bluuebunny/crossref_metadata_2025 huggingface dataset:
202-OR: Cell-Autonomous Impairment of BCAA Catabolism in White Adipocytes Leads to Systemic Metabolic Dysregulation
Authors: TZENG JOYCE , AGUILLARD ASHLEY , LORENZO DAMARIS
Published: June 2021

Increased levels of serum branched-chain amino acids (BCAA) is associated with obesity, insulin resistance (IR), and type 2 diabetes (T2D). However, the mechanisms that trigger perturbations in BCAA homeostasis, and whether elevated BCAA causes obesity and other metabolic impairments or is a consequence of them is not clear. Young knock-in mice bearing the human T2D-linked R1788W variant in the cytoskeletal protein ankyrin-B (AnkB) show normal body weight and composition. These mice display increased glucose uptake by white adipose tissue (WAT) due to deficient internalization of the glucose transporter GLUT4. We reported that sustained elevation in glucose disposal in WAT leads to the onset of increased adiposity, lipotoxicity, systemic inflammation, and IR in AnkB mutant mice with age or in young animals fed Western diets. Non-obese R1788W AnkB mice also exhibit transcriptional changes consistent with lower BCAA catabolism in WAT. Here, we show that AnkB deficits impair BCAA catabolism in WAT prior to the onset of obesity. Lean R1788W AnkB mice show reduction in surface levels of the BCAA transporter Asct2 and BCAA uptake together with downregulation of BCAA catabolic enzymes in WAT. These deficits are concomitant with elevations in serum levels of BCAA and related acylcarnitines. Reduced expression of BCAA catabolic enzymes was also observed in WAT of lean WAT-specific AnkB KO mice. In contrast, AnkB deficiency did not alter BCAA oxidation in skeletal muscle (SKM), brown adipose tissue, or liver. Studies in control and R1788W AnkB mice fed isocaloric low and high fat (HFD) diets enriched in BCAA suggest that BCAA elevation triggers mitochondrial dysfunction, impairments in insulin secretion by the pancreas and in insulin signaling in SKM. Our data indicates that elevated circulating BCAA impair glucose tolerance and insulin sensitivity independently of obesity, and that these deleterious effects are potentiated by HFD.

Disclosure

J. Tzeng: None. A. Aguillard: None. D. Lorenzo: None.

Funding

American Diabetes Association (1-19-JDF-081 to D.L.)
21-OR: Real-World Treatment Escalation from Metformin Monotherapy in Youth-Onset Type 2 Diabetes Mellitus: A Retrospective Cohort Study
Authors: VAJRAVELU MARY ELLEN , HITT TALIA A. , AMARAL SANDRA , KATZ LORRAINE E. , LEE JOYCE M. , KELLY ANDREA
Published: June 2021

Background: Due to high rates of comorbidities and rapid progression, youth with type 2 diabetes may benefit from early and aggressive treatment. However, until 2019, the only approved medications for this population were metformin and insulin.

Objective: To investigate patterns and predictors of treatment escalation within 5 years of metformin monotherapy initiation for youth with type 2 diabetes in clinical practice.

Subjects: Commercially-insured patients with incident youth-onset (10-18 years) type 2 diabetes initially treated with metformin only.

Methods: Retrospective cohort study using a patient-level medical claims database with data from 2000 - 2019. Frequency and order of treatment escalation to insulin and non-insulin antihyperglycemics were determined and categorized by age at diagnosis. Cox proportional hazards regression was used to evaluate potential predictors of treatment escalation, including age, sex, race/ethnicity, comorbidities, and metformin adherence (medication possession ratio ≥0.8).

Results: The cohort included 806 (66% female; median age at diagnosis 15 years; 19% Hispanic, 16% Black) patients, with median 3.0-year follow-up after metformin initiation. One-quarter underwent treatment escalation (n=198; 78 to insulin, 160 to non-insulin antihyperglycemic). Younger patients were more likely to have insulin as the initial or only antihyperglycemic prescribed. Age at diagnosis (HR 1.14, 95% CI 1.07-1.22), medication adherence (HR 3.77, 95% CI 2.71-5.23), and Hispanic ethnicity (HR 1.46, 95% CI 1.05-2.04) were positively associated with treatment escalation, but comorbidities were not associated.

Conclusions: In clinical practice, treatment escalation for pediatric type 2 diabetes differs with age. Off-label use of non-insulin antihyperglycemics occurs and is most common among older adolescents.

Disclosure

M. Vajravelu: None. T. A. Hitt: None. S. Amaral: None. L. E. Katz: None. J. M. Lee: Advisory Panel; Self; GoodRx. A. Kelly: Consultant; Self; Vertex Pharmaceuticals Incorporated, vTv Therapeutics.

Funding

National Institutes of Health (K23DK125719-01, 5T32DK063688-17, R01DK110749, R01DK120886, R01HD091185, 5U01DK061230, UL1-TR000003, 2P30DK089503-11, R01HD074559-01-A1, UH3HD087979, R01DK115648, DK97830, UL1TR001878); Caswell Diabetes Institute at the University of Michigan
211-LB: Antifibrotic Effect of a Novel Long-Acting GLP-1/GCG/FGF21/Anti-Cytokine Tetra-Specific Liver Microenvironment-Targeting Drug (OGB21502) in CCl4-Induced Liver Fibrosis Mice Model
Authors: KIM MIN SUN
Published: June 2021

Liver fibrosis is a feature in the majority of chronic liver disease and oxidative stress. If not treated, it may lead to fibrotic liver disease, liver failure and hepatocellular carcinoma (HCC). Since complex biological pathways are involved, therapeutic strategies simultaneously targeting multiple aspects might be required to effectively treat fibrosis as well as NASH. Therefore, we developed a novel long-acting and multi-target drug (GCGR, GLP-1R, FGFR1/KLB, cytokineR), OGB21502 using UniStac technology, which is our proprietary multi-specific platform. OGB21502 prevents inflammation and fibrosis of liver tissue by controlling players in liver microenvironment (LME) such as apoptosis, macrophage activation, and fibroblast activation. Here we evaluate the effect of OGB21502 in liver fibrosis using CCl4 induced mice. Ocaliva was used as comparative control. In CCl4 induced mice (8 weeks induction), OGB21502 treatment led to a significant decrease in blood ALT (-38.1% vs. vehicle); hepatic hydroxyproline (-31.5% vs. vehicle) and total bilirubin in blood. Histopathological analysis indicated that OGB21502 meaningfully reduced fibrosis score (-37.5% vs. vehicle); hepatocyte ballooning score (-50% vs. vehicle) and inflammation score (-16.7% vs. vehicle). While all of the vehicle progressed to cirrhosis, 80% of the population administered OGB21502 at high concentrations had cirrhosis progression inhibition. Also, OGB21502 reduced the level of picosirius red positive area (-32.5% vs. vehicle); collagen I (-23.7% vs. vehicle); TGF-β (-27.2% vs. vehicle) and α-SMA (-32.3% vs. vehicle). Based on these results, OGB21502, a novel long-acting tetra-specific LME-targeting drug offers a therapeutic anti-inflammatory and anti-fibrotic effect.

Disclosure

M. Kim: None.
212-LB: Therapeutic Effect of a Novel Long-Acting GLP-1/GCG/FGF21/Anticytokine Tetra-Specific Liver Microenvironment-Targeting Drug (OGB21502) in MCD-Induced NASH Mice Model
Authors: KIM MIN SUN
Published: June 2021

Nonalcoholic steatohepatitis (NASH) is liver inflammation and damage caused by a buildup of fat in the liver. It is characterized by varying degrees of hepatic steatosis, cytoskeletal damage, and lobular inflammation which further leads to fibrosis, cirrhosis and even liver failure. Due to the complexity of the occurrence of NASH and fibrosis, a multi-targeting strategy attracts much attention to effectively address the vicious cycle formed in liver microenvironment. In this respect, we developed a novel long-acting and multi-target drug (GCGR, GLP-1R, FGFR1/KLB, cytokineR), OGB21502, using UniStac technology, which is our proprietary multispecific platform. Here we evaluate the effect of OGB21502 in NASH and fibrosis using MCD diet induced mice model. Liraglutide (Saxenda, Eli lilly) and dulaglutide (Trulicity, Eli lilly) was used as comparative control. In MCD diet-fed mice (8 weeks induction), OGB21502 treatment led to a significant decrease in blood ALT (-45.2% vs. vehicle). Histopathological analysis indicated that OGB21502 meaningfully reduced NAS score (NAFLD activity score, -56.5% vs. vehicle); steatosis score (-57.1% vs. vehicle) and inflammation score (-84.6% vs. vehicle). Compared to vehicle, 100% of OGB21502 dramatically showed “Not NASH” histopathological results. Also, the level of TGF-β (-39.9% vs. vehicle) and α-SMA in liver were significantly decreased in the OGB21502 treatment group. Based on these results, OGB21502, a novel long-acting tetra-specific drug, elicited anti-inflammatory and anti-fibrotic effects in MCD-induced mice model.

Disclosure

M. Kim: None.
219-LB: The Changes in Body Composition in Obese Patients with Polycystic Ovary Syndrome after Laparoscopic Sleeve Gastrectomy: A 12-Month Follow-Up
Authors: CAI MEILI , GAO JINGYANG , LEI DU , CHENG XIAOYUN , ZHU JIANGFAN , QU SHEN , ZHANG MANNA
Published: June 2021

Objectives: To investigate the changes in body fat distribution in obese women with polycystic ovary syndrome (PCOS) after laparoscopic sleeve gastrectomy (LSG), and to explore the factors that may predict changes in body fat distribution in PCOS patients after LSG.

Methods: A total of 83 obese patients with PCOS aged 18-45 years and 70 patients without PCOS were consecutively enrolled in the Hospital, between May 2013 and September 2020. The demographic characteristics, metabolic and sex hormone parameters, and body fat distribution were collected at baseline, and again at 3, 6, and 12 months after LSG in all patients. Dual-energy X-ray absorptiometry (DEXA) was used to assess body fat distribution.

Results: Although the loss of percentage of fat mass in the visceral adipose tissue (VAT) region was more than that in any other body region at 12 months after LSG in all patients, homeostatic model assessment of insulin resistance (HOMA-IR) at baseline and the change of HOMA-IR were only negatively correlated with the variations in VAT mass and volume at 3 months after LSG in PCOS women with obese. Logistic regression analysis showed that HOMA-IR<6.65 was an independent predictive factor for the changes in VAT mass [OR=0.145 (0.024-0.887) P=0.037] and volume at 3 months [OR=0.045 (0.005-0.393) P=0.005] after surgery in patients with PCOS.

Conclusions: Compared with control patients, HOMA-IR at baseline was an independent risk factor for the changes in VAT mass and volume at 3 months after surgery in patients with PCOS.

Disclosure

M. Cai: None. J. Gao: None. D. Lei: None. X. Cheng: None. J. Zhu: None. S. Qu: None. M. Zhang: None.

Funding

National Natural Science Foundation of China (81601269)
220-OR: Comparing Cardiovascular Benefits between GLP-1RA and SGLT2i as an Add-On to Metformin among U.S. Adults with Type 2 Diabetes (T2D)
Authors: DEREMER CHRISTINA E. , GUO JINGCHUAN , VOURI SCOTT M. , HALLER MICHAEL J. , DONAHOO WILLIAM T. , WINTERSTEIN ALMUT G. , SHAO HUI
Published: June 2021

Head-to-head comparison of clinical benefits between glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) are scarce. In this study, we aimed to compare real world cardiovascular benefits associated with the use of GLP-1RA vs. SGLT2i as add-on therapies to metformin among US adults with T2D.

Methods: This study used data from the IBM® MarketScan® Commercial Claims Databases (2012-2018). We identified metformin users, age ≥ 18 and with T2D, who initiated GLP-1RA or SGLT2i between Mar 29th and Dec 31st, 2013. Patients were followed until the primary endpoint, end of the study period (Dec 31st 2018), study drug discontinuation or initiation of the other study drug, or disenrollment from the health plan (whichever occurred first). The primary endpoint was a major cardiovascular composite (MCC), including acute myocardial infarction (MI), hospitalization for congestive heart failure (CHF), and stroke. The secondary endpoints included individual components of MCC. We constructed Cox proportional hazard regression models to compare the risks of cardiovascular endpoints between GLP-1RA and SGLT2i users, controlling for demographics, clinical characteristics, and the Diabetes Complication Severity Index.

Results: We identified 11,911 adults with T2D who initiated a GLP-1RA or SGLT2i as an add-on therapy to metformin. No difference in the risk of MCC or any secondary endpoints was observed between GLP-1RA users and SGLT2i users who did not have established cardiovascular disease. However, significantly lower risks of MCC (HR:0.67, 95% CI: 0.47-0.97) and CHF (HR:0.47, 95% CI:0.28-0.79) was observed among SGLT2i users compared with GLP-1RA users, among individuals with established cardiovascular complications.

Conclusions: Results suggest a greater cardioprotective benefit from SGLT2i compared to GLP-1RA when used for secondary prevention among adults with T2D.

Disclosure

C. E. Deremer: Research Support; Self; Pfizer Inc., Speaker’s Bureau; Spouse/Partner; Pharmacy Times, Stock/Shareholder; Self; Portola Pharmaceuticals, Inc. J. Guo: None. S. M. Vouri: None. M. J. Haller: Board Member; Self; SAB Biotherapeutics, Inc., Consultant; Self; MannKind Corporation, Other Relationship; Self; Janssen Pharmaceuticals, Inc., Sanofi. W. T. Donahoo: None. A. G. Winterstein: Research Support; Self; Merck Sharp & Dohme Corp. H. Shao: Research Support; Self; Sanofi.
228-LB: ß-arrestin-2 Deletion Influences GLP-1 Receptor Signaling in Pancreatic ß Cells In Vivo
Authors: BITSI STAVROULA , SUBA KINGA , MOHAMED NIMCO , LECLERC ISABELLE , RUTTER GUY A. , SALEM VICTORIA , JONES BEN , TOMAS ALEJANDRA
Published: June 2021

β-arrestin-2 (Barr2) is typically associated with G protein-coupled receptor desensitization and endocytosis, and reduced Barr2 recruitment is thought to enable prolongation of pharmacodynamic effects of biased glucagon-like peptide-1 receptor (GLP-1R) agonists. However, the precise role of Barr2 in GLP-1R function in β-cells is poorly understood. To study this role, a tamoxifen-inducible β-cell specific Barr2 knockout mouse model was generated (Pdx1CreERT/Barr2 fl/fl, referred to as β-Barr2 KO). β-Barr2 KO animals on high-fat high-sucrose diet were less glucose tolerant and tended to respond worse to acute exendin-4 (Ex4) treatment vs. controls (Barr2 fl/fl). However, Ex4 effects on blood glucose were more pronounced in KO mice 6h post-agonist injection [IPGTT AUC (6h) for Ex4/ vehicle: 0.84 ± 0.04 vs. 1.08 ± 0.05, p<0.001; ΔAUC (6h-0h): -49.8 ± 65.8 vs. 158.2 ± 43.6, p<0.05; KO vs. control]. This effect was not apparent with Ex-phe1, an Ex4 derivative biased away from Barr2 recruitment. Ex4-induced potentiation of insulin secretion in β-Barr2 KO islets was reduced acutely, but tended to increase overnight, resulting in significantly reduced desensitization vs. control islets. On chow diet, acute Ex4-stimulated calcium increases were unaffected, but acute cAMP responses were attenuated in KO islets [Emax (vs. baseline): 1.51 ± 0.17 vs. 1.72 ± 0.07, p<0.05; KO vs. control]. The latter was corroborated in INS1 832/3 Barr2 KO CRISPR cells, as NanoBiT™ functional assays showed reduced Ex4-induced Gs protein activation vs. control. GLP-1R trafficking profiles observed in vivo by imaging of Ex4-TMR uptake into islets implanted in the anterior chamber of the eye, as well as in vitro with GLP-1R-NLuc - KRAS/Rab5 NanoBRET assays were unaltered by Barr2 deletion. Thus, we provide evidence for opposing effects of Barr2 in acute vs. prolonged GLP-1R signaling, supporting a direct role for Barr2 in mediating the anti-hyperglycemic effects of biased GLP-1R agonists, but dispensability for GLP-1R trafficking.

Disclosure

S. Bitsi: None. K. Suba: None. N. Mohamed: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. G. A. Rutter: Advisory Panel; Self; Sun Pharmaceutical Industries Ltd. V. Salem: None. B. Jones: Research Support; Self; Sun Pharmaceutical Industries Ltd. A. Tomas: Other Relationship; Self; Sun Pharmaceutical Industries Ltd.

Funding

Medical Research Council (MR/R010676/1)
231-OR: Neighborhood Walkability Is Associated with Prediabetes in a Behavioral Weight Loss Study
Authors: KARIUKI JACOB K. , BIZHANOVA ZHADYRA , ROCKETTE-WAGNER BONNY , GIBBS BETHANY B. , SEREIKA SUSAN M. , KLINE CHRISTOPHER , ERICKSON KIRK , MENDEZ DARA , PULANTARA I. WAYAN , CHENG JESSICA , BURKE LORA E.
Published: June 2021

Background: Behavioral interventions targeting weight loss may be affected by socio-environmental factors that influence physical activity (PA) and cardiometabolic outcomes.

Purpose: To evaluate the relation of neighborhood walkability on PA levels and glucose control in a sample of adults participating in a weight loss study.

Methods: Secondary analysis of a prospective observational study providing a 12-month behavioral weight loss intervention to examine lapses after intentional weight loss. Neighborhood walkability was assessed via Walk Score (0-100), PA via waist-worn ActiGraph GT3X, and blood glucose via phlebotomy. Study variables included car-dependent and walkable neighborhoods (Walk Score < vs. ≥50), prediabetes (fasting blood glucose from 100-126mg/dL) and recommended PA (moderate-to-vigorous PA [MVPA] >22 minutes/day; steps ≥7500/day). Standard descriptive and group comparative statistics were employed. Regression results are reported as adjusted odds ratios (OR) with 95% confidence intervals (CI).

Results: The sample (N=112) was mostly female (90.2%), white (90.2%), well educated (75.9% with ≥4 years of college) and on average 51.5±9.8 years of age. At baseline, no differences existed between persons from car-dependent vs. walkable neighborhoods across all metrics. At 12 months, PA and glucose control were improved for the entire sample, with no differences across walkability categories. Neighborhood walkability did not predict attainment of recommended MVPA (OR=1.16, 95% CI: 0.97-1.39) or steps (OR=1.08, 95% CI: 0.90-1.30) at 12 months. However, those from walkable neighborhoods had 17% lower odds of having prediabetes compared to those from car-dependent neighborhoods (OR=0.83, 95% CI: 0.72-0.97).

Conclusion: Our findings corroborate previous studies showing an inverse relation between neighborhood walkability and prediabetes. The key drivers of this association warrant further investigation in a study with a larger, more diverse sample.

Disclosure

J. K. Kariuki: None. J. Cheng: None. L. E. Burke: None. Z. Bizhanova: None. B. Rockette-wagner: None. B. B. Gibbs: None. S. M. Sereika: None. C. Kline: None. K. Erickson: None. D. Mendez: None. I. Pulantara: None.

Funding

National Heart, Lung, and Blood Institute (HL107370S to J.K.K.)
238-OR: Treatment with Testosterone Undecanoate Injections (TU) Up to 12 Years Improves Glycemic Control in Patients with Hypogonadism and Type 2 Diabetes (T2DM): Update of Real-World Data with 3,149 Patient-Years
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD
Published: June 2021

Background: Prevalence of hypogonadism has been reported as high as 50% in men with T2DM. ADA Guidelines recommend assessment of hypogonadism in men with T2DM.

Methods: In a registry of 865 men with hypogonadism, 361 men (41.7%) had T2DM. 183 received TU 1000 mg/12 weeks (T-group), 178 opted against treatment (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups.

Results: Mean follow-up 8.7±3.1, baseline age: 60.7±5.5 (T-group) and 63.0±4.9 (CTRL) years. T-group: HbA1c progressively decreased by 3.7±0.2% at 12 years (unadjusted from 9.4±1.4% to 5.6±0.2%). CTRL: HbA1c increased by 3.2±0.2% (from 7.8±0.7% to 10.4±1.2%) (p<0.0001 for both). Fasting glucose (mmol/L) decreased in T-group by 1.9±0.1 (from 7.8±1.3 to 5.4±0.1) and increased in CTRL by 1.8±0.1 (from 6.3±0.7 to 8.0±1.2) (p<0.0001 for both). In the T-group, 89 men (48.6%) received insulin at baseline at a mean dose of 38.0±13.3 U/d. Dose requirement declined by 32.7±1.3 U/d (from 38.0±13.3 to 8.8±9.2) during the observation period. In CTRL, 69 men (38.8%) received insulin at baseline at a mean dose of 31.3±6.2 U/d. Dose requirement increased by 20.0±1.4 U/d (from 31.3±6.2 to 43.8±7.8) (p<0.0001 for both). HOMA-IR decreased by 8.0±0.3 (from 10.1±2.1 to 1.7±0.4) in the T-group and increased by 6.5±0.4 (from 7.3±1.3 to 14.3±2.3) in CTRL (p<0.0001 for both). In CTRL, 22 patients were started on insulin during the observation period. 37 patients had incident T2DM during the observation time.

Conclusions: Long-term testosterone therapy with TU in men with hypogonadism and T2DM progressively improved glycemic control which deteriorated in untreated men.

Disclosure

F. Saad: Consultant; Self; Bayer AG, Stock/Shareholder; Self; AbbVie Inc., Bayer AG, Novo Nordisk. K. S. Haider: Other Relationship; Self; Bayer AG. A. Haider: Other Relationship; Self; Bayer AG.

Funding

Bayer AG
249-OR: Type 2 Diabetes (T2D) Genetic Clusters for Association with Glycemic Responses to Intervention for Diabetes Prevention
Authors: BILLINGS LIANA K. , JABLONSKI KATHLEEN A. , FRANKS PAUL W. , GOLDBERG RONALD B. , HIVERT MARIE-FRANCE , KAHN STEVEN E. , KNOWLER WILLIAM C. , LEE CHRISTINE , MERINO JORDI , RAGHAVAN SRIDHARAN , SRINIVASAN SHYLAJA , XU JIANFENG , FLOREZ JOSE C. , UDLER MIRIAM ,   GROUP DPP RESEARCH
Published: June 2021

Polygenic scores (PS) of T2D genetic variants based on pathophysiologic mechanisms underlying diabetes have been developed. We investigated whether T2D cluster PS influences response to interventions for diabetes prevention. We examined 2,647 DPP participants with impaired glucose tolerance and genetic data randomized to intensive lifestyle, metformin or placebo arms for diabetes prevention. We generated five PS clusters including β-cell related clusters (β-cell, proinsulin) and insulin resistance clusters (liver/lipid, obesity, lipodystrophy).

We examined associations of PS with baseline and 1-year glycemic traits after intervention derived from oral glucose tolerance tests using general linear models, and with diabetes incidence over an average period of 3 years using Cox Regression Models. Models were adjusted for sex, age, and 10 principal components, respective baseline trait, and treatment group.

At one-year follow-up, β-cell PS was associated with reduction in the insulinogenic index and corrected insulin response, in each treatment group and, statistically significant, in all combined (P<0.001), with no statistically significant interaction term between treatment groups, a finding consistent with a slightly increased diabetes incidence (HR 1.02 per weighted allele [CI 95% 1.00, 1.03]). The remaining PS were associated with baseline participant features, but not with diabetes incidence or change in glycemic parameters from baseline.

We conclude that high genetic burden in β-cell cluster PS is associated with greater risk of diabetes and a decrease in insulin secretion, seen across all treatment groups. Despite interventions with intensive lifestyle and metformin, participants with high β-cell cluster genetic burden had an increased risk of diabetes and worsening in insulin secretion similar to placebo group. These data suggest that alternate therapies may be needed to prevent β-cell decline in this subset of prediabetes patients.

Disclosure

L. K. Billings: Advisory Panel; Self; Bayer Inc., Lilly Diabetes, Novo Nordisk, Sanofi. S. Raghavan: None. S. Srinivasan: None. J. Xu: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. M. Udler: None. D. Research group: None. K. A. Jablonski: None. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. R. B. Goldberg: None. M. Hivert: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W. C. Knowler: None. C. Lee: None. J. Merino: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)
25-LB: Are You a Good Steward of Data?
Authors: BAKER REBECCA , OWEN JOHN M.
Published: June 2021

The Problem: There is an urgent need for innovative solutions for new and improved treatments and therapies. Often clinical research data is “silo-ed” within an organization, preventing the broader research community from leveraging aggregated information from individuals and studies globally. This isolation of data limits the discoveries possible within a disease preventing the discovery of new scientific links between disease areas. Inconsistent and ambiguous data representation leads to a lack of transparency, traceability and reproducibility, in turn fostering inefficiencies and inaccuracies in research that loses time and increases costs. Simply put Are we being good stewards of our study data?

Data Standards and Data Sharing as part of the solution: Describing data consistently using data standards can bring clarity to data that amplifies its value. The T1D Data Standards Project builds on existing CDISC diabetes standards by describing concepts relevant to T1D in the areas of: • Pediatrics and Devices (Released Sep 2020) • Exercise and Nutrition (Due Q2-2021) • Screening, Staging and Monitoring for Pre-Clinical Type 1 Diabetes (Due Q3-2021). The team of CDISC standards experts, T1D experts from CDISC member organizations and T1D subject matter experts from academia and industry followed a consensus-driven process to ensure the final standards are fit for use within the research community, reinforced by the open community review.

How data standards help overcome some of the challenges: Publicizing the availability and promoting adoption of consistent standards brings clarity to data, reduces data collection, organization and analysis time, and facilitates interoperability that promotes data re-use and operational efficiencies. When researchers speak the same harmonized language, talking and understanding each other is much easier leading to the sharing of common, understandable data within the research community, thereby promoting scientific and therapeutic advances general confidence in the data.

Disclosure

R. Baker: None. J. M. Owen: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D069)
259-OR: The Effect of Impaired Glucagon Suppression on Endogenous Glucose Production Is Independent of Insulin Action
Authors: LAURENTI MARCELLO C. , EGAN AOIFE M. , WISMAYER DANIEL SCHEMBRI , COBELLI CLAUDIO , MAN CHIARA DALLA , VELLA ADRIAN
Published: June 2021

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and Endogenous Glucose Production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic, insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (non-suppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose (56±5 vs. 44±6 vs. 31±6 %, p=0.01 - 0.6, 0.8 and 1.0 dose respectively) but not in integrated (area above basal - AAB) glucose (39±4 vs. 43±9 vs. 36±9 %, p=0.82) caused by non-suppressed glucagon. The % change in integrated EGP was unaffected by insulin dose (51±20 vs. 27±19 vs. 22±18 %, p=0.53). Multivariate regression analysis, adjusted for age, sex, weight and insulin dose, did not show a relationship (R2=0.04, p=0.21) between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action did not show a relationship (R2=0.06, p=0.06) with the EGP response to non-suppressed glucagon. These data indicate that the change in EGP produced by impaired glucagon suppression is independent of anthropometric characteristics and insulin action.

Disclosure

M. C. Laurenti: None. A. M. Egan: None. D. Schembri wismayer: None. C. Cobelli: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Research Support; Self; Novo Nordisk.

Funding

National Institutes of Health (DK116231, DK78646)
261-OR: Transcriptional Profiling of the Intestinal Serotonin System in Individuals with Type 2 Diabetes and Healthy Individuals
Authors: LEGART CHRISTIAN , HAGEMANN CHRISTOFFER A. , ELLEGAARD ANNE MARIE , KEATING DAMIEN , JORSAL TINA , KNOP FILIP K.
Published: June 2021

Obesity is characterized by increased gut serotonin signaling, which has been shown to enhance hepatic gluconeogenesis favoring hyperglycemia and adipose tissue lipolysis promoting raised levels of free fatty acids and, thus, peripheral insulin resistance. Little is known about the potential involvement of the human gut serotonin system in the pathophysiology of type 2 diabetes. We investigated the transcriptional profile of key enzymes, receptors and transporters in the serotonin system in intestinal biopsies sampled using double-balloon enteroscopy from the duodenum, the jejunum, throughout the remaining small intestine with 30 cm intervals, the ileocecal region, the cecum, the four segments of the colon and the rectum in 12 individuals with type 2 diabetes and 12 gender, age and body mass index-matched healthy controls. Global gene expression analysis was performed on all biopsies, and intestinal expression profiles of genes involved in the serotonin system were mapped and compared between the two groups. We used false discovery rate adjustment to correct for multiple testing. Patients with type 2 diabetes exhibited 2-fold increased mRNA encoding the serotonin-synthesizing enzyme TPH1 in the sigmoid colon (P = 0.027) and the rectum (P < 0.001), and lower levels of mRNA encoding the transporter responsible for reuptake of serotonin in enterocytes, SERT (P = 0.038), and the serotonin-metabolizing enzymes MAOA (P = 0.001) in the distal small intestine and MAOB in the cecum (P = 0.013), the ascending colon (P = 0.020) and the transverse colon (P = 0.011). Our findings provide the first detailed transcriptional profile of key factors in the serotonin system along the entire intestinal tract in humans and lend support to previous animal and human studies suggesting that increased gut serotonin signaling may be involved in the development of dysmetabolic conditions including type 2 diabetes.

Disclosure

C. Legart: None. C. A. Hagemann: None. A. Ellegaard: None. D. Keating: None. T. Jorsal: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.
272-OR: Impact of Maternal Diabetes on MicroRNA Expression in Fetal Tissue
Authors: RUGHANI ANKUR , TRYGGESTAD JEANIE B.
Published: June 2021

In utero diabetes (DM) exposure alters offspring metabolic memory and increases future cardiovascular risk (CVD) risk. MicroRNAs (miR), small noncoding RNAs that repress mRNA translation, have been proposed as an epigenetic mechanism that alters metabolic programming. Using an unbiased sequencing approach, the impact of in utero DM exposure on miR abundance in human umbilical vein endothelial cells (HUVEC) from 6 DM-exposed infants and 6 infants born to mothers with normal glycemia matched for infant sex, ethnicity, and gestational age was examined. Computational target prediction algorithms were used to identify genes targeted by the most abundant miRNAs. The gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the most abundant miRNAs and their mRNA targets were annotated. MiRNA expression was quantified using RT-PCR. GO target enrichment analysis suggested the targets of the most abundant miRNAs were involved in transport, protein binding, mitochondria, DNA transcription, and cell cycle. The KEGG analysis found the most significantly enriched pathways were PI3K-Akt, AGE-RAGE signaling in diabetic complications, apoptosis, FoxO signaling, MAPK signaling, and cell senescence. In HUVEC from infants exposed to DM in utero, 31 miRNAs were more abundant including miR-210, miR-130b-3p, miR-491-5p while 6 miRs were less abundant including miR-146b-5p, mIR-192-3p, and miR-30e-5p (p<0.05) compared to matched controls. Analysis with RT-PCR revealed a 25% decrease in miR-146b (p 0.03) from the HUVEC of DM-exposed infants (N = 23) compared to controls (N = 39). MiRNA-146b is an anti-inflammatory molecule that targets IRAK1 and TRAF6 both of which modulate the NF-kB inflammatory pathway and affect the progression of CVD. MiRNA-146b is reduced in hypercholesterolemia and is protective to cardiomyocytes under chronic hypoxia. Sortilin, a target of miR-146b, is also associated with CVD. Thus, miR-146b may play a role in the development of excess CVD risk noted after in utero DM exposure.

Disclosure

A. Rughani: None. J. B. Tryggestad: None.
278-OR: Ancestry-Specific Genetic Risk Scores of Type 2 Diabetes and Longitudinal Fetal Growth in a Race-Ethnic Diverse Population
Authors: OUIDIR MARION , ZENG XUEHUO , CHATTERJEE SUVO , ZHANG CUILIN , TEKOLA-AYELE FASIL
Published: June 2021

It is well documented that maternal type 2 diabetes (T2D) is related to fetal overgrowth. Further, maternal T2D genetic risk score (GRS) has been associated with increased offspring birthweight. However, the earliest gestational age when fetal growth starts to be associated with T2D GRS is unknown. We investigated the associations between maternal T2D GRS and longitudinal ultrasound measured fetal weight.

We included 1,513 women of diverse race/ethnicity from the NICHD Fetal Growth Studies-singleton cohort. Women were enrolled at gestational weeks 8-13 and randomly assigned to four ultrasound schedules to capture weekly fetal growth. Genome-wide single nucleotide polymorphisms (SNPs) previously known to be associated with T2D in European-, African-, and Asian- ancestry populations (380, 104, and 19 SNPs, respectively) were used to calculate weighted GRS. The analysis involved European GRS for Whites and Hispanics, African GRS for Blacks and Asian GRS for Asians. Associations between quartiles of GRS and fetal weight were adjusted for pre-pregnancy BMI, population structure, fetal sex and gestational weeks.

Among Whites, the highest quartile of European GRS was related to a 53.8 g increment in fetal weight (95% CI 19.2-88.5 g) over the pregnancy, and across 24 to 40 weeks (from 15.8 g increase at week 24 to 196.0 g increase at week 40). Similar findings were observed in analysis that excluded women with impaired glucose tolerance. African-, European- and Asian-GRSs were not significantly associated with fetal weight among other race/ethnic groups.

Genetic susceptibility to T2D based on European-specific GRS among Whites was related to increased fetal weight starting at week 24 even among normal glycemia women, suggesting an early influence of genetic factors on fetal growth. Absence of similar associations in non-Whites is likely due to the small number of established T2D genetic loci warranting the need for genetic studies of T2D in diverse populations.

Disclosure

M. Ouidir: None. X. Zeng: None. S. Chatterjee: None. C. Zhang: None. F. Tekola-ayele: None.
287-OR: M6A mRNA Methylation Regulates the Innate Immune Response in Human ß-Cells
Authors: DE JESUS DARIO F. , ZHANG ZIJIE , BROWN NATALIE K. , HU JIANG , KAHRAMAN SEVIM , MATHEWS CLAYTON E. , POWERS ALVIN C. , ATKINSON MARK A. , EIZIRIK DECIO L. , HE CHUAN , KULKARNI ROHIT
Published: June 2021

Type 1 diabetes (T1D) is an autoimmune disease characterized by a progressive destruction of β-cells and several candidate genes associated with T1D have been linked to innate immunity. Recently, N6-methyladenosine (m6A) has been shown to modulate human β-cell biology and to target type I interferons. Here, we focused on the contribution of m6A mRNA methylation in modulating innate immunity and β-cell destruction. Immune cells contribute to β-cell apoptosis by the release of pro-inflammatory cytokines during the onset of T1D. We assessed whether m6A abundance or expression of m6A modulators was altered in human islets and EndoC-βH1 cells treated with cytokines to mimick T1D onset. LC-MS/MS analyses of human islets showed that treatment with IL-1β plus IFN-α for 48h increased m6A levels. Consistently, IL-1β plus IFN-α treatment of human islets and EndoC-βH1 induced upregulation of the m6A writer METTL3. Next, we applied m6A-sequencing in cytokine-treated human islet preparations, and in parallel studies, treated EndoC-βH1 cells followed by RNA-sequencing. Intersection of m6A-decorated genes in cytokine-treated human islets with common differentially expressed genes in human islets and EndoC-βH1 cells revealed enrichment in pathways associated with the innate immune response, negative regulation of immune response, and extrinsic apoptotic signaling pathway. Differentially expressed and m6A decorated genes included genes associated with T1D that are involved in innate immunity. Re-analyses of RNA-seq. data in sorted-β-cells from T1D patients revealed downregulation of METTL3. These data suggest that while healthy β-cells are able to upregulate m6A levels and METTL3 early in T1D (e.g., when they are exposed to cytokines), this response is lost in established T1D that allows an exacerbated immune response and β-cell death. Together, these results point to a possible therapeutic approach in targeting METTL3 to modulate innate immunity and promote β-cell survival.

Disclosure

D. F. De jesus: None. C. He: None. R. Kulkarni: None. Z. Zhang: None. N. K. Brown: None. J. Hu: None. S. Kahraman: None. C. E. Mathews: None. A. C. Powers: None. M. A. Atkinson: None. D. L. Eizirik: None.

Funding

National Institutes of Health (1UC4DK116278)
294-OR: RIPK3-Mediated Necroptosis Is an Alternative Form of TNFa-Induced ß-Cell Death
Authors: CONTRERAS CHRISTOPHER J. , LIN LI , HOGAN MEGHAN F. , OBERST ANDREW , KAHN STEVEN E. , TEMPLIN ANDREW T.
Published: June 2021

Necroptosis is an inflammatory and immunogenic form of lytic cell death that can occur downstream of TNFα signaling. Receptor interacting protein kinase 3 (RIPK3) mediates TNFα-induced necroptosis when caspase activity is repressed, but this pathway has not been examined in insulin-producing β-cells. As TNFα contributes to β-cell death in the setting of diabetes and since we found RIPK3 is expressed in INS-1 β-cells and mouse islets, we hypothesized that β-cells are susceptible to necroptosis. To test this hypothesis, INS-1 cells were treated with TNFα (40 ng/ml) in the absence or presence of a synthetic pan-caspase inhibitor (zVAD, 50 μM) for 24 h, cell death was monitored in real-time, and caspase activity was determined. TNFα increased INS-1 cell death (1.63 ± 0.13 vs. 2.44 ± 0.13 fold, n=7, p<0.001) and caspase activity, consistent with apoptosis. When caspases were inhibited with zVAD, TNFα no longer increased caspase activity, but induced a similar degree of cell death (1.63 ± .013 vs. 2.82 ± 0.23 fold, n=7, p<0.001), suggesting an alternate mechanism under these conditions. Moreover, when TNFα-induced cell death was amplified by the SMAC/DIABLO mimetic BV6 (5 μM), we again observed similar levels of cell death with or without zVAD. To further investigate the mechanism of cell death under caspase inhibition, we used the RIPK3 inhibitor GSK ‘872 (5 μM). GSK ‘872 had no effect on TNFα+BV6-induced cell death when caspases were activated (3.35 ± 0.61 vs. 3.48 ± 1.21 fold, n=3, p=0.93), but reduced cell death when caspases were inhibited (4.69 ± 0.57 vs. 1.81 ± 0.57 fold, n=3, p=0.04). These data indicate that TNFα induces β-cell death independent of caspase activity level. However, the mechanism by which TNFα elicits β-cell death does depend on caspase activity, with apoptosis occurring when caspases are activated, and RIPK3-mediated necroptosis occurring when caspases are inhibited. Additional studies are required to understand the factors that may promote β-cell necroptosis in the setting of human diabetes.

Disclosure

C. J. Contreras: None. L. Lin: None. M. F. Hogan: None. A. Oberst: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. A. T. Templin: None.

Funding

U.S. Department of Veterans Affairs (IK2BX004659, I01BX001060)
299-OR: Relative Contribution of Statin Intensity, Low-Density Lipoprotein Cholesterol Level and Duration of Statin Therapy for Cardiovascular Risk Reduction in Patients with Type 2 Diabetes
Authors: KIM JI YOON , CHOI JIMI , KIM SIN GON , KIM NAM HOON
Published: June 2021

Objectives: To estimate the optimal statin therapy including statin intensity, low-density lipoprotein cholesterol (LDL-C) level and duration of statin therapy among patients with type 2 diabetes (T2D) in a real-world setting.

Research Design and Methods: From the Korean National Health Insurance Service Cohort (2007-2015), 8,937 patients with T2D (≥40 years) who had received statin therapy for at least 90 days were included. Risk of major adverse cardiovascular events (MACE) including coronary heart disease (CHD), ischemic stroke (IS) and cardiovascular death was estimated according to statin intensity, on-treatment serum concentration of LDL-C and duration of statin therapy, respectively. The relative contribution of these three factors for the risk of MACE was quantified by calculating the proportion of log-likelihood explained by each factor.

Results: The hazard ratio (HR) of MACE was higher in patients receiving low intensity statins compared with those receiving moderate-to-high intensity statins (HR 1.38, p=0.027). As a reference to LDL-C of 100 mg/dl, below 80 mg/dl was associated with lower risk of MACE. Among patients who received moderate-to-high intensity statins, there was a trend that the longer the duration of statin therapy, the lower the risk of MACE; and HRs of MACE reduced significantly after at least 18 months of statin therapy (adjusted HR 0.71, p=0.011) as a reference to 3 months of statin therapy. The proportion of explainable log-likelihood for MACE was biggest for duration of statin (0.047), followed by statin intensity (0.013) and on-treatment LDL-C level (0.001).

Conclusion: Longevity of statin therapy is as important as, or more important than, statin intensity or achieved LDL-C for the reduction of cardiovascular risk in T2D patients.

Disclosure

J. Kim: None. J. Choi: None. S. Kim: None. N. Kim: None.
3-LB: Glutamate Metabolism Is Coupled to Lactate Production from Astrocytes under Low-Glucose Conditions
Authors: APPADURAI DANIEL A. , CHAN OWEN
Published: June 2021

Recurrent hypoglycemia (RH) results in elevated lactate levels in the ventromedial hypothalamus that impair the counter-regulatory responses to hypoglycemia. While the mechanisms that enhance lactate production are not clear, our previous data suggests that astrocytic glycogen is the major source of lactate resulting from RH. A number of different inputs regulate glycogen turnover in astrocytes and the interaction between metabolic and neurotransmitter signals may alter glycogenolytic capacity and ultimately, lactate production. The current study investigates how the interaction between norepinephrine and glutamate influence lactate production from astrocytes in the setting of hypoglycemia. We cultured primary rat astrocytes in normal (2.5mM) and low (0.1mM) glucose medium in the presence and absence of norepinephrine and/or glutamate for 3 hours and quantified lactate in the culture media. We also examined the contribution of glutamate oxidation using the glutamate dehydrogenase inhibitor, hexachlorophene. Our data indicates that under low glucose conditions, glutamate alone dramatically enhances lactate production in astrocytes compared to controls (P<0.0001). Of note, the inhibition of glutamate oxidation also increased lactate secretion, but not to the same extent as glutamate alone (P<0.01). In contrast, the addition of norepinephrine and glutamate significantly reduced lactate secretion (P<0.05). Our data suggests that glutamate uptake during acute hypoglycemia likely plays a large role in driving astrocytic lactate production, a metabolic deficit that is offset by the oxidation of glutamate and by norepinephrine. In conclusion, our data suggests that under low glucose conditions, the metabolism of glutamate is tightly coupled to lactate production in astrocytes.

Disclosure

D. A. Appadurai: None. O. Chan: None.

Funding

National Institutes of Health (DK099315)
310-OR: Five-Year Trends in American Diabetes Association Recommended Metabolic Screening for Youth Prescribed Antipsychotic Medications
Authors: HSUEH LORETTA , SLAMA NATALIE , SPALDING SCOTT , STERLING STACY , ITURRALDE ESTI
Published: June 2021

Importance: In recent decades, youth have increasingly been prescribed antipsychotic medications to treat a range of mental health conditions. These medications are associated with metabolic disturbances elevating type 2 diabetes risk, but ADA-recommended metabolic screening rates have stagnated at low levels (<50%) for youth treated with antipsychotics. We examined 5-year metabolic screening trends and predictors for this population in a large, integrated health system.

Methods: In this serial cross-sectional study, we assessed metabolic screening (fasting glucose or hemoglobin A1c test) from health record data for 4,541 youth age 10-21 starting antipsychotic treatment in Kaiser Permanente Northern California during 2013-2017. We evaluated time and demographic predictors of metabolic screening within 2 years of medication start using logistic regression. To understand screening trends by age, sex, and racial groups, we estimated additional models with time x group interaction terms.

Results: Participants were mean ± SD age 16.9 ± 3.0; 52% were boys. Half were racial minorities (22% Hispanic/Latino; 13% Black; 12% Asian/Nat. Hawaiian/Pac. Islander [ANHPI]). Screening significantly increased over the 5 cohort years (adj. rates rising from 54% to 64%). Younger participants, girls, and ANHPI and Hispanic/Latino participants had higher screening rates overall (all p<0.05); time trends did not differ by age, sex, or race.

Conclusions and Relevance: In this large health system, which has established processes to promote preventive care (e.g., automatic patient reminders), metabolic screening has increased for youth treated with antipsychotics and exceeds those reported in other samples. Future research should examine processes contributing to this upward trend and identify remaining barriers to achieving ADA-recommended metabolic screening rates for this vulnerable population.

Disclosure

L. Hsueh: None. N. Slama: None. S. Spalding: None. S. Sterling: None. E. Iturralde: None.

Funding

Permanente Medical Group