean glucose. There were no safety concerns. Time in target glucose range was high, minimizing the potential for further improvement with closed loop. These findings are reassuring for the use of closed loop insulin delivery postpartum because of its’ potential to reduce hypoglycemia.

Disclosure
L.E.Donovan: Research Support; Dexcom, Inc., Medtronic, Tandem Diabetes Care, Inc., Inner Analytics. D.Feig: Advisory Panel; Novo Nordisk Canada Inc., Speaker's Bureau; Sanofi, Novo Nordisk Canada Inc. P.Lemieux: Other Relationship; Dexcom, Inc. H.R.Murphy: Advisory Panel; Medtronic, Research Support; Dexcom, Inc. R.C.Bell: None. R.J.Sigal: Research Support; Novo Nordisk. J.Ho: None. J.M.Yamamoto: None.

Funding
Calgary Health Trust
283-OR: ADA Presidents' Select Abstract: An Isogenic hPSC-Based Platform for Functional Interrogation of the Role of Multiple T2D-Associated Genes in Pancreatic Beta-Cell Failure
Authors: XUE DONGXIANG , NARISU NARISU , YAN TINGFEN , ZHANG MEILI , GRENKO CALEB , TANG XUMING , ZHU JIAJUN , BONNYCASTLE LORI L. , ERDOS MICHAEL , VANDANA J JEYA , CHONG ANGIE , COLLINS FRANCIS S. , CHEN SHUIBING 
Published: June 2023

Type 2 diabetes (T2D) mellitus is a complex polygenic disease. Multiple genome-wide association studies (GWAS) have identified hundreds of T2D-related genetic variants, the vast majority of which are non-coding. Pinpointing the actual causal variants and their target gene transcripts has been challenging. Building on recent advances in CRISPR technology and protocols that allow differentiation into functional pancreatic beta cells, we created isogenic hPSCs encompassing knockout (KO) mutations in 20 GWAS-identified T2D risk genes, and systematically examined their roles in beta cell differentiation, insulin production, glucose response, and apoptosis. As a result, loss of TCF7L2, HNF4A, TLE4, TGFB1, GIPR and COBLL1 severely impaired the differentiation capacities of hPSCs into functional beta cells and over half of the 20 T2D genes shared implications in beta cell dysfunctions including decreased insulin content, impaired insulin secretion and high susceptibility to lipotoxicity. Next, we sorted beta cells from each KO and performed RNA-seq and ATAC-seq assays. An integrative analysis revealed KO of HNF4A, HNF1A, ABCC8, KCNJ11, TLE4 and WDR13 resulted in extensive transcriptomic and epigenetic changes in the beta cells. We identify that KO of HNF4A results in dramatic expressional changes of dozens of known T2D effector genes and additional ones critical to beta cell functions and biology. An analysis of T2D GWAS credible set of SNPs using ATAC-seq and RNA-seq coupled with functional assays, helped us to nominate a single likely T2D causal SNP (rs7132908) at FAIM2 locus. Finally, a correlation analysis of gene expression levels and insulin content across KO lines identified 1,867 differential genes including PCSK1N that likely serves as a hub gene by mediating insulin production in beta cells. This study thus offers a powerful strategy to interrogate shared molecular pathways among multiple risk genes for diabetes.

Disclosure
D.Xue: None. J.Vandana: None. A.Chong: None. F.S.Collins: None. S.Chen: Consultant; Vesalius Therapeutics, Stock/Shareholder; Oncobeat Theraputics. N.Narisu: None. T.Yan: None. M.Zhang: None. C.Grenko: None. X.Tang: None. J.Zhu: None. L.L.Bonnycastle: None. M.Erdos: None.

Funding
American Diabetes Association (9-22-PDFPM-06 to D.X.)
286-OR: Using iPSC-Derived Islets to Model the Effect of an ABCC8 Arg1420His Mutation in Fetal and Adult Islets
Authors: NAIR ANUP K. , BARKHO KATIYA , TRAURIG MICHAEL , NELSON ROBERT G. , BOGARDUS CLIFTON , BAIER LESLIE 
Published: June 2023

We previously reported an Arg1420His mutation in ABCC8 in an Indigenous community that resulted in hyperinsulinemic hypoglycemia in infancy in a homozygous carrier and a doubling in type 2 diabetes (T2D) risk in heterozygous carriers (3% of the population). Previous studies of ABCC8 mutations have suggested a loss of pancreatic beta cells as a probable cause of future T2D. To understand the pathomechanism behind the increased risk of T2D due to the Arg1420His mutation, we generated two sets of isogenic iPSCs from two different Indigenous community members. These iPSCs were used to generate pancreatic islets and assess insulin secretion using a dynamic glucose stimulated insulin secretion (D-GSIS) assay when the islets were immature (resembling fetal islets) and during multiple days after maturation (resembling adult islets). In immature islets, the D-GSIS assay confirmed the clinical phenotype of significantly higher insulin secretion in islets with the His-allele under basal conditions (2mM glucose) and a lower response to diazoxide in islets homozygous for the His-allele. Both Arg1420 and His1420 mature islets had lower insulin secretion under basal conditions, however, insulin secretory response to high glucose (20mM) and Tolbutamide (sulphonylurea) was significantly lower in islets heterozygous for the His-allele whereas no response was seen in islets homozygous for the His-allele despite having similar proportion of beta cells as assessed by flow cytometry (~50% cells positive for INS and NKX6-1). This suggests a mechanism other than beta cell loss as the cause of lower insulin secretory response in these impaired islets. Single cell RNA sequencing showed higher expression of G6PC2, which inhibits insulin secretion by opposing the action of GCK, in islets with the His-allele. Our ongoing work includes knockout of G6PC2 in the isogenic iPSCs and using a GCK activator (Dorzagliatin) to correct the insulin secretory response to high glucose in the His-allele carrying islets.

Disclosure
A.K.Nair: None. K.Barkho: None. M.Traurig: None. R.G.Nelson: None. C.Bogardus: None. L.Baier: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases