bluuebunny/crossref_metadata_2025_split huggingface dataset:
222-LB: Diabetes Induces Liver Inflammation and FGF21 through C-Jun NH2-Terminal Kinase Pathways
Authors: CHEN LEE-WEI 
Published: June 2020

Fibroblast growth factor 21 (FGF-21) is a hormone that regulates important metabolic pathways. Serum fibroblast FGF-21 levels were significantly higher in obesity and type 2 diabetes mellitus (T2DM). Previously, we have found that the JNK pathway played a critical role in diabetes-induced Kupffer cell activation, and pJNK1 inhibition decreases Kupffer cell activation induced by diabetes. We aim to study the involvement c-Jun NH2-terminal kinase pathways in the regulatory mechanisms of liver inflammation and FGF-21 in diabetes. Type 1 diabetic Akita mice (C57BL/6J-Ins2Akita) and type 2 diabetic Leprdb/db mice (C57BL/6J- Leprdb/db) were used. Leprdb/db-JNK1-/- and Ins2Akita-JNK1-/- mice were produced and used to study the role of pJNK in the regulatory mechanisms of diabetes on liver inflammation and FGF-21. Diabetic mice demonstrated increased ICAM, iNOS, interleukin 1 beta (IL-1β), FGF-21, and FMO3 expression of liver; and tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells; and plasma FGF-21 levels. Ins2Akita-JNK1-/- and Leprdb/db-JNK1-/- mice demonstrated decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver; and ICAM, iNOS, and FMO3 expression in aorta, tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells, plasma IL-6 and TNF-α levels; dipeptidyl peptidase (DPP-4) activity. JNK inhibitor, SP600125, injection into adipose tissue of Leprdb/db mice significantly decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver and serum FGF-21 levels. Altogether, our data suggest that diabetes induces liver inflammation, FGF-21, and insulin resistance through c-Jun NH2-terminal kinase.

Disclosure
L. Chen: None.

Funding
National Science Council (MOST 107-2314-B-010-043-MY3)
2239-PUB: Best Practices for Implementing Diabetes Prevention in Health Care Settings
Authors: WILLIAMS JANET , SACHDEV NEHA , MOIN TANNAZ , DURU O. KENRIK 
Published: June 2020

One in 3 adults in the U.S. has prediabetes and 90 percent don’t even know they have it. If left untreated or treated with usual care, many will go on to develop type 2 diabetes. The Centers for Disease Control and Prevention’s National Diabetes Prevention Program (DPP) was created in 2010 to address the increasing burden of prediabetes and type 2 diabetes in the United States. Despite the demonstrated effectiveness of an intensive lifestyle invention program, there are still millions of undiagnosed and untreated individuals with prediabetes. Identification of prediabetes and referral of eligible adults to a lifestyle change program is recommended in both the ADA and USPSTF clinical guidelines and standards of care. However, only a minority of clinicians are systematically addressing prediabetes in their patient population or referring their patients to a lifestyle change program. Although existing research has evaluated the uptake of clinical guidelines regarding diabetes prevention and the availability of coverage for lifestyle change programs, there is a gap in collecting and sharing best practices for building a diabetes prevention strategy that includes the CDC’s National DPP lifestyle change program. The AMA convened a diverse group of leading health care organizations that were successful in establishing system-based strategies. This session will describe a best practice implementation framework for health systems to consider when establishing or expanding a diabetes prevention strategy and engaging with clinical champions to improve identification and treatment of patients with prediabetes.

Disclosure
J. Williams: None. N. Sachdev: None. T. Moin: None. O. Duru: None.
2246-PUB: "There’s a Disconnect Here": A Study Evaluating Blood Glucose Trends at a Youth Diabetes Camp
Authors: RANDALL MARTIN , DEGNAN BERNARD M. 
Published: June 2020

Introduction: Camp Midicha is an American Diabetes Association summer camp for children aged 8-17 with type 1 diabetes mellitus located in Fenton, Michigan. Blood glucose (BG) levels of campers are closely monitored so that hypoglycemia and hyperglycemia can be treated and ideally prevented. Hyperglycemia is a particular concern for campers who use insulin pumps because of an increased risk for ketoacidosis. It has been previously observed that campers who disconnect their pumps for swimming have higher BG levels later in the day. Swimming occurs for approximately 1.5 hours between lunch and dinner for all campers daily. This study aims to compare trends in BG for campers who wear insulin pumps that are removed prior to afternoon swimming versus those who do not.
Methods: This study was conducted as a retrospective review of the camp’s medical records. Trends in BG at lunch and dinner were compared between campers who A) wear a removable insulin pump and B) wear a non-removable pump or utilize insulin injections. This study included all campers at Camp Midicha from 2017 and 2018, encompassing 862 campers. Multivariate linear regression was used to compare the two groups.
Results: The average change in BG from lunch to dinner was 38.13 mg/dL for campers who removed their insulin pumps (174.62 to 212.75 mg/dL) and 16.42 mg/dL for campers who did not (177.14 to 193.59 mg/dL). The difference in BG change between the groups was 21.68 mg/dL (P &lt; 0.0001) with variance between the different days analyzed.
Conclusion: This study showed a significant difference in the change in BG from lunch to dinner between the two groups despite insulin pumps being disconnected for only 1.5 hours. While the magnitude of this difference may not necessitate follow-up studies to assess potential interventions, further analysis to evaluate differences in BG change between days could be valuable for insulin dosing at future camps.

Disclosure
M. Randall: None. B.M. Degnan: None.
2301-PUB: The Role of Muramyl Dipeptide in Glucagon-Like Peptide-1 Regulation
Authors: WILLIAMS LAURA , ALSHEHRI AMAL , MUSTAFA SALMA , GAGNON JEFFREY 
Published: June 2020

The host’s intestinal microbiota contributes to endocrine and metabolic responses, but a dysbiosis in this environment can lead to obesity and insulin resistance. A new area a research is focused on understanding how bacterial metabolites contribute to intestinal glucagon-like peptide-1 (GLP-1) release. Muramyl dipeptide (MDP) is a bacterial cell wall component which has been shown to improve insulin sensitivity and glucose tolerance in diet-induced obese mice. The purpose of this study was to understand MDP’s mechanism of action in glucose regulation. We hypothesized that MDP enhances glucose tolerance by inducing intestinal GLP-1 secretion. We observed a significant increase (P&lt;0.001, n=7) in GLP-1 secretion when mouse L-cells were treated with an MDP derivative at 10ug/ml. Using fluorescent immunohistochemistry and RT-PCR we located MDP’s receptor, nucleotide oligomerizing domain 2 (NOD2), in mouse intestine and mouse L-cells. In mice, two intraperitoneal injections of MDP (5mg/kg body weight) or PBS caused a significant increase (P=0.0009, n=15-19) in fasting total GLP-1. Understanding how bacterial products influence GLP-1 secretion and subsequent insulin release, could be translated into novel treatments options for improving glucose regulation in metabolic disease.

Disclosure
L. Williams: None. A. Alshehri: None. S. Mustafa: None. J. Gagnon: None.

Funding
Natural Sciences and Engineering Research Council of Canada (2016-05905)
233-OR: Ultra-Rapid Lispro (URLi) Demonstrates Similar Time-in-Target Range to Humalog with the Medtronic MiniMed 670G Hybrid Closed-Loop System
Authors: BODE BRUCE W. , CARLSON ANDERS L. , LIU RONG , HARDY THOMAS , BOYD JENNIFER , BERGENSTAL RICHARD M. , MORRETT SCOTT , IGNAUT DEBRA A. 
Published: June 2020

URLi is a novel ultra rapid formulation of insulin lispro that shows improved postprandial glucose control and similar compatibility with continuous subcutaneous insulin infusion (CSII) vs. Humalog. In this study URLi was evaluated for the first time in a hybrid closed-loop system using the Medtronic MiniMed 670G. Primary objective was to compare URLi to Humalog with respect to the percentage of time with glucose values within target range 70-180 mg/dL (%TIR). This double-blind, crossover study included two 4-week treatment periods with URLi or Humalog. After a 2-week lead-in on Humalog, 42 adults with type 1 diabetes using personal MiniMed 670G pumps were randomized to 1 of the 2 treatment sequences with boluses initiated 0-2 minutes before meals. Both treatments achieved good glycemic control with mean TIR &gt;75% (Fig 1). Mean time above and below range met consensus recommendations for both treatments. The percentage of time in Auto Mode was similar between treatments: URLi 92.0%; Humalog 91.4%. Insulin doses and pump settings were generally similar between treatments. There were no serious adverse events or early discontinuations. Overall incidence of treatment-emergent adverse events was similar between treatments. URLi demonstrated comparable glycemic control and a similar safety profile to Humalog with the MiniMed 670G system in patients with type 1 diabetes.

Disclosure
B.W. Bode: Advisory Panel; Self; InPen, Medtronic. Consultant; Self; ADOCIA, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Pfizer Inc. Research Support; Self; Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Medtronic, Novo Nordisk A/S, Provention Bio, Inc., Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., InPen, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Sanofi, Senseonics, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Glytec. A.L. Carlson: Consultant; Self; Medtronic. Research Support; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S, Sanofi, UnitedHealth Group. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. T. Hardy: Other Relationship; Self; Eli Lilly and Company. J. Boyd: None. R.M. Bergenstal: Consultant; Self; Ascensia Diabetes Care, Johnson & Johnson. Other Relationship; Self; Abbott, Dexcom, Inc., Hygieia, Lilly Diabetes, Medtronic, Novo Nordisk A/S, Onduo, Roche Diabetes Care, Sanofi, UnitedHealth Group. S. Morrett: Other Relationship; Self; Eli Lilly and Company. D.A. Ignaut: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Funding
Eli Lilly and Company
235-LB: Postprandial Short-Chain Fatty Acid Concentrations in the Intestinal Lumen and Plasma
Authors: MEYER RACHEL , LANE ADELINA I.L. , KANGATH ARCHANA , WENINGER SAVANNA N. , MARTINEZ TAYLOR , DUCA FRANK 
Published: June 2020

Obesity continues to be a global health risk affecting over 650 million adults worldwide. Fiber intake is negatively correlated with obesity, and increased fiber intake is associated with weight loss. Fiber is digested by the gut microbiota to produce short chain fatty acids (SCFA), which may have a beneficial effect on metabolic disease. While it is well known that SCFAs are mostly utilized by enterocytes as a fuel source, the timing of postprandial production and absorption of SCFAs from a meal, as well as the effect of high-fat feeding, has yet to be characterized. In the present study, we aimed to determine the levels of acetate, butyrate, and propionate, the major SCFAs, after a meal in rats maintained for 4wks on a chow, high-fat diet (45% kcal from fat; HFD) or HFD with 10% oligofructose (OFS), a well-studied prebiotic known to induce weight loss. SCFA levels were measured in the distal small intestine, cecum, and colon of rats, as well as the portal vein and vena cava at 0, 2, 4, 6, and 8 hours following consumption of an isocaloric meal of the maintenance diet. Chow rats had significantly increased levels of SCFAs as early as 2h postprandially, in the cecum, colon, portal vein, and vena cava compared to baseline levels, whereas HFD-fed rats displayed minimal increases in SCFAs. Addition of OFS rescued SCFA production, peaking at 4h postprandial; however, concentrations were not rescued to chow values at all timepoints. Increased body weight and adiposity was not associated with baseline SCFA levels in any compartment, but was negatively associated with postprandial SCFA levels in the cecum, colon, and portal vein. Overall, this study demonstrates that SCFAs exhibit a post-prandial rise similar to ingested macronutrients, and that baseline fasting levels of SCFAs may be an inaccurate indication of SCFA production in rodents. These data lay the groundwork for future studies to examine how rises in SCFA levels from breakdown of non-digestible carbohydrates can contribute to improve metabolic disease.

Disclosure
R. Meyer: None. A.I.L. Lane: None. A. Kangath: None. S.N. Weninger: None. T. Martinez: None. F. Duca: None.
240-OR: Combining Type 2 Diabetes Polygenic Scores Improves Prediction in 36,000 European and Non-European Participants in the Partners Healthcare Biobank
Authors: MERCADER JOSEP M. , FLOREZ JOSE C. , LEONG AARON , KAUR VARINDERPAL , UDLER MIRIAM , MEIGS JAMES B. , PORNEALA BIANCA 
Published: June 2020

Polygenic scores constructed by the aggregation of effect sizes of associated genetic variants have been shown to predict type 2 diabetes (T2D). Polygenic scores can be defined as “restricted-to-significant polygenic scores” (rsPS), and “globally expanded polygenic scores” (gePS), which can include millions of variants beyond those that are genome-wide significant. Most polygenic scores have been generated based on genome-wide association studies (GWAS) conducted predominantly in participants of European ancestry (EU); how these polygenic scores perform in non-European individuals in the healthcare system has not been thoroughly evaluated.
We applied the rsPS and gePS for T2D in 30,240 EU participants, 3,029 Latinos (LA), and 2,201 African Americans (AA) from the Partners HealthCare Biobank, which maintains blood and DNA samples from patients seen at Partners HealthCare-affiliated hospitals in Boston. We compared rsPS based on the DIAMANTE consortium meta-analysis, with 398 variants (rsPS_398), rsPS based on the latest Million Veterans Program meta-analysis, with 682 variants (rsPS_682), and a gePS based on ldpred, including 6.9M variants adjusted for their effects based on linkage disequilibrium.
rsPS_682 was most strongly associated with T2D in all ancestries (OR per SD in EU=1.73 p=7×10-142, OR per SD in LA =1.88, p=7×10-19, OR per SD in AA =1.47, p=1×10-8 compared to the other polygenic scores. We observed that rsPS_682 and the gePS provided both complementary information, and that combining them into the model improved the prediction in all ancestries, with 16%, 22%, and 16% increase in accuracy in EU, LA, and AA, respectively.
We show the advantage of combining rsPS and gePS to improve prediction of T2D in multi-ethnic populations within a healthcare system. The results suggest that larger and multi-ethnic T2D GWAS are needed to avoid major health disparities.

Disclosure
J.M. Mercader: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. A. Leong: None. V. Kaur: None. M. Udler: None. J.B. Meigs: Consultant; Self; Quest Diagnostics. B. Porneala: None.

Funding
American Diabetes Association (1-19-ICTS-068 to J.M.M.)
262-OR: The Transcription Factor Yin Yang 1 (YY1) Is Critical to Beta-Cell Maintenance and Glucose Homeostasis
Authors: PEÇANHA FLAVIA LETÍCIA M. , BERNAL-MIZRACHI ERNESTO 
Published: June 2020

Diabetes is characterized by loss of β cell mass and function. mTORC1 has an important role in the control of insulin secretion, β cell proliferation and death. YY1 is important in development, apoptosis, metabolism and growth in several tissues. In muscle, mTORC1 regulates the expression of insulin signaling genes by controlling YY1 binding to the promoter region. However, YY1 role in β cells was not addressed so far. Here we observed that diabetic and diet-induced obese mice exhibited lower levels of YY1 in the β cells. To understand the role of YY1 in β cell, we developed a new β cell YY1 depleted mouse model (β-YY1KO) by crossing our floxed YY1 mouse with a Ins-cre mouse. Haploinsufficiency of YY1 (β-YY1HET) did not impair fed or fasting glycemia, blood insulin levels and glucose tolerance. Even after 10 weeks in HFD, β-YY1HET did not differ from littermate controls in terms of glucose tolerance and glucose-stimulating insulin secretion. However, β-YY1KO mice exhibited a profound diabetic phenotype. While glucose and insulin levels in newborn β-YY1KO were normal, blood glucose begun to rise in the β-YY1KO mice at 2 weeks. All β-YY1KO became diabetic at 3 weeks presenting fed hyperglycemia and lower fed insulin levels, suggesting decreased β cell function and/or β cell loss. Remarkably, β cell mass is reduced at 2 and 3 weeks. To understand the decrease in β cell mass, we assessed β cell proliferation and death by IHF for Ki67 and flow cytometry for active Casp 3, respectively. Although β cell proliferation was normal at 2 weeks, there was a reduction Ki67+ β cell at 3 weeks. However, active casp 3 was already increased at 2 weeks. One striking role of YY1 is to regulate mitochondrial function and structure, therefore, we evaluated mitochondrial morphology by electron microscopy. We found that β-YY1KO mice presented less mitochondrial area and abnormal structure. Altogether, these results show that YY1 is important for appropriate control of glucose homeostasis and β-cell maintenance.

Disclosure
F.M. Peçanha: None. E. Bernal-Mizrachi: None.
3-LB: Golimumab (GLM) Preserves ß-Cell Function and Reduces Insulin Use and Hypoglycemia in Children and Young Adults with Recently Diagnosed Type 1 Diabetes (T1D): The Phase 2 T1GER Study
Authors: QUATTRIN TERESA , HALLER MICHAEL J. , STECK ANDREA , FELNER ERIC , LI YINGLEI , XIA KAREN , LEU JOCELYN , RIGBY MARK , ZOKA RAMINEH , HEDRICK JOSEPH , VERCRUYSSE FRANK 
Published: June 2020

T1D is an autoimmune disease characterized by progressive loss of pancreatic β cells. GLM is a human IgG1κ monoclonal antibody specific for tumor necrosis factor α. This study assessed whether GLM preserves β-cell function in children and young adults with newly diagnosed stage 3 T1D.
This Phase 2a, double-blind, placebo (PBO)-controlled study randomized participants aged 6-21 yrs with newly diagnosed stage 3 T1D to receive subcutaneous GLM (BSA-based dose if &lt;45 kg; fixed dose if ≥45 kg) or PBO (2:1) for 52 weeks. The primary endpoint was C-peptide area under the curve (AUC) at Week 52 after a 4-hour mixed-meal tolerance test. Insulin use, HbA1c, hypoglycemia rates, and proinsulin/C-peptide ratios were assessed.
84 participants were enrolled (GLM, n = 56; PBO, n = 28). The study was positive as mean (SD) 4-hour C-peptide AUC at Week 52 was 0.64 (0.423) and 0.43 (0.388) pmol/mL with GLM and PBO, respectively (P&lt;0.001; Figure). GLM-treated participants had lower insulin use, hypoglycemia rates, and proinsulin/C-peptide ratios vs. PBO. Both groups maintained good glycemic control. GLM was well tolerated, without any new safety signals.
In this study, golimumab demonstrated the ability to preserve endogenous insulin production and improve clinical and metabolic parameters in children and young adults with newly diagnosed stage 3 T1D.

Disclosure
T. Quattrin: Consultant; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; Janssen Pharmaceuticals, Inc., Provention Bio, Inc. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. A. Steck: None. E. Felner: None. Y. Li: Employee; Self; Janssen Research & Development, LLC. K. Xia: Employee; Self; Janssen Research & Development, LLC. J. Leu: Employee; Self; Janssen Research & Development, LLC. M. Rigby: None. R. Zoka: Employee; Self; Janssen Research & Development, LLC. J. Hedrick: Employee; Self; Janssen Pharmaceuticals, Inc. F. Vercruysse: Employee; Self; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Johnson & Johnson.

Funding
Janssen Research & Development, LLC
3-OR: Intensive Glycemic Control Can Reduce Major Adverse Cardiovascular Events (MACE): A Bayesian’s Narrative
Authors: SHAO HUI , YANG SHUANG , FONSECA VIVIAN , BIAN JIANG , SHI LIZHENG 
Published: June 2020

The American College of Physicians 2018 guidance statement recommended an A1c goal of 7%-8% for patients with type 2 diabetes because of a lack of statistically significant MACE risk reduction through intensive glycemic control in long-term clinical trials (e.g., ACCORDION trial and VADT). However, interpreting clinical trial results merely based on statical inference (p&lt;.05) may prevent a large number of patients from receiving treatments that may be appropriate otherwise. Also, these trials’ point estimates of MACE risk reduction are all in favor of intensive glycemic control, regardless of its statistical significance. This study aimed to use Bayesian analysis to re-interpret the ACCORD and VADT trials. The data from the ACCORD and VADT trials were simulated by the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes model to generate the prior distribution of the MACE risk reductions as a result of intensive glycemic control. From the published distribution of the MACE risk reduction as data input, the Gibbs sampler was used to generate the posteriors distribution of the MACE risk reduction as result of intensive glycemic control. Intensive glycemic control appeared to be 99.9% likely to reduce MACE for T2DM patients in both trials. The Bayesian interpretation could be used to supplement statistical inferences of intensive glycemic control in the ACCORD and VADT trials.

Disclosure
H. Shao: None. S. Yang: None. V. Fonseca: Consultant; Self; Abbott, Asahi Kasei Corporation, AstraZeneca, Bayer Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Stock/Shareholder; Self; Amgen, Bravo4health. J. Bian: None. L. Shi: None.
360-OR: BETA-2 Score Is Highly Correlated with Acute Insulin Response to Intravenous Glucose: An Analysis of the Clinical Islet Transplantation Consortium Trials
Authors: SENIOR PETER A. , RICKELS MICHAEL R. , EGGERMAN THOMAS , BAYMAN LEVENT , QIDWAI JULIE , ALEJANDRO RODOLFO , MARKMANN JAMES F. , HUNSICKER LAWRENCE G. ,   CLINICAL ISLET TRANSPLANT CONSORTIUM
Published: June 2020

Accurate measurement of islet function after clinical islet transplantation (CIT) is challenging. Maximum insulin secretion can be estimated from the acute insulin response to glucose (AIRg) during frequently sampled intravenous glucose tolerance tests (FSIGT). BETA-2, a composite measure derived from a single blood test is practical for routine use. To test the validity of BETA-2, we examined its relationship with AIRg in subjects participating in CIT Consortium trials. 128 C-peptide negative subjects (48.2 ± 10.9 yrs, 38.7% male) underwent 355 FSIGTs prior to and every 6 months after CIT. They received 1-3 islet infusions of &gt;4000 IE/kg. AIRg was derived using the minimal model. BETA-2 was calculated within 90 days of FSIGT (&gt;75% were within 1 day). BETA-2 is plotted against log (AIRg+1) with a loess smoothing curve. BETA-2 is linearly related to log(AIRg) particularly when AIRg &gt; ∼ 6.5 (ie log(AIRg +1) &gt; 2). A linear regression, after raising AIRgs below 6.5 to 6.5, shows an intercept close to 0, a slope of 8.71, and an R2 of 0.69. Limiting the linear regression to test pairs done on successive days had no significant or meaningful effect on this relation. BETA-2 is highly correlated with AIRg, which is related to maximum insulin release and can be used as a validated measure to estimate beta cell mass in CIT.

Disclosure
P.A. Senior: None. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. T. Eggerman: None. L. Bayman: None. J. Qidwai: None. R. Alejandro: None. J.F. Markmann: None. L.G. Hunsicker: Advisory Panel; Self; Allergan plc., Bristol-Myers Squibb.