bluuebunny/crossref_metadata_2025 huggingface dataset:
1778-P: Endoplasmic Reticulum Stress Leads to Pancreatic Beta-Cell Failure by Suppressing cAMP Signaling via ATF4
Authors: LEE JAEMIN
Published: June 2023

Type 2 diabetes (T2D) is characterized by β-cell dysfunction and loss. Endoplasmic reticulum (ER) stress responses, especially the PERK-ATF4 pathway, promote β-cell disorders. The role of the PERK-ATF4 pathway in β-cell dysfunction is still unknown. We report that ATF4 induces PDE4D production which impairs β-cell function by downregulating cAMP signaling. Transgenic expression of ATF4 in β-cells caused early β-cell dysfunction and loss, resembling accelerated T2D. ATF4 expression enhanced PDE4D, decreased cAMP signaling, and inhibited incretin and glucose responses in β-cells. In leptin receptor-deficient diabetic (db/db) mice, β-cells displayed higher nuclear ATF4 localization along with elevated PDE4D expression. Inhibiting PDE4 activity with selective pharmacological agents increased β-cell function in db/db and ATF4 transgenic mice.

In summary, ER stress promotes β-cell failure via ATF4-mediated PDE4D synthesis, proposing PDE4D as a therapeutic target for safeguarding β-cell function in T2D.

Disclosure

J. Lee: None.

Funding

National Research Foundation of Korea (2019R1A4A102972413, 2020M3A9D8038660)
179-LB: Should We Screen with a Fasting Blood Glucose Test? A Novel Two-Step Screening Strategy for Gestational Diabetes—A Large Tertiary Comparative Cohort Study
Authors: DEITCH JESSICA , LEE I-LYNN , YATES CHRISTOPHER J. , KATHPAL ESHA , LAWTON PAUL , SHAHID IBRAHIM , STEELE CHERYL , HAMBLIN PETER S. , KRISHNAMURTHY BALASUBRAMANIAN , SAID JOANNE M. , TEALE GLYN R. , KEVAT DEV
Published: June 2023

Background: Gestational diabetes mellitus (GDM) diagnosis is resource intensive and controversial. A modified COVID-19 GDM diagnostic method was introduced at Western Health Melbourne, an Australian tertiary hospital caring for a multi-ethnic population with a high GDM prevalence at 20-23%. In place of a universal 2 hour 75g OGTT, a novel two step diagnostic method was instituted. A fasting blood glucose (FBG) was performed with thresholds based on a secondary analysis of HAPO data. A FBG of ≥5.1mmol/L (91.8mg/dL) diagnosed GDM; women with FBG 4.7-5.0mmol/L (84.6-90.0mg/dL) proceeded to an OGTT (IADPSG diagnostic criteria); FBG ≤4.6mmol/L (82.8mg/dL) was considered to exclude GDM.

Methods: A retrospective cohort study of singleton pregnancies birthing after 20 weeks’ gestation compared perinatal outcomes in 6469 women who underwent modified screening (MS) during the COVID-19 pandemic with 8669 women who had conventional screening (CS) prior to COVID-19.

Results: GDM prevalence was the same using either MS or CS (22.9 vs 22.2% p=0.31) with similar rates of insulin use. There was no difference in the prevalence of large for gestational age infants (10.3 vs 9.4% p=0.06), pre-term birth (6.6 vs 6.4% p=0.53) or gestational age at birth (39.2 vs 39.1 weeks). Mean birth weight was increased with MS (3335g vs 3307g) and small for gestational age rate reduced (9.1 vs 10.5% p=0.01). The MS group had fewer inductions (34.2 vs 39.8% p<0.01). Primary caesarean section rate was unchanged (18.4 vs 18.4% p=0.91). MS reduced the need for an OGTT by 76%. Women with a FBG ≤4.6mmol/L by MS had non-inferior outcomes compared to women with a FBG ≤4.6mmol/L with CS irrespective of GDM diagnosis.

Conclusion: In a large multi-ethnic cohort with a high prevalence of GDM, modified screening using FBG greatly reduced the number of resource intensive OGTTs with non-inferior perinatal outcomes. A prospective randomised trial comparing these methods is warranted.

Disclosure

J. Deitch: None. J. M. Said: None. G. R. Teale: None. D. Kevat: Advisory Panel; Novo Nordisk, Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance, Novo Nordisk, Abbott Diabetes, AstraZeneca. I. Lee: None. C. J. Yates: None. E. Kathpal: None. P. Lawton: None. I. Shahid: None. C. Steele: None. P. S. Hamblin: None. B. Krishnamurthy: None.

Funding

Australian Government Research Training Program; Sheppard Millar Lowe Research Trust Scholarship
18-OR: Implementation of a Hybrid Screening and Monitoring Model in Colorado—Autoimmunity Screening for Kids (ASK)
Authors: GENO RASMUSSEN CRISTY , BAUTISTA KIMBERLY A. , KARBAN RACHEL , BEDOY RUTH , FELIPE-MORALES DANIEL , REWERS MARIAN
Published: June 2023

Objective: Screening for type 1 diabetes (T1D) in the general population is becoming more accessible. We examined facilitators and barriers to implementing a hybrid screening and monitoring model utilizing telehealth in Colorado.

Methods: Qualitative, semi-structured interviews to define key factors for establishing a telehealth T1D screening and monitoring program were conducted with 14 parents who had a child identified as high risk of developing T1D participating in the ASK study and 10 ASK providers. Purposeful sampling was used to identify participants. Interviews explored opinions regarding a hybrid model that includes cloud-based glucose monitoring, education via telehealth, parental placement of continuous glucose monitors, home finger pokes to check for islet autoantibody status and glucose, use of home oral glucose tolerance tests, as well as engagement of primary health care providers for monitoring across stages of T1D.

Results: Between 1/2020 and 9/2022, 133 participants in the ASK study participated in the ASK hybrid screening and monitoring model completing at least two remote telehealth visits. Thematic analysis from parent interviews (n=14; 71% female, 79% had no family history of T1D) identified two key themes:1) appreciation for flexibility offered through hybrid monitoring, and 2) importance of coordinated communication between provider team regardless of location. Provider interviews (n=10; 70% female) identified three key themes:1) interest in hybrid model that was not time intensive to implement, 2) access to monitoring and educational resources to support clinic team and patients with remote care, and 3) for rural areas, potential constraints regarding access to consistent broadband that could interfere with telehealth visits.

Conclusion: The use of a hybrid care model may be warranted to support clinics and families with screening and monitoring for early stages of T1D toward translation into standard practice regardless of location.

Disclosure

C.Geno rasmussen: None. K.A.Bautista: None. R.Karban: None. R.Bedoy: None. D.Felipe-morales: None. M.Rewers: Research Support; Provention Bio, Juvenile Diabetes Research Foundation (JDRF), Hemsley Charitable Trust, Dexcom, Inc., Janssen Research & Development, LLC.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (2109-04818)
183-LB: A Randomized Placebo-Controlled Trial of the Effectiveness of Early Metformin in Addition to Usual Care in the Reduction of Gestational Diabetes Mellitus Effects (EMERGE)
Authors: DUNNE FIDELMA P. , ALVAREZ-IGLESIAS ALBERTO , NEWMAN CHRISTINE , SMYTH ANDREW , BROWNE MARIE , DEVANE DECLAN , GILLESPIE PADDY , O'DONNELL MARTIN
Published: June 2023

The optimal approach to managing GDM is uncertain. We sought to determine whether early introduction of metformin (at diagnosis) plus lifestyle modification was superior to standard care (lifestyle modification alone).

Methods: EMERGE is a phase III, superiority, parallel-group, 1:1 randomized trial comparing effectiveness of early metformin vs placebo initiated before 28 weeks +6 days. GDM was confirmed using WHO 2013 criteria. Metformin (or placebo) was initiated at 500mg/day titrated to 2500mg. The primary outcome was the composite of insulin initiation or fasting glucose ≥ 5.1 mmol/L at weeks 32 or 38.

Results: Between June 2017-September 2022, 535 women were randomized, 268 to metformin, 267 to placebo; mean (SD) age of 34.3 (4.8), 23.7% primigravid, 17.6% non-Caucasian, 31.4% had prior GDM, 39.4% had BMI<30, mean gestation 25.4 weeks. There was no significant difference in the primary outcome between metformin and placebo treatments (56.8% vs 63.7%; RR=0.89 95%CI: 0.78-1.02). Insulin initiation was significantly lower in metformin (38.4%) vs placebo (51.1%) group (RR 0.75; 95%CI 0.62-0.91). Compared to placebo, metformin treated women achieved better glycemic control (HbA1C at 38 weeks; 33.9 vs 35 mmol/mol; P=0.004) and gained less weight between randomization and delivery (0.8kg vs 2.0kg; P=0.03), while infants were less likely to weigh >4000g (7.6% vs 14.8%; P=0.013). There was no significant difference in infants weighing <2500g (6.1% vs 3.4%; P=0.215), in infants needing NICU admission (15.3% vs 12.5%; P=0.439) or in infants born preterm <37weeks (9.2% vs 6.5%; P=0.329) in the metformin versus placebo groups.

Conclusions: In a Phase III trial, early introduction of metformin did not reduce the composite of insulin initiation or elevated fasting glucose at week 32 or 38 in women with GDM, but was associated with important maternal and neonatal benefits with no increase in adverse perinatal events.

Disclosure

F. P. Dunne: None. A. Alvarez-Iglesias: None. C. Newman: None. A. Smyth: None. M. Browne: None. D. Devane: None. P. Gillespie: None. M. O'Donnell: None.

Funding

Health Research Board of Ireland
185-OR: Machine-Learning Approach Reveals Microbiome, Metabolome, Lipidome, and Their Interaction in Type 1 Diabetes Mellitus
Authors: TAN HUILING , SHI YU , YUE TONG , ZHENG DONGXUE , WANG CHAOFAN , LIU ZIYU , YANG DAIZHI , DING YU , XU WEN , YAN JINHUA , LUO SIHUI , WENG JIANPING , ZHENG XUEYING
Published: June 2023

Background: An increasing amount of research shows that the gut microbiota and metabolites play a role in type 1 diabetes mellitus (T1D). We aimed to use machine learning to explore gut microbiota, serum metabolites, and lipids signatures in T1D individuals.

Methods: We evaluated 137 individuals in a cross-sectional cohort that included 38 T1D patients, 38 healthy controls, and 61 T1D patients for validation. After clinical examination and biospecimen collection, we characterized the gut microbiome profile with 16S rRNA gene amplicon sequencing and analyzed serum metabolites and lipids with liquid chromatography-mass spectrometry. All molecular data were analyzed using a combination of univariate, multivariate, and machine-learning approaches (Logistic Regression, Support Vector Machine, Gaussian Naive Bayes, and Random Forest).

Results: Machine-learning approaches using microbiota composition did not accurately predict T1D status (model accuracy=0.7555), while the accuracy of model using metabolite composition was 0.9333. Based on bacterial species-level composition, Ruminococcus torques, Anaerostipes, Veillonella, Erysipelotrichaceae UCG-003, Blautia, and Coprococcus were coincident microbes which all increased in T1D. Increased 3-hydroxybutyric acid and 9-oxo-ode (AUC=0.70 and 0.67) were meaningful coincident metabolites in T1D. PC(36:4e)(rep) was the most significant lipid (coefficient index=3.11e-9, increased in T1D). We confirmed the biological relevance of the microbiome, metabolome, and lipidome features in the validation group. Ruminococcus torques was positively associated with 3-hydroxybutyric acid (p<0.01).

Conclusions: By using machine-learning algorithms and multi-omics, we demonstrated that T1D patients are associated with altered microbiota, metabolites, and lipidomic signatures or functions. Machine-learning approaches have potential clinical applications in T1D diagnostics and treatment.

Disclosure

H.Tan: None. J.Yan: None. S.Luo: None. J.Weng: None. X.Zheng: None. Y.Shi: None. T.Yue: None. D.Zheng: None. C.Wang: None. Z.Liu: None. D.Yang: None. Y.Ding: None. W.Xu: None.

Funding

National Natural Science Foundation of China (82100822); Anhui Provincial Natural Science Foundation (2008085MH248, 2008085MH278); Guangdong Basic and Applied Basic Research Foundation (2019A1515010979); National Key R&D Program (2017YFC1309600)
189-OR: FGF21-Mediated Signaling Defects and Their Effects on Insulin Resistance in Insulin-Mediated Pseudoacromegaly
Authors: PHAN NHUNG , ORNITZ DAVID M. , STONE STEPHEN I.
Published: June 2023

Insulin-mediated pseudoacromegaly (IMPA) is a rare, severe insulin resistance syndrome linked to digenic mutations in FGFR1 and KLB. These proteins form the receptor complex for FGF21, a hepatokine that plays a critical role in adipose tissue insulin sensitivity. Patients with IMPA have normal growth hormone and IGF-1. However, they have markedly increased insulin levels, tall stature, and obesity. To assess the pathogenicity of these mutations, we isolated iPSC from the proband with IMPA. We used CRISPR gene editing to correct the FGFR1 and KLB mutations and differentiated the iPSC lines into adipocytes. Western immunoblotting demonstrated that the uncorrected (mutant) cells demonstrated decreased levels of FGFR1 and pERK1/2 in response to insulin and/or FGF21 compared to corrected (wild-type) cells. Additionally, mutant adipocytes demonstrated significantly larger lipid droplets when stained with BODIPY. To complement the iPSC work, a humanized transgenic knock-in mouse line was created using CRISPR gene editing. When exposed to a high fat diet (HFD), female mice harboring variants in FGFR1 and KLB (DM - Double Mutant) developed significant weight gain compared to wild-type (WT) littermates. The difference in body weight was attributed to a difference in body fat. Similar to the human phenotype, the DM mice experience intermittent hyperglycemia and significant hyperinsulinemia. Explants of gonadal white adipose tissue demonstrated decreased lipolysis and pAKT and pERK. Mac-2 staining of white adipose tissue demonstrated abundant adipose tissue macrophages forming crown-like structures, suggesting adipose tissue inflammation. Additionally, we measured gene expression in brown adipose tissue, and noting that Ucp1 expression in DM mice was 37% when compared to WT. These results suggest pathogenic mechanisms in which FGFR1 and KLB mutations lead to IMPA via decreased FGF21-mediated signaling in the adipose tissue.

Disclosure

N.Phan: None. D.M.Ornitz: None. S.I.Stone: None.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD098872); National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK124574, P30DK020579, P30DK056341); National Center for Advancing Translational Sciences
191-LB: The Impact of Urbanization on the People of the Upper Amazon
Authors: GERHOLD CHAD , ROBBINS DAVID C. , GARCIA-TOUZA MARIANA , DEAN BARTHOLOMEW C.
Published: June 2023

Although it has gotten little attention, T2D has become a public health issue in the Peruvian Amazon, particularly among urban dwellers. The growing rate of T2D in the global south has been attributed to greater access to industrial foods and sedentary lifestyles ensuant of rapid urbanization. In Amazonia, people migrate from rural communities to urban hubs searching for socioeconomic opportunities. As a result, prevalence of T2D and obesity has rapidly increased in these cities. Our study compared the diabetes status of people living in Yurimaguas (YU) with those living in traditional rural villages in the Balsapuerto District (BD), Peru, to understand health differences between rural and urban Amazonians.

Methods Participants were recruited in YU (M/F = 114/52) and 11 rural villages in BD (F/M = 92/77). We collected blood pressure, glucose, insulin, glycosylated hemoglobin (A1c), lipids panels, and body measurements. T2D status was determined using ADA guidelines for A1c and glucose.

Results Mean age of participants was younger in BD (44.4 yrs) compared to YU (50.3 yrs; t335 = 3.52, p < 0.01). After adjusting for age, we found participants in YU had greater A1c (F2, 328 = 49.14, p < 0.01), BMI (F2, 328 = 28.79, p < 0.01), glucose (F2, 328 = 8.85, p < 0.01), insulin (F2, 328 = 7.11, p < 0.01), triglycerides (F2, 328 = 3.84, p < 0.01), and systolic pressure (F2, 328 = 37.45, p < 0.01) compared to participants living in BD. The proportion of individuals with diabetes and prediabetes was greater in YU (37%, 34% respectively) compared to BD (4%, 12% respectively; χ2 = 119.9, df =2, p < 0.01). The percentage of individuals with BMIs > 25 in YU was 68% (n = 112) and 29% (n = 49) in BD respectively (χ2 = 51.8, df =1, p < 0.01).

Discussion Results suggest Peruvians living in YU generally had poor health profiles, higher incidence of diabetes, and higher BMIs compared to their rural counterparts 40km away. Given the stark differences between these communities, efforts should be made to understand the nutritional and lifestyle factors leading to this health decline.

Disclosure

C. Gerhold: None. D. C. Robbins: None. M. Garcia-touza: None. B. C. Dean: None.

Funding

Kansas University Diabetes Institute
191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice
Authors: EL-AGROUDY NERMEEN N. , SCHUMANN TINA , KURZBACH ANICA , SANCAR GENCER , SANDFORTH LEONTINE , HERRMANN CHRISTINE , SHULMAN GERALD I. , BIRKENFELD ANDREAS L.
Published: June 2023

Background and Aims: Recent GWAS in large human populations identified the monocarboxylate transporter SLC16A11 as a candidate gene for T2D. While previous studies postulated that SLC16A11 plays a role in hepatic lipid and glucose metabolism, the existing data are controversial and exact mechanisms of how SLC16A11 affects T2D are missing. Here, we aimed at elucidating the role of SLC16A11 in the development of metabolic disease.

Methods: HEK293 cell lines expressing murine and human SLC16A11 were established. Moreover, using CRISPR/Cas9, a SLC16A11 knockout mouse model was generated. Finally, SLC16A11 mRNA expression was measured in various insulin responsive tissues of ob/ob and db/db mice.

Results: In HEK293 cells, substrates of the transporter were identified. mRNA expression of SLC16A11 was reduced in skeletal muscle of ob/ob and db/db mice (-69.8% and -22.8%; p<0.05) compared to littermate controls. SLC16A11 KO and WT littermate mice fed NCD or HFD did not differ in body weight and composition, energy expenditure or food intake. While basal glucose and insulin in SLC16A11 KO and WT littermates on a HFD were not different, glucose infusion rate during hyperinsulinemic euglycemic clamp was lower in SLC16A11 KO mice (SLC16A11 WT= 36.4±3 mg/kg/min; SLC16A11 KO= 24.7±2 mg/kg/min; P<0.01), indicating reduced whole-body insulin sensitivity. No changes were observed in hepatic glucose production, liver fat content or hepatic mitochondrial function using PINTA method. Instead, clamped 2-deoxy-glucose uptake was significantly reduced in skeletal muscle (-41%; p<0.05) of SLC16A11 KO, together with increased DAGs levels and PKCθ activation, indicating skeletal muscle insulin resistance.

Conclusions: Our data show for the first time that in contrast to previous assumptions, SLC16A11 impairs skeletal muscle insulin sensitivity without affecting hepatic metabolism. Taking also human GWAS into account, we propose that SLC16A11 may be an interesting target for the treatment of T2D.

Disclosure

N.N.El-agroudy: None. T.Schumann: None. A.Kurzbach: None. G.Sancar: None. L.Sandforth: None. C.Herrmann: None. G.I.Shulman: Consultant; Novo Nordisk, DiCerna Pharmaceuticals, Inc., Bayer Consumer Care AG, Kriya Therapeutics, Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Other Relationship; AstraZeneca, Merck & Co., Inc., Janssen Research & Development, LLC, iMetabolic Biopharma Corporation, Maze Therapeutics, 89bio, Inc., Equator Therapeutics, Inc., Generian Pharmaceuticals, Fortress Biotech, Inc., OrsoBio, Aro Biotherapeutics Company, Stock/Shareholder; Levels Health, Inc. A.L.Birkenfeld: None.
193-LB: Refining Diabetes Risk for Individuals with Prediabetes
Authors: KIM SUN H. , HSIA DANIEL S. , LEBLANC ERIN S. , STATEN MYRLENE , CHATTERJEE MONTGOMERY RANEE , RASOULI NEDA , ARODA VANITA R. , PITTAS ANASTASSIOS G.
Published: June 2023

Rate of progression from prediabetes to diabetes varies greatly, and better risk stratification would help guide prevention efforts. We evaluated predictors of incident diabetes in the placebo arm (n=1212) of the vitamin D and type 2 diabetes (D2d) study. At baseline, participants met 2 or 3 ADA glycemic criteria for prediabetes (fasting glucose, FPG, 100-125mg/dL; 2-hour glucose during a 75-g OGTT, 2hPG, 140-199 mg/dL; HbA1c, 5.7-6.4%). Diabetes was diagnosed based on semiannual testing. After a median follow up of 2.5 years, 27% met criteria for diabetes. Among those who did and did not develop diabetes, mean BMI (±SD) was similar (32.1 kg/m2 ± 4.4), as well as other demographic factors including age, race, and ethnicity. More men than women developed diabetes (29% vs 23%, p=0.02). Incident diabetes rates differed by prediabetes subgroups (Figure); and those meeting all three prediabetes criteria at baseline (35.4%) were most likely to develop diabetes (log-rank p <0.001). There were no differences in the incident diabetes rate among those people meeting only 2 of the prediabetes criteria (Figure). Also, area under the receiver operator characteristic curves for incident diabetes at 36 months increased when all 3 criteria were used in the diagnosis (0.736) vs only FPG and HbA1c (0.686). We conclude that ‘prediabetes’ is heterogeneous, and the 2hPG may refine diabetes risk and guide intervention strategies in adults with high-risk prediabetes.

Disclosure

S. H. Kim: Advisory Panel; GI Dynamics, Consultant; Aligos, Research Support; Fractyl Health, Inc. D. S. Hsia: None. E. S. Leblanc: Other Relationship; Dexcom, Inc. M. Staten: None. R. Chatterjee montgomery: Research Support; Bristol-Myers Squibb Company, Epigenomics AG. N. Rasouli: Research Support; Novo Nordisk, Eli Lilly and Company, Somalogic. V. R. Aroda: Consultant; Applied Therapeutics Inc., Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Applied Therapeutics Inc., Eli Lilly and Company, Fractyl Health, Inc., Novo Nordisk, Sanofi. A. G. Pittas: None.

Funding

National Institutes of Health (U01DK098245)
20-OR: Loss of Characteristic ß-Cell Function in Autoantibody-Positive (Ab+) Individuals during the Progression to Type 1 Diabetes (T1D)
Authors: ISMAIL HEBA M. , CUTHBERTSON DAVID D. , SKYLER JAY S. , EVANS-MOLINA CARMELLA , SOSENKO JAY
Published: June 2023

We used correlations of C-peptide secretion between follow-up time points (autocorrelation) of Ab+ relatives in the TrialNet Pathway to Prevention study to assess the loss of characteristic β-cell function during progression to T1D. Measures of β-cell function: AUC C-peptide; C-peptide Index (30-0 min C-peptide)/(30-0 min glucose); and Index60 (composite of glucose and C-peptide during first 60 minutes of OGTT)] were assessed (table 1). Spearman correlations of AUC C-peptide from baseline to pre-diagnosis (6 months before) OGTTs of progressors (Pro; Age=8.7±3.6 yrs; n=182) were lower than correlations of AUC C-peptide from baseline to last OGTTs of non-progressors (NPro; Age=9.6±3.8 yrs; n=3,137; p<0.001 for all). Among Pro, correlations of AUC C-peptide from baseline to diagnosis OGTTs were considerably lower than correlations of AUC C-peptide from baseline to pre-diagnosis OGTTs (p=<0.001 for all). In conclusion, the lower C-peptide autocorrelation from baseline to last OGTTs of Pro compared to NPro indicates that β-cell function is already appreciably altered 6 months before diagnosis. Among Pro, the substantial decline of C-peptide autocorrelation from 6 months before diagnosis to diagnosis suggests a marked loss of β-cell function in that interval. Autocorrelation offers another approach for providing insight into β-cell compromise.

Disclosure

H.M.Ismail: Consultant; Rise Therapeutics. D.D.Cuthbertson: None. J.S.Skyler: Advisory Panel; Adocia, Altheia Sciences, Arecor, Avotres Inc., Bayer Inc., COUR Pharmaceuticals, Dance Biopharm/Aerami, Diasome, Enthera, Immnomolecular Therapeutics, Kriya Therapeutics, Oramed Pharmaceuticals, Orgenesis Inc., Precigen, Inc., ViaCyte, Inc., Board Member; Applied Therapeutics Inc., Dexcom, Inc., Consultant; Novo Nordisk, Sanofi, Signos, 4Immune, Other Relationship; Imcyse, Provention Bio, Inc. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. J.Sosenko: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK129799-01A1)
200-OR: Role of Insulin-Degrading Enzyme (IDE) in the Tubulin–Primary Cilium Axis to Regulate Glucagon Secretion
Authors: CASANUEVA-ALVAREZ ELENA , SANZ-GONZÁLEZ ALBA , MERINO BEATRIZ , PERDOMO GERMAN , COZAR-CASTELLANO IRENE
Published: June 2023

Hyperglucagonemia is a hallmark of T2D, although molecular mechanisms underlying glucagon secretion dysregulation are poorly understood. We have recently reported that genetic ablation of IDE in α-cells (A-IDE-KO mouse) leads to constitutive glucagon secretion, hypertrophy, hyperplasia and increased proliferation. αTC1.9-KD-IDE cells (~30% IDE-knock-down) displayed reduced tubulin and acetylated-α-tubulin protein levels, impaired primary cilium and increased proliferation. Thus, we aimed to elucidate the role of IDE in α-cells tubulin network and ciliogenesis, and how this axis may be part of the glucagon secretion machinery. We have studied by western-blot IDE, tubulin, acetylated-α-tubulin and Arl13b (primary cilium marker) levels in αTC1.9 cells under low- and high-glucose conditions. We have found that high-glucose lowers IDE protein levels by 50% compared to low-glucose conditions, leading to a similar decrease in tubulin, acetylated-α-tubulin and Arl13b protein levels. These findings agree with our previous results using αTC1.9-KD-IDE cells, suggesting a relevant role of IDE in microtubule dynamics to control glucagon granules exocytosis. On the other hand, αTC1.9-KD-Arl13b cells (~70% Arl13b-knock-down) were used as a model of impaired ciliogenesis, showing 50% decrease in tubulin, and dysregulated glucagon secretion, mimicking αTC1.9-KD-IDE cells phenotype. In parallel, insulin-mediated inhibition of glucagon secretion is lost and insulin receptor protein levels were decreased by 40% in both, αTC1.9-KD-IDE and αTC1.9-KD-Arl13b cells, showing the relevance of IDE and primary cilium in the paracrine regulation of α-cells. Furthermore, these results have been reproduced in A-IDE-KO mice isolated islets. In conclusion, our results show that IDE-tubulin-primary cilium axis is regulated during glucose-stimulated glucagon secretion, this axis is also required for the paracrine action of insulin on α-cells to inhibit glucagon secretion.

Disclosure

E.Casanueva-alvarez: None. A.Sanz-gonzález: None. B.Merino: None. G.Perdomo: None. I.Cozar-castellano: None.

Funding

Ministerio de Ciencia e Innovación-Spain (PID2019-110496RB-C21)
206-LB: Overview of the All of Us Research Program 2023 Data Release for Type 2 Diabetes
Authors: DEDE YILDIRIM ELIF , SULIEMAN LINA , GIANNINI JOHN , OSTCHEGA YECHIAM , OCHSENFABER EVAN , BERMAN LEW , RAMIREZ ANDREA
Published: June 2023

The National Institutes of Health's All of Us Research Program is collecting data from one million or more participants throughout the U.S. to advance precision medicine. The program enrolls individuals from diverse backgrounds with a focus on groups that are traditionally under-represented in biomedical research. The spring 2023 curated dataset release makes All of Us the world's largest and most diverse dataset of its kind available for broad research use, with nearly 45% of the data from people who identify with a racial or ethnic minority group.

The expanded phenotypic data includes survey data from 413,396 participants and electronic health record data from 287,012 participants that can be used to study diabetes and other metabolic disorders. The platform supports Jupyter notebooks to build queries using R or Python3, as well as custom interface tools that allow identification of data and health conditions within the large relational database using the OMOP common data model. Currently, the dataset includes 33,849 participants with at least one T2D condition code, one T2D drug exposure, or one T2D lab result, excluding T1D condition codes.

We will discuss the utility of this expansive dataset for T2D researchers and participants, and its potential to answer critical questions about metabolic health outcomes.

Disclosure

E. Dede yildirim: None. L. Sulieman: None. J. Giannini: None. Y. Ostchega: None. E. Ochsenfaber: None. L. Berman: None. A. Ramirez: n/a.
208-LB: Plasma Lipidomics Reveals Sex-Specific Associations with? Brown Adipose Tissue in Asian Children
Authors: THWAY TINT MYA , CHEN LI , KOTHANDARAMAN NARASIMHAN , LEOW MELVIN K. , PRAKASH KN BHANU , YAP FABIAN , SENG LEE YUNG , THAM ELIZABETH H. , CHONG YAP-SENG , V FORTIER MARIELLE , GODFREY KEITH , WENK MARKUS , ERIKSSON JOHAN
Published: June 2023

Brown adipose tissue (BAT) plays a crucial role in lipid metabolism. Activated BAT oxidizes fatty acids from triglycerides in lipid droplets during thermogenesis, increasing energy expenditure. The lipidomic profile of BAT has been primarily studied in animals but little in humans. We sought to identify the plasma lipidomic profile associated with BAT in a thermoneutral condition in 6-year-old children (n=134) in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. LC-MS/MS-based quantification of 480 lipids was performed on plasma samples; %BAT was quantified based on fat-signal-fractions of water-fat-MRI. Associations between plasma lipids and the child's %BAT were investigated using multivariate regression analysis adjusting for sex, ethnicity, and BMI. Sex stratification was applied to investigate the sex-specific lipid signatures of %BAT among the 68 boys and 66 girls. The inverse association between %BAT and BMI was stronger in boys (R2 =0.28) than in girls (R2 =0.07). More lipid signatures of %BAT were observed in boys compared to girls; of 63 unique lipid species significantly associated with %BAT, 12 were associated in both genders, 50 in boys and 11 in girls. In boys, lipid species representing triacylglycerol, cholesteryl ester, acylcarnitine, sphingomyelin, ceramide, hexosylceramides and lysophosphatidylcholine classes showed negative associations with %BAT, whereas several phosphatidylethanolamine lipids displayed positive association with %BAT. In girls, opposite trends in effect sizes (R=-0.44) were, however, observed; several lipids in acylcarnitine, diacylglycerol and sphingolipid classes presented positive association with %BAT, while phosphatidylethanolamine lipids showed negative associations with %BAT. These unique associations between plasma lipid species and BAT in a sex-specific manner provide insights into the different potential lipidomic pathways involved in BAT energy metabolism.

Disclosure

M. Tint: None. M. Fortier: None. K. Godfrey: Other Relationship; See box. M. Wenk: None. J. Eriksson: None. L. Chen: None. N. Kothandaraman: None. M. K. Leow: None. B. Kn: None. F. Yap: None. Y. Lee: None. E. H. Tham: None. Y. Chong: None.

Funding

Open Fund Large-Collaborative Grant (000504)
208-OR: Comparable Improvement in NAFLD, Weight Loss, and Lipid Metabolism in Rats Treated with Dual GLP-1–GIP Receptor Agonist (Tirzepatide) and Gastric Sleeve
Authors: ABUBAKER JEHAD , ALSABAH SALMAN , AL-KHAIRI IRINA , CHERIAN PREETHI T. , ABUKHALAF NERMEEN A. , AREFANIAN HOSSEIN , DSOUZA CAROL , AL-SABAH SULEIMAN , AL-MULLA FAHD , ABU-FARHA MOHAMED
Published: June 2023

Background: Bariatric surgery is increasingly utilized as a weight management and metabolic control procedure, hence the name metabolic Surgery. Metabolic surgery is currently considered as an effective procedure for the treatment of diabetes providing a phenomenal hope for a long-lasting remission of diabetes. The use of combined GIPR and GLP-1R activation has recently emerged as a novel therapeutic tool in the treatment of T2D that produces profound weight loss, glycemic control, and lipid lowering. Tirzepatide (LY3298176) is a novel dual GIP and GLP-1 receptor agonist.

Objectives: The aim of this study is to evaluate the difference between GLP-1/GIP receptor agonist (Tirzepatide) treatment vs bariatric surgery on weight loss, NAFLD, insulin signaling and insulin resistance in SD rats.

Methods: Sprague-Dawley rats between the age of 4-6 weeks were either placed on regular rat chow diet (n=7) or cafeteria diet "high-fat/carbohydrate diet" ad libitum (n=42). After 21 weeks, rats on high fat diet were divided into either Obese control (n=6) gastric sleeve (n=6), Semaglutide 10nM/Kg (n=6), or various concentrations of Tirzepatide (10nM/Kg (n=6), 50nM/Kg (n=6) or 100nM/Kg (n=6). The treatments lasted for six weeks before animals were euthanized. Weight, OGTT, as well as liver biopsy analysis and gene expression analysis was performed.

Results: Gastric sleeve resulted in about 15.5 % weight loss compared to 10.7% in Semaglutide, and 5.0%, 14.9% and 17.7% in the 10, 50 and 100 nM/Kg Tirzepatide groups. Glucose tolerance was improved after all treatments. NAFLD was also improved in all treatment with surgery and 100 nM/Kg Tirzepatide showing highest improvement. Additionally, gene expression of lipid metabolism markers such as ANGPTL3 and 8 were markedly reduced in all treatments.

Conclusions: Tirzepatide is a novel dual GIP and GLP-1 receptor agonist that can lead to improved metabolic conditions similar to sleeve gastrectomy.

Disclosure

J.Abubaker: None. M.Abu-farha: None. S.Alsabah: None. I.Al-khairi: None. P.T.Cherian: None. N.A.Abukhalaf: None. H.Arefanian: None. C.Dsouza: None. S.Al-sabah: None. F.Al-mulla: None.
209-OR: DJB Surgery Improves Oxidative Stress and Alleviates Neuron Cell Injury of Hypothalamus in T2DM Rats by Nrf2/HO-1 Signal
Authors: WANG HUAIJIE , YAN QINGTAO , QU MEIHUA
Published: June 2023

Metabolic surgery has become an effective treatment for type 2 diabetes mellitus (T2DM). T2DM is often accompanied with impaired glucose utilization and energy metabolism in the brain, leading to oxidative stress, neuron cells injury and inflammation. Previous studies showed that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats. This study investigated the protective effect and regulatory mechanism of DJB surgery on T2DM induced brain injury. In this study, differential expression of hypothalamic proteins and genes was analyzed by protein microarray, Flow cytometry, qRT-PCR, western blot and immunofluorescence. The protein microarray results showed that there were significant differences in the expression of hypothalamic hormone and redox regulation-related proteins between the T2DM-DJB rats and the T2DM-Sham rats. Western blot, qRT-PCR, and immunofluorescence results showed DJB surgery significantly down-regulated the expressions of GFAP, NF-κB, p-NF-κB, IL-1β and IL-6 in the hypothalamus of T2DM rats, and reduces hypothalamic inflammation and glial cell proliferation. DJB surgery up-regulated the expression of C-fos, Ki67, BCL-2 and BDNF, and down-regulated the expression of Caspase-3, Cleaved caspase-3 in the hypothalamus of T2DM rats, which played a neuroprotective role, and reduced the damage of hypothalamus cells. DJB surgery up-regulated the expression of Nrf2 and HO-1 in the hypothalamus of T2DM rats and reduces oxidative stress. Those results indicated that DJB surgery improves hypothalamic inflammation and alleviates neuron cells injury in T2DM rats by activating Nrf2/HO-1 mediated antioxidant signaling. Key words: DJB surgery; T2DM; Apoptosis; Inflammatory; Oxidative stress.

Disclosure

H.Wang: None. Q.Yan: None. M.Qu: None.

Funding

National Natural Science Foundation of China (82070856); Shandong Provincial Medicine and Health Commission (202102040075); Weifang Science and Technology Bureau (2021YX071)
210-LB: Impact of COVID-19 Pandemic on the Outcomes of Patients with Diabetes in Colombia
Authors: MORENO-MONTOYA JOSÉ , BALLESTEROS SILVIA , DE LA HOZ-VALLE JOSÉ
Published: June 2023

Objective: Aside the direct health implications of COVID-19, pandemic has had multiple consequences, especially in chronic patients. This paper aimed to evaluate the impact of the COVID-19 pandemic on mortality and the search for health care of patients with diabetes in Colombia.

Methods: Nationwide ecological panel study of secondary data from the Colombian official records of mortality and medical attentions due to diabetes between 2015 and 2021. Hospitalizations, ambulatory and emergency care visits, as well as death rates were assessed once adjusted by the availability of specialized health institutions and rurality.

Results: During the COVID-19 pandemic, the mortality rate from diabetes increased by 30.4% (pre-pandemic average by semester: 7.73 deaths per 100,000 inhabitants; pandemic average: 10.08 deaths per 100,000 inhabitants), the average rate of medical attention increased by 67.2% (pre-pandemic: 3163 per 100.000; pandemic: 5290 per 100.000), in which, ambulatory care arose by 44.6% and hospitalizations by 42.3%. Rurality was inversely associated with health visits, and the availability of tertiary care institutions was associated with both diabetes mortality and medical consultations.

Conclusions: Beyond the direct effect of the COVID-19 virus on patients with diabetes, their overall health outcomes worsened during pandemic. Availability of high specialized health facilities is related to the number of medical consultations, which suggests that people who did not have access to specialized health services were neglected. Actual and total impact of COVID-19 pandemic in patients with diabetes remains unclear.

Disclosure

J. Moreno-montoya: None. S. Ballesteros: None. J. De la hoz-valle: None.
210-OR: Long-Acting GIPR Agonism Enhances Body Weight Regulation of Multiple Weight-Reducing Agents in Diet-Induced Obese Mice
Authors: ROELL WILLIAM , O'FARRELL LIBBEY , REGMI AJIT , COSKUN TAMER
Published: June 2023

The development of multi-agonists targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) has resulted in significant clinical improvements in body weight management, however the contribution of GIPR agonism to this effect is incompletely understood. Using a diet induced obese (DIO) mouse model, GIPR agonism (LAGIPRA) alone has demonstrated little to no efficacy in weight management, whereas the addition of LAGIPRA to long acting GLP-1R agonism decreased food intake and increased energy expenditure resulting in greater weight loss compared with GLP-1R agonism alone suggesting a synergistic benefit. To determine whether GIPR agonism would provide similar synergistic improvements in energy metabolism with additional pharmacologic drivers of weight loss, we treated DIO mice with various weight reducing agents plus and minus LAGIPRA in metabolic chambers. Interestingly, addition of LAGIPRA enhanced weight loss, fat mass reduction, energy expenditure, and lipid oxidation whether combined with T3, FGF21, or long-acting glucagon (IUB288); consistent with earlier experiments, it had little effect on its own. Assessment of adipose tissue engagement in these and subsequent studies suggest GIPR agonism in this tissue may enhance lipolysis, potentially enabling greater energy expenditure via release of stored lipids. These findings suggest a unique role for GIPR agonism to regulate energy expenditure when combined with molecules that reduce body weight generating a greater negative caloric balance and enhancing body weight reduction.

Disclosure

W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. L.O'farrell: None. A.Regmi: Employee; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.
212-LB: Implementation of the Avantect Pancreatic Cancer Test in Newly Diagnosed Type 2 Diabetes Patients in a Clinical Setting
Authors: CHOWDHURY SHIMUL , VILALTA ADRIAN , COLLINS MICAH , RIVIERE MICHAEL , LOPEZ VANESSA , LEIGHTON ANNA , ANTONY MARTY , NILSON ERIC , BERGAMASCHI ANNA , HAAN DAVID , VOLKMUTH WAYNE , LEVY SAMUEL
Published: June 2023

Pancreatic Cancer (PaC) is the 3rd leading cause of cancer mortality and is predicted to be the 2nd-leading cause by 2030. PaC and lacks effective early detection tools. Studies have identified patients with new-onset type II diabetes (diagnosis made ≤36 months; NOD) as a high-risk patient population that could benefit from early detection of PaC. ClearNote Health has validated a non-invasive, blood-based, epigenomic early-detection pancreatic test called Avantect. The test has been validated in a large case-control study, including patients with NOD. A pilot program to deploy the test in a clinical setting of NOD was conducted to assess the feasibility and integration of the test into a clinical workflow. Fifty patients received the Avantect test from ClearNote Health. Test results were delivered to the clinical site for post-test follow-up. Feedback on the clinical impact of the testing and logistics were reviewed at the conclusion of testing. The cohort consisted of 30 males (60%) and 20 females (40%). The average patient age was 68 years (range 38-87), and patients had an average time from diabetes diagnosis to testing of 22.9 months (range 1-36). A family history of PaC was observed in 29/50 patients (58%). Of the 50 total test orders, the required test blood volume of 10 mL was obtained in 45 patients (90%). These results included 43 patients with no abnormal signal detected (95.6%), and two patients with an abnormal signal detected (4.4%). The two abnormal signal-detected results are awaiting further clinical evaluation. These results demonstrate early success in the delivery of the Avantect test to the clinical practice of diabetic patients. The test is tailored to facilitate clinical implementation because of its non-invasive nature and its high-performance characteristics (sensitivity - 66.7%; sensitivity- 96.9%).

Disclosure

S. Chowdhury: Employee; ClearNote Health. D. Haan: Employee; ClearNote Health. W. Volkmuth: Employee; ClearNote Health. S. Levy: Employee; ClearNote Health. A. Vilalta: Consultant; ClearNote Health. M. Collins: Employee; ClearNote Health. M. Riviere: Employee; ClearNote Health. V. Lopez: Employee; ClearNote Health. A. Leighton: Employee; ClearNote Health. M. Antony: Employee; ClearNote Health. E. Nilson: Employee; ClearNote Health. A. Bergamaschi: Employee; ClearNote Health.
212-OR: Leptin Reduction as a Required Component for Weight Loss
Authors: ZHAO SHANGANG , SCHERER PHILIPP E.
Published: June 2023

A significant reduction in circulating leptin levels is well corelated with substantial weight loss. However, it is still not clear whether the observed leptin reduction is a cause or consequence of weight reduction. Here, we showed that FGF21 and liraglutide could rapidly induce leptin reduction, and this reduction contributes to the beneficial effects of FGF21 and liraglutide, as blocking the leptin reduction by a transgenic approach curtails the beneficial effects. Moreover, a higher degree of leptin reduction, induced by combination of leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, after removing liraglutide and FGF21, a significant weight gain is associated with rapid increase in circulating leptin levels and prevention of leptin surge by leptin neutralizing antibody slows down weight gain and preserves a better glucose tolerance. Mechanically, a significant reduction in leptin reduction induces a higher degree of leptin sensitivity in neurons, located in hypothalamic region, other than AP. In conclusion, this study supports a model that leptin reduction is required for substantial weight loss and partial leptin reduction may be a novel strategy to treat obesity and its associated metabolic syndromes.

Disclosure

S.Zhao: None. P.E.Scherer: None.
215-LB: Comparison of Clinical and Serological Features among Type III APS, Isolated T1DM, and LADY/LADA
Authors: QIU YAWEI , GUO JING , WEI PENGFEI , HE HUAQIU , JIN MINGYUE , ZHAO HUIJUAN , LI HUAIZHI , LI QIANG
Published: June 2023

Type III autoimmune polyendocrine syndromes (APS) is characterized by the coexistence of autoimmune thyroid disease (AITD) and T1DM. There is a rare series of studies on APS in Chinese population. This paper retrospectively analyzed the clinical and serological features of Chinese patients with type III APS who admitted to our center from Sept 2018 to Oct 2022, and compared the similarities and differences with isolated T1DM, LADY/LADA patients at the same time. The study included 69 patients, 18 patients with type III APS, 20 patients with T1DM, and 31 patients with LADY/LADA. Type III APS was predominantly female, while T1DM and LADY/LADA groups were the opposite (72.22% vs 35.00% vs 38.71%, P = 0.037). The median age of onset of diabetes in the three groups was 30.50, 23.00 and 41.00 years, respectively (P < 0.001). Hashimoto's thyroiditis (HT) (n=13, 72.22%) was the main AITD in type III APS group, followed by Graves’ disease (Table 1). The median of GADAb in the three groups were 1501.43, 115.01 and 301.02 U/mL, respectively (P = 0.022). And the levels of TPOAb and TGAb in type III APS group were significantly higher than those in the other two groups (P <0.05). Type III APS is more common in women with diabetes onset later than those with isolated T1DM and earlier than those with LADY/LADA. HT is the main AITD in type III APS patients, and the levels of GADAb and thyroid autoantibodies in patients with type III APS are often higher.

Disclosure

Y. Qiu: None. J. Guo: None. P. Wei: None. H. He: None. M. Jin: None. H. Zhao: None. H. Li: None. Q. Li: None.
215-OR: Barriers and Facilitators of Implementing a Pediatric Type 1 Diabetes Psychosocial Intervention—Provider and Leader Perspectives
Authors: PRICE JULIA , THOMAS COURTNEY , DEATRICK JANET A. , OKONAK KATHERINE , KAZAK ANNE
Published: June 2023

Introduction: Behavioral Family Systems Therapy for Diabetes (BFST-D) is an efficacious, family-based pediatric psychosocial type 1 diabetes (T1D) intervention that improves family conflict and glycemic levels. A briefer group-based version (bBFST-D) has some evidence of effectiveness. However, few families receive this care. Using the Consolidated Framework for Implementation Research, this national qualitative study examined T1D provider and hospital leader perspectives on barriers and facilitators of implementing bBFST-D.

Methods: Psychosocial (n = 10) and medical T1D providers (n = 10), clinical leaders (n = 11), and billing/practice managers (n = 9) were recruited from 5 children's hospitals across the US. Across these 4 stakeholder groups, participants (M age = 42.22 - 55.10 yrs, SD Age = 9.15 - 12.98 yrs) largely identified as female (55-100%), White (67-100%), and non-LatinX (90-100%). A minority were African American (0-22%) or Asian (0-11%). Each participant completed a qualitative phone interview, which was recorded, transcribed, and analyzed using a rapid analysis approach.

Results: Stakeholder groups identified multi-level factors that influence implementation of bBFST-D, such as those specific to the intervention (delivery format, required evidence of effectiveness), the providers (knowledge, beliefs about bBFST-D), the hospital setting (leadership engagement, available resources), and factors outside of the hospital (family needs, billing, national performance guidelines). The most important factors among leaders were evidence bBFST-D improves health outcomes and among providers were buy-in from hospital leadership and hospital resources (staffing, space, scheduling).

Conclusions: Study findings offer foundational knowledge on factors that influence implementation of evidence-based pediatric psychosocial T1D care, which can be used to develop and then test strategies to increase delivery of this care.

Disclosure

J.Price: None. C.Thomas: None. J.A.Deatrick: None. K.Okonak: None. A.Kazak: None.

Funding

National Institutes of Health (1K23DK125666)