bluuebunny/crossref_metadata_2025 huggingface dataset:
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 <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<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<.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 >4000 IE/kg. AIRg was derived using the minimal model. BETA-2 was calculated within 90 days of FSIGT (>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 > ∼ 6.5 (ie log(AIRg +1) > 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.
38-OR: Differences in Diabetes Medication Use between Commercial and Medicare Advantage Beneficiaries, 2013-2018
Authors: MCCOY ROZALINA G. , HOUTEN HOLLY VAN , ROSS JOSEPH , KARACA-MANDIC PINAR , MONTORI VICTOR M. , SHAH NILAY
Published: June 2020

DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors have low hypoglycemia risk, do not cause weight gain, and post-marketing outcomes trials found cardiovascular and renal benefits with GLP-1RA and SGLT2i use. Using 2013-2016 data, we previously found low and delayed early adoption of SGLT2i among Medicare Advantage (MA) beneficiaries compared to commercial beneficiaries, despite similar formulary coverage. With greater experience using these medications and emerging evidence supporting their preferred use by patients with comorbidities, prescribing patterns may have changed. Using OptumLabs Data Warehouse, a de-identified dataset of commercial and MA beneficiaries, we examined the proportions of pharmacologically-treated adults with type 2 diabetes with commercial vs. MA insurance who filled a DPP-4i, GLP-1RA, or SGLT2i each quarter between 2013-2018. We found significant differences across medications and health plans (Figure). Overall, after adjusting for age, gender, race/ethnicity, baseline medications, year, prescriber specialty, and comorbidities, the odds of DPP-4i, GLP-1RA, and SGLT2i use were significantly lower for MA vs. commercial beneficiaries: OR 0.61 (95% CI 0.60-0.63), 0.45 (95% CI 0.44-0.46), and 0.31 (95% CI 0.30-0.31), respectively. These findings call for better understanding of non-clinical factors contributing to treatment decisions.

Disclosure

R.G. McCoy: None. H. Van Houten: None. J. Ross: Research Support; Self; Centers for Medicare and Medicaid Services, Janssen Pharmaceuticals, Inc., U.S. Food and Drug Administration. P. Karaca-Mandic: None. V.M. Montori: None. N. Shah: None.

Funding

National Institutes of Health (K23DK114497); Agency for Healthcare Research and Quality (1U19HS024075, R01HS025164)
386-P: Acute Hypoglycemia Does Not Alter Serum Levels of Amyloid-Related Proteins Associated with Dementia
Authors: MOIN ABU , SATHYAPALAN THOZHUKAT , ATKIN STEPHEN , BUTLER ALEXANDRA E.
Published: June 2020

Objective: Hypoglycemia is a common complication of tighter glucose control regimens in type 2 diabetes (T2D) and may increase the risk of dementia, Alzheimer’s disease being the most common form. We measured amyloid-related proteins during induced hypoglycemia in a cohort of subjects with and without T2D, hypothesizing that these protein levels would be further elevated during hypoglycemia in T2D subjects.

Methods: A prospective, parallel study was conducted in individuals with T2D (n=23) and controls (n=22). Hypoglycaemia (<2.2mmol/l: <40mg/dl) was achieved by intravenous infusion of soluble insulin. Blood samples were collected at baseline and at 0, 30, 60, 120, 240 minutes and 24 hours following hypoglycaemia and proteomic (Somalogic) analysis of four amyloid-related proteins (Amyloid P component [APCS], Amyloid precursor protein [APP], Pappalysin [PAPPA] and Serum amyloid A1 [SAA1]) at baseline, at hypoglycemia and at 24-hours post-clamp was undertaken.

Results: No changes from baseline in serum levels of the four amyloid-related proteins were seen in subjects with or without T2D, either at the time of hypoglycemia or at 24-hours post-clamp.

Conclusions: Induced hypoglycemia is not associated with a significant increase in serum levels of amyloid-related proteins. Thus, no clear mechanistic link based on serum proteins between T2D-related hypoglycemic episodes and Alzheimer’s disease emerged from this study, although it is important to consider that protein levels in the cerebrospinal fluid may differ.

Disclosure

A. Moin: None. T. Sathyapalan: Research Support; Self; Amgen, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; Ipsen Biopharmaceuticals. S. Atkin: None. A.E. Butler: None.
417-P: Impact of Preventative Therapies on the Extent of Coronary Artery Disease in People with and without Diabetes
Authors: KIBURG KATERINA V. , MACISAAC ANDREW I. , MCCLUSKEY GEORGIA E. , SUNDARARAJAN VIJAYA , MACISAAC RICHARD
Published: June 2020

Objective: To assess the impact of preventative therapies on the extent of coronary artery disease (CAD) in people with and without diabetes in a real-world setting.

Research Design and Methods: Patient-level linked coronary angiography and hospital separation data at a large Australian tertiary referral hospital between 2013 and 2019 were obtained and a random sample of patient charts reviewed for medication use (renin-angiotensin system (RAS) inhibitors, statins and antiplatelets). Indication for angiography and extent of CAD were based on the original classification by treating cardiologists, classified as no disease, mild, moderate or severe. Propensity scores were estimated and used to weight in the ordinal logistic regression models. Models were fitted to assess trends in CAD severity in people with and without diabetes with adjusted odds ratios (adjOR) reported.

Results: For 805 people identified in the coronary angiography database with medication use information available, 386(48%) were diagnosed with diabetes. Angiographic evidence of CAD was found in 297(71%) and 301(78%) of people without and with diabetes, respectively. People with diabetes were at an increased risk of more extensive CAD disease compared to people without diabetes (adjOR: 1.37 95% C.I. 1.00, 1.88). However, when adjusted for the use of RAS inhibitors, statins and antiplatelets there was no difference in the extent of CAD between people with and without diabetes (adjOR: 1.22 95% C.I. 0.87, 1.69).

Conclusions: These findings highlight the increased risk that people with diabetes have for more extensive CAD than people without diabetes. Our results also suggest that with the aggressive and appropriate use of traditional cardiovascular disease preventative therapies it may be possible to significantly reduce the excess CAD burden observed in people with diabetes.

Disclosure

K.V. Kiburg: None. A.I. MacIsaac: None. G.E. McCluskey: None. V. Sundararajan: None. R. MacIsaac: None.
450-P: Development and Validation of a Predictive Major Adverse Cardiac Events (MACE) Risk Model for Diabetes Patients with Acute Coronary Syndrome (ACS)
Authors: HU PENGWEI , DI XIN , ZHANG YUAN , TANG ZEFANG , LI SHAOCHUN , MEI JING , MA CHANGSHENG
Published: June 2020

Background: Studies have shown that acute coronary syndrome (ACS) has a higher incidence of MACE in diabetic patients than in nondiabetic patients by 39%. The complexity of the MACE limits clinical predictions, the success rate is shallow. Several existing MACE risk prediction models, including some developed specifically for ACS patients, also stuck with low accuracy and are not suitable for complications scenarios.

The objective of this study is to develop and validate a model based on EHR data to predict MACE risk in patients with type 2 diabetes mellitus (T2DM) complicated with ACS.

Methods: This study recruited 16,807 in-hospital T2DM patients with ACS from 38 urban and rural hospitals. Patients with 41 variables, including age, demographics, living habits, ACS type, and Killip class. The criteria for the diagnosis of MACE developed for this study consider cardiovascular death, myocardial infarction, or ischemic stroke. There are 711 MACE records diagnosed by doctors during patients’ hospitalization and recorded in medical records, only 4.2% of the total cohort. Very low morbidity inspires us to introduce a model called Support Vector Data Description (SVDD) to combat this uneven distribution of data. SVDD only maps the features of MACE patients to the high-dimensional space and constructs a minimum sphere to contain all the target data, taking the sphere as the boundary to classify the risk of newly admitted patients. Models were developed and validated on 80% and 20% of the sample, respectively. The model performance was assessed by C-statistics and the F1.

Results: The model performed with C-statistics of 0.873 and F1 of 0.833. We found 5 variables had a significant univariate association with MACE included Age, Heart rate, Killip class, white blood cell count and Creatinine at p<10-4.

Conclusions: This novel study suggests that the well trained SVDD model would be possible to predict the harmful MACE among T2DM patients with ACS.

Disclosure

P. Hu: None. X. Di: None. Y. Zhang: None. Z. Tang: None. S. Li: None. J. Mei: None. C. Ma: None.
482-P: The GLP-1 Receptor Agonist Liraglutide Improves Glomerular Filtration Rate, Renal Inflammation, and Fibrosis in the Type 2 Diabetic SDT Fatty Rat
Authors: BRIAND FRANCOIS , SHINOHARA MASAMI , BROUSSEAU EMMANUEL , KAGEYAMA YASUSHI , SULPICE THIERRY
Published: June 2020

The Glucagon-Like Peptide 1 (GLP-1) receptor agonist liraglutide (LIRA) may reduce the rate of development and progression of diabetic kidney disease in type 2 diabetic patients. To evaluate its impact on kidney function, we evaluated the effects of LIRA on glomerular filtration rate (GFR), in both the hyperfiltration and GFR decline phases in the Spontaneously Diabetic Torii (SDT) fatty rat, a preclinical model of type 2 diabetes. SDT fatty male rats were treated subcutaneously, once daily with vehicle or LIRA 0.4mg/kg for 10 weeks. To measure the effects of LIRA on glomerular hyperfiltration, rats were injected with FITC-sinistrin at 4 weeks of treatment to measure GFR. After 5 weeks of treatment, rats underwent unilateral nephrectomy and were put on a 0.3% salt diet to induce a GFR decline for the last weeks of treatment, then GFR was measured at 10 weeks of treatment. Urine biochemistry and kidney histology analysis were also performed. Compared with vehicle, LIRA resulted in significant body weight loss and lower body weight. LIRA also reduced blood glucose levels significantly by up to ∼20%, as expected. During the hyperfiltration phase, LIRA attenuated hyperfiltration, with a 19% lower GFR vs. vehicle (vehicle: 21 ± 1.1 mL/min/kg; LIRA: 17.1 ± 1.0 mL/min/kg, p<0.05 vs. vehicle). In vehicle treated animals, unilateral nephrectomy and 0.3% salt diet induced a major reduction (-56%) in GFR, as expected. After 10 weeks of treatment, LIRA markedly attenuated this GFR decline (vehicle: 9.3 ± 0.5 mL/min/kg; LIRA: 13.3 ± 0.9 mL/min/kg, p<0.001 vs. vehicle). In line with the benefits observed on GFR, LIRA lowered urine albumin to creatinine ratio both in the hyperfiltration and GFR decline phases. Moreover, histology analysis showed that LIRA significantly reduced kidney inflammation and fibrosis scores, as compared with vehicle.

In conclusion, LIRA shows significant benefits on GFR, renal inflammation and fibrosis in the SDT fatty rat model.

Disclosure

F. Briand: Employee; Self; Physiogenex. Stock/Shareholder; Self; Physiogenex. M. Shinohara: None. E. Brousseau: Employee; Self; Physiogenex. Y. Kageyama: None. T. Sulpice: Employee; Self; Physiogenex. Stock/Shareholder; Self; Physiogenex.
499-P: Clinical Validation of an AI-Enabled Prognostic Test (KidneyintelX) to Accurately Predict Rapid Kidney Function Decline in Patients with Type 2 Diabetic Kidney Disease
Authors: CHAN LILI , NADKARNI GIRISH N. , FLEMING FERGUS , SALEM FADI E. , MURPHY BARBARA , DONOVAN MICHAEL J. , COCA STEVEN , DAMRAUER SCOTT M.
Published: June 2020

The ability to predict rapid kidney function decline (RKFD) in patients with early stages of type 2 diabetic kidney disease (T2DKD) can improve long-term health outcomes through earlier intervention. Our objective was to develop a robust risk score for patients with early stages of T2DKD. We obtained EHR and plasma from patients with T2DKD (Kidney Disease Improving Global Outcomes [KDIGO] G1-G2, A2-A3 or G3a-G3b, A1-A3) from the Mount Sinai BioMe Biobank and the Penn Medicine Biobank and measured soluble tumor necrosis factor receptor (sTNFR1, sTNFR2) and kidney injury molecule-1 (KIM-1) via a validated quantitative electrochemiluminescent assay. A machine learning model was trained using the EHR/biomarker data to predict RKFD, defined as eGFR decline of ≥5 ml/min/year or ≥40% sustained decline in eGFR or kidney failure within 5 years, and performance was compared to a clinical model and KDIGO risk-matrix. A total of 1146 subjects with a mean age of 63, baseline eGFR 54 ml/min, and median UACR 61 mg/g were randomly divided into 60% training (n=686) and 40% validation (n=460) sets. The median follow-up was 4.3 years and 241 (21%) experienced RKFD. The AUC of KidneyIntelX for RFKD was 0.85 (95% CI 0.84-0.86) in training and 0.77 (95% CI 0.76-0.79) in the validation set vs. AUC of 0.67 (95% CI 0.64-0.70) for a clinical model. Using pre-specified cutoffs from the training set, KidneyIntelX stratified 47%, 37% and 16% of the validation set into low-, intermediate- and high-risk strata, with a PPV of 62% (vs. 41% for KDIGO) in the high-risk group (p <0.001), a net reclassification improvement for events of 41% (p <0.05), and a NPV of 91% in the low-risk group (vs. 85% for KDIGO). KidneyIntelX, a machine learning model combining biomarkers and EHR data, improved prediction of RKFD over standard clinical metrics in patients with T2DKD. Future studies will prospectively evaluate KidneyIntelX in clinical decision-making and impact.

Disclosure

L. Chan: None. G.N. Nadkarni: Advisory Panel; Self; Renalytix AI. Consultant; Self; AstraZeneca, Reata, Renalytix AI. Stock/Shareholder; Self; Renalytix AI. Other Relationship; Self; Renalytix AI. F. Fleming: Board Member; Self; Renalytix AI plc. F.E. Salem: None. B. Murphy: Board Member; Self; RenalytixAI. M.J. Donovan: Consultant; Self; Renalytix AI plc. S. Coca: Advisory Panel; Self; Renalytix AI plc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., CHF Solutions, Relypsa, Inc., Takeda Pharmaceutical Company Limited. Stock/Shareholder; Self; Renalytix AI plc. S.M. Damrauer: Consultant; Spouse/Partner; Rhythm Pharmaceuticals. Research Support; Self; CytoVas LLC, Renalytix AI plc.

Funding

Renalytix AI plc
517-P: Serum Galectin-3 and the Risk of Rapid Renal Function Decline in Type 2 Diabetes
Authors: TAN KATHRYN C.B. , ALAN LEE CHUN HONG , WONG YING , SHIU SAMMY
Published: June 2020

Background and Aims: Galectin-3 is a broad-spectrum biological response modifier and belongs to the multifunctional galectin family. It is involved in tissue fibrosis, immunity, and inflammatory response and recent evidence suggests that galectin-3 is associated with chronic kidney disease (CKD) in both diabetic and nondiabetic populations. We therefore aim to determine whether serum galectin-3 level is associated with rapid kidney function decline in type 2 diabetic individuals without overt nephropathy.

Methods: Galectin-3 was measured in the baseline samples by ELISA in 998 type 2 diabetic patients with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73m2 and no macroalbuminuria. Rapid renal progression during follow up was defined as a rate of eGFR decline >5 ml/min/year according to Kidney Disease Improving Global Outcomes (KDIGO) Guideline.

Results: Over a median follow up of 12 years, 91 subjects had eGFR decline >5 ml/min/year and they had significantly higher serum galectin-3 level than those with more stable renal function (8.52 ± 2.20 ng/ml vs. 7.58 ± 2.38 respectively, p<0.01). In an unadjusted model, serum galectin-3 was associated with rapid decline in kidney function [hazard ratio (HR) 1.16, 95% CI 1.07-1.26, p<0.001]. Serum galectin-3 remained a significant independent predictor even after adjustment for age, gender, body mass index, smoking, baseline eGFR, systolic blood pressure, HbA1c and duration of diabetes, the presence of microalbuminuria and renin-angiotensin system blockers therapy (p=0.004).

Conclusion: In type 2 diabetic subjects without overt nephropathy, serum galectin-3 was a significant independent risk factor for rapid decline in kidney function.

Disclosure

K.C.B. Tan: None. C. Lee: None. Y. Wong: None. S. Shiu: None.
542-P: Association of Cardiac Autonomic Dysfunction with Plasma Lipid Metabolites in Recent-Onset Type 2 Diabetes
Authors: BÖNHOF GIDON J. , STROM ALEXANDER , STRASSBURGER KLAUS , KNEBEL BIRGIT , KOTZKA JORG , AL-HASANI HADI , SZENDROEDI JULIA , ZAHARIA OANA P. , KARUSHEVA YANISLAVA , RODEN MICHAEL , ZIEGLER DAN
Published: June 2020

Emerging evidence suggests that obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterized by reduced heart rate variability (HRV). In this context we assessed the relationship of 127 biomarkers of lipid metabolism (11 acylcarnitines, 39 free fatty acids, 12 sphingomyelins, 56 phosphatidylcholines, and 9 lysophosphatidylcholines) in plasma using mass spectrometry with HRV indices in individuals with recent-onset type 1 (T1D) or type 2 diabetes (T2D) from the baseline cohort (known diabetes duration (DD) ≤1 year) of the German Diabetes Study (T1D/T2D [mean±SD]: n=126/243; age: 34.5±12.9/53.4±11.0 years; BMI: 24.7±4.3/31.7±6.0 kg/m²; DD: 211±93/198±90 days; HbA1c: 6.8±1.4/6.5±0.9 %). Time domain and frequency domain HRV indices were derived from NN intervals recorded during a 3 h hyperinsulinemic-euglycemic clamp. After adjustment for age, sex, and BMI as well as Bonferroni correction including seven HRV parameters and the number of metabolites of the corresponding lipid class, higher levels of three free fatty acids (myristic acid: β=-0.14, p=0.049; palmitic acid: β=-0.19, p=0.007; palmitoleic acid: β=-0.15, p=0.048), eight phosphatidylcholines (e.g., phosphatidylcholine diacyl (PC aa) C32:0: β=-0.28, p<0.001; phosphatidylcholine acyl-alkyl C34:3: β=-0.20, p<0.004), and two sphingomyelins (sphingomyelin C16:0: β=-0.15, p=0.028; sphingomyelin C16:1: β=-0.18, p=0.020) were inversely associated with the standard deviation of NN intervals (SDNN) in recent-onset T2D but not T1D. PC aa C32:0 was inversely associated with both low (LF) and high frequency (HF) power spectrum in T2D (LF: β=-0.23, p=0.001; HF: β=-0.23, p=0.001).

In conclusion, the link between higher plasma levels of specific lipid metabolites and early cardiac autonomic dysfunction in recent-onset type 2 diabetes suggests that plasma lipid panels could be useful to improve the prediction of the development or progression of CAN.

Disclosure

G.J. Bönhof: None. A. Strom: None. K. Strassburger: None. B. Knebel: None. J. Kotzka: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. O.P. Zaharia: None. Y. Karusheva: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. D. Ziegler: None.
560-P: The Liver Fibrosis Score Is Associated with Diabetic Peripheral Neuropathy in Type 2 Diabetes Mellitus
Authors: KIM KYUHO , OH TAE JUNG , SHIN YUJIN , CHOI SUNG HEE , JANG HAK CHUL
Published: June 2020

Background: Type 2 diabetes mellitus (T2DM) is interrelated with nonalcoholic fatty liver disease (NAFLD) and liver fibrosis. However, the association between NAFLD and diabetic peripheral neuropathy (DPN) has not been well studied.

Methods: We prospectively enrolled subjects with T2DM to evaluate risk factors of DPN and to develop a screening tool of DPN. In this study, we analyzed the data of 127 subjects in whom we could calculate NAFLD and liver fibrosis scores. DPN was diagnosed using the Michigan Neuropathy Screening Instrument. Non-invasive markers of NAFLD (hepatic steatosis index, and NAFLD liver fat score) and liver fibrosis (NAFLD fibrosis score, and fibrosis-4 score) were calculated using equations containing several combinations of age, the presence of obesity or metabolic syndrome, liver function test, fasting insulin level, and platelet count. Body composition was measured by bio-impedance analysis. Clinical parameters and various markers were compared according to the presence of DPN.

Results: The prevalence of DPN in our study was 39.3%. There was no significant difference in body mass index, diabetes duration, and liver function test between subjects with DPN and those without DPN. Subjects with DPN showed older age, and higher fasting blood glucose level. Hepatic steatosis index and NAFLD liver fat score were comparable between subjects with or without DPN. In contrast, subjects with DPN showed significantly higher NAFLD fibrosis score (-0.7 vs. -1.3, P = 0.004) and fibrosis-4 score (1.6 vs. 1.2, P = 0.014) compared to those without DPN. These two scores were negatively associated with lean body mass. After adjusting lean body mass, the association between liver fibrosis scores and DPN was still significant.

Conclusion: The liver fibrosis scores but not NAFLD scores were higher in subjects with DPN compared to those without DPN. Liver fibrosis and DPN might share common pathophysiology.

Disclosure

K. Kim: None. T. Oh: None. Y. Shin: None. S. Choi: None. H. Jang: Speaker’s Bureau; Self; Daiichi Sankyo, Handok, Pfizer Inc., Takeda Pharmaceutical Company Limited.
561-P: Activated Xanthine Oxidase in Serum Is a Potent Therapeutic Target for Experimental Diabetic Polyneuropathy
Authors: ICHINOHE HIROSHI , MIZUKAMI HIROKI , OSONOI SHO , KUDO KAZUHIRO , YAGIHASHI SOROKU
Published: June 2020

Xanthine oxidase (XO), a potent inducer of reactive oxygen species, catalyzes purine metabolism. XO is expected to be implication of the macrophage activation. XO is also expressed in the peripheral nerve system, while its role in diabetic polyneuropathy (DPN) has not been clarified. We explored the implication of XO in DPN of db/db mice (db/db) treating with XO-inhibitor, topiloxostat (To). C57BL6 mice (C57) and db/db (5 wks of age) were daily treated with 1mg/kg (dbT1) and 2mg/kg (dbT2) To (per os) for 8 wks. During experimental period, peripheral nerve function was monitored. At end, serum and dissected sciatic nerves and dorsal root ganglia (DRG) served for evaluation of uric acid metabolism. Primary culture of DRG neuron was performed to evaluate the effects of To on neurite outgrowth in vitro. To improved significant delay of nerve conduction velocities and elevation of threshold for tail flick test in db/db in a dose dependent manner (p<0.05 dbT2 vs. C57 for NCVs, p<0.05 db/db vs. dbT1, p<0.01 db/db vs. dbT2 for tail flick). XO activity was significantly up-regulated in DRG (p<0.01) and serum of db/db compared to those of W (p<0.05). To successfully suppressed the elevated XO activity in a dose dependent manner (p<0.05, W vs. T1, p<0.01, T1 vs. T2). Uric acid was significantly accumulated in serum and DRG of db/db compared to those of C57 (p<0.05). To could significantly reduce the accumulation (p<0.01). In primary culture of DRG neuron, extrinsic 100 μM XO depleted the neurite outgrowth more than 50 % than that of non-stimulated neurons (p<0.01). 4.3ng/ml To could significantly restored the reduction of neurite outgrowth compared to that of non-treated neurons (p<0.05).

As a conclusion, increase in XO activity in serum and DRG may be implicated in the pathophysiology of DPN in db/db. Activation of XO in serum may directly exacerbate neuronal injury for DRG in DPN. To has a beneficial effect on DPN through its specific property to suppress serum XO activity.

Disclosure

H. Ichinohe: None. H. Mizukami: None. S. Osonoi: None. K. Kudo: None. S. Yagihashi: None.
568-P: ATF4 Regulates the Inflammatory Responses via the Modulation of NLRP3 Inflammasome in Diabetic Retinopathy
Authors: LI TING , HE XUEMIN , PENG RONGDONG , GAO RONG , SHI GUOJUN , CHEN YANMING
Published: June 2020

Aims: Previously we reported that ATF4-mediated endoplasmic reticulum (ER) stress led to endothelial inflammation and retinal vascular leakage under diabetic condition. In this study, we aimed to investigate if ATF4 regulated the inflammatory responses through modulating NLRP3 inflammasome activation in diabetic retinopathy.

Methods: Streptozotocin (STZ) was applied to induced diabetes in mice. Mice were sacrificed at day 15 and day 30 after onset of diabetes, and retinas were collected for analyses. To mimic the diabetic condition in vitro, human retinal microvascular endothelial cells (HRMECs) were exposed to palmitate (50 μM), accompanied with adenoviruses overexpressing human ATF4 or shRNA of ATF4.

Results: ATF4 level was closely correlated with the activation of NLRP3 inflammasome in STZ-diabetic retinas and palmitate-treated HRMECs, followed by increases of inflammatory factors (ICAM-1, VCAM-1 and TNF-α) and loss of endothelial junction proteins (ZO-1, occludin-1 and VE-cadherin). Moreover, diabetes-induced ATF4 and NRLP3 were colocalized in the ganglion cell layer, inner plexiform layer and outer plexiform layer. Overexpression of ATF4 augmented the palmitate-elicited activation of NLRP3 inflammasome, whereas knocking-down of ATF4 abolished the activation. By analyzing the promoter region of NLRP3 gene, three potential binding sites of ATF4 were identified: -1418bp∼-1406bp, -1332bp∼-1320bp, -65∼-53bp. Overexpression of ATF4 potentiated the palmitate-induced nuclear translocation of ATF4, followed by enhanced activation of NLRP3 inflammasome. In addition, treatment with ISRIB, an inhibitor of ER stress, significantly abolished the palmitate-induced elF2α phosphorylation but not NLRP3 activation when ATF4 is overexpressed.

Conclusion: We have demonstrated that ATF4 is a directly regulator of NLRP3 inflammasome, independent of ER stress response, thus providing a novel insight into the pathogenesis of ATF4-elicited diabetic retinopathy.

Disclosure

T. Li: None. X. He: None. R. Peng: None. R. Gao: None. G. Shi: None. Y. Chen: None.

Funding

Research and Development Plans in Key Areas of Guangdong Province (2019B020227003); National Natural Science Foundation of China (81770826); National Key Research and Development Program of China (2017YFA0105803)
606-P: Artificial Neuronal Network Model for Three-Month Prognosis in Diabetic Foot Syndrome
Authors: PORADZKA ANNA A. , CZUPRYNIAK LESZEK
Published: June 2020

Background: To make a reliable prognosis on wound healing in patients with diabetic foot syndrome (DFS) is extremely difficult. We used the artificial neuronal network (ANN) to identify the most significant variables which affect DFS healing process. We also aimed at providing data for designing a digital application which would help practitioners to predict the course of DFS.

Methods: We enrolled 213 DFS patients and examined them using a variety of diagnostic tests. The patients were followed for three months. In the initial model, we assessed 35 clinical and biochemical variables. Subsequently, with the help of traditional statistics we reduced their number to twelve, and after conducting the sensitivity analysis, we found out that the final number of significant variables is as low as six.

Results: The most significant variables in predicting the outcome of DFS treatment were: probe-to-bone test result, presence of blood flow in Doppler probe, prior amputation within the foot, erythrocyte sedimentation rate, and the area and duration of the ulceration. The area under the ROC curve was 0.87 (Figure). The total accuracy was 85%, sensitivity 94.6%, specificity 66% and F1 score 89%.

Conclusions: ANN can be used in the prediction of the DFS course. The algorithm, which is the source of a digital application, is particularly useful in identifying individuals with diabetic foot ulcerations who fail to be healed in three months.

Disclosure

A.A. Poradzka: Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Urgo Medical. L. Czupryniak: None.
612-P: Randomized Controlled Prospective Study of the Effects of Structured Outpatient Diabetes Program on the Hospital Readmission Rates (RR) in Patients with Diabetes (DM)
Authors: BHALODKAR ARPITA , SONMEZ HALIS , LESSER MARTIN , LEUNG TUNG MING , ZISKOVICH KARINA , INLALL DAMIAN , PORETSKY LEONID , KRYMSKAYA MARINA , MURRAY-BACHMANN RENEE
Published: June 2020

Introduction: DM is associated with a higher risk of readmissions. We examined the effects of a structured diabetes outpatient program on RR.

Methods: Patients hospitalized with a primary or secondary diagnosis of DM were randomized to standard care (control group [C]) or a structured diabetes program (intervention group [I]) upon discharge. The structured program included a visit to the CDE nurse practitioner (NP) who developed individualized plan for every subject. Subsequent visits were with an NP, nutritionist, social worker and endocrinologist as needed. RR data were generated from electronic medical records and included emergency department (ED) as well as hospital admissions. RR were calculated by dividing the number of readmissions by the number of initial (index) admissions and expressed as %.

Results: 192 subjects were recruited (95 into [C] and 97 into [I]). The mean age was 56±13 yrs [C] and 60±12 yrs [I]. The [C] had 56 (29%) males and 39 (20%) females; [I] had 60 (31%) males and 37 (19%) females. 66 (35%) subjects were African American, 2 (1%) American Indian, 1 (0.5%) Hawaiian, 57 (30%) Caucasian, 11 (5%) Asian, 12 (6%) identified as more than one race, 43 (22%) of unknown race. There were no statistically significant differences between the groups in these characteristics. The 30-day RR: overall (ED and Hospital): 19% [C] and 7% [I], p=0.01; Hospital: 9% [C] and 4% [I], p=0.14; ED: 17% [C] and 4% [I], p=0.003. The 365-day RR: overall 38% [C] and 14% [I], p=0.0002; Hospital: 33% [C] and 8% [I], p<0.001; ED: 34% [C] and 11% [I], p=0.0002.

Conclusion: A structured outpatient diabetes program reduced RR in DM patients when compared with standard care. 30 day RR were reduced primarily due to a reduction in the ED visits, whereas 365 day RR were reduced due the reduction in both ED visits and hospital admissions. Larger multicenter studies are needed to confirm these data.

Disclosure

A. Bhalodkar: None. H. Sonmez: None. M. Lesser: None. T. Leung: None. K. Ziskovich: None. D. Inlall: None. L. Poretsky: None. M. Krymskaya: None. R. Murray-Bachmann: None.
630-P: Targeting Workload Experienced by Diabetes Camp Medical Staff: A Novel Training Curriculum
Authors: ATWOOD ERIN S. , SHEANON NICOLE M. , AMANAT SHEILA , KHOURY JANE C. , KLEIN MELISSA
Published: June 2020

More than 5700 children with diabetes attend American Diabetes Association (ADA) camps each year. Training volunteer medical staff has become more challenging given the rapid advances in diabetes technology. Through a prospective, multi-site pilot study at 4 ADA camps, we assessed the efficacy of an educational bundle of online interactive cases with in-situ simulation in preparing medical volunteers for management of type 1 diabetes (T1D). We hypothesized that our curriculum would reduce the workload necessary to manage children with T1D as measured by the NASA-Task load index (TLX), a validated workload assessment tool comprised of 6 self-rated scales; mental, physical, and temporal demand, performance, effort, and frustration. No statistical difference in change in workload was observed between the intervention and control groups (Table 1). However, both groups were small and had different experiences prior to camp. The reduction in temporal demand reported by the intervention group by the end of camp may signal an impact among medical providers. Future interventions, with larger, more balanced groups, could evaluate timing of TLX change and the effect on medical staff’s camp experience and patient care.

Disclosure

E.S. Atwood: Research Support; Self; American Diabetes Association. N.M. Sheanon: Research Support; Self; American Diabetes Association. S. Amanat: None. J.C. Khoury: None. M. Klein: None.
648-P: Do Social Determinants of Health (SDoH) Influence Participant Outcomes of Those Enrolled in the Diabetes Prevention Program, Montana 2015-2018?
Authors: CARPENEDO DOROTA , TYSK SONJA , HOUSE MELISSA , FERNANDES JESSIE , BUTCHER MARCI K. , HARWELL TODD S. , HELGERSON STEVEN D. , GOHDES DOROTHY M.
Published: June 2020

Research on health disparities among participants in the Diabetes Prevention Program (DPP) is limited. This study examined the outcomes of the DPP participants in Montana based on their Social Determinants of Health (SDoH) risk score. Participants in Montana’s DPP were assigned 1 point for each of the SDoH variables; ≤ High School, unemployment, annual household income below Federal Poverty Level, no health insurance, or lived in rural area. From 2015 through 2018, 2,900 MT adults enrolled in the DPP; 39% had a total SDoH risk score of ≥1 (Table). All risk groups lost weight, although logistic regression models found that as the SDoH risk score increased, the odds of achieving 5% weight loss decreased [AOR 1.61, 95% 1.24-2.09], compared to enrollees who scored 0. Characteristics independently associated with not meeting the 5% weight loss included age 18-44 years [AOR 1.58, 95% 1.26-1.99], BMI (kg/m2) 35+ [AOR 1.38, 95% 1.12-1.69], and female [AOR 1.31, 95% 1.08-1.60]. To effectively address health disparities and assist participants in meeting the 5% weight loss, the DPP lifestyle coaches (LSCs) and health care providers can use the SDoH risk score to identify participants who can benefit from accessing community-based programs. Additionally, LSCs can eliminate barriers by offering childcare, transportation or other incentives to better participation.

Disclosure

D. Carpenedo: None. S. Tysk: None. M. House: None. J. Fernandes: None. M.K. Butcher: None. T.S. Harwell: None. S.D. Helgerson: None. D.M. Gohdes: None.
655-P: Improved Outcomes with Diabetes Devices Using Lower-Literacy Teaching Guides in a Center for Underserved Individuals with Type 1 Diabetes
Authors: PETERS ANNE L. , WALKER MARTHA A. , RUELAS VALERIE F.
Published: June 2020

Healthcare disparities exist between those in more or less affluent communities. This is particularly true for diabetes devices, where intensive training and follow-up is needed. Materials are generally written at an 11th grade reading level. Further, illustrations generally show low ethnic diversity. To reduce this educational gap, we created lower literacy, English and Spanish, multicultural guides for insulin pen and pump use. Focus groups provided input, nonbranded illustrations were created, and the text was edited by the “Clear Language Group.”

Methods: The guides were implemented in our clinic for underserved, largely Hispanic, individuals in East Los Angeles. 47 adults with T1D were included. Subjects were given the low literacy guides and participated in guide driven individual and group education. Measures administered at baseline and 12 months were assessed for normality and independent sample t-tests. A 2-sided alpha of 0.05 was used.

Results: Initial A1C was 9.2 +/- 1.97 (SD) with no change over the study course (12-month A1C = 9.3 +/- 1.92). However, patients showed an improved overall self-report of health (p = 0.012), improvement in diabetes knowledge (Michigan Diabetes Knowledge Test, p=.004), a reduction in symptoms of depression (PHQ8, p=.042), and diabetes distress (Diabetes Distress Scale, T1D Redeem, p = 0.0123). Though no change in rates of hypoglycemia, a reduction in fear of hypoglycemia (Hypoglycemia Fear Scale, Fear sub-scale, P=0.025) was significant. Additionally, there was a reduction in rates of DKA (0.0108). Time in range was minimal, based on blinded CGM, at baseline (22.4%) and did not change at 12 months (24.0%). CGM data was only available on 25 patients due to patient reluctance to wear the device.

Conclusions: Appropriately targeted teaching guides can be used to improve a variety of outcomes in people with T1D, including rates of DKA. However, more work is needed to make a significant impact on glycemic control.

Disclosure

A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. M.A. Walker: None. V.F. Ruelas: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
659-P: Effect of Coaching en Diabetes (CoeD) Program on Glycemic Control in Steel Workers with Type 2 Diabetes
Authors: ROMERO-IBARGUENGOITIA MARIA ELENA , CANTU SANTOS OSCAR M. , GONZALEZ DALIA GUTIERREZ , FACIO ROSALINDA GONZALEZ , GONZALEZ-CANTU ARNULFO
Published: June 2020

Patients with type 2 diabetes (T2D) could improve its glucose control with a multidisciplinary cultural management. Coaching en Diabetes (CoeD) is a multicomponent program for steel workers and their direct families with T2D when their A1C is >9% as an effort to increase attachment to medical treatment. The program focusses on the empowerment and glucose treatment sensibilization through a group medical visit, improvement of self-management and medical treatment. CoeD is performed by a multidisciplinary team (internist, nutritionist, diabetes educator, social worker, etc.). The aim of this study is to evaluate the effect of this program in glycemic control through 2 years of follow-up. This is a retrospective and longitudinal study of patients with uncontrolled T2D at Clinica Nova from Monterrey, Mexico. This study was conducted from May 2017 to 2019. We used descriptive statistics and ANOVA of repeated measures when it was appropriate. We included a total of 153 [115 (75.2%) males], with a mean (SD) age of 62.9 (11.2) years. The duration of T2D was 9.7 (6.6) years. During the follow-up 26 patients (17%) left the program, 2 of them died in relation to cardiovascular disease. All patients maintained a controlled blood pressure. We found a reduction of A1C of 1.5% [Mean (SD) 9.8% (1.5) to 8.3% (1.6), p=0.032) and fasting glucose of 41.8 mg/dl [Mean (SD) 180mg/dl (67) to 138.2mg/dl (55), p=0.021). These reductions were maintained through the 24 months of follow-up. The CoeD program was successful in reducing and sustaining A1C and pre-prandial glucose reduction in this group of patients.

Disclosure

M. Romero-Ibarguengoitia: None. O.M. Cantu Santos: None. D. Gutierrez Gonzalez: None. R. Gonzalez Facio: None. A. Gonzalez-Cantu: None.
66-LB: Combined Immunotherapy with T Regulatory Cells and Anti-CD20 Antibody Prolongs Survival of Pancreatic Islets in Type 1 Diabetes
Authors: ZIELINSKI MACIEJ , ZALINSKA MAGDALENA , IWASZKIEWICZ-GRZES DOROTA , GLIWINSKI MATEUSZ , HENNIG MATYLDA , JAZWINSKA-CURYLLO ANNA , KAMINSKA HALLA , SAKOWSKA JUSTYNA , OWCZUK RADOSLAW , MLYNARSKI WOJCIECH , JAROSZ-CHOBOT PRZEMYSLAWA , BOSSOWSKI ARTUR , SZADKOWSKA AGNIESZKA , SIEBERT JANUSZ , MYSLIWIEC MALGORZATA , MAREK-TRZONKOWSKA NATALIA M. , TRZONKOWSKI PIOTR
Published: June 2020

Background: Immunotherapy using T regulatory cells (Tregs, Tr) prolongs remission in type 1 diabetes (T1DM) but the effect fades with the time. Here, we report phase II trial in which Tregs therapy was combined with anti-CD20 antibody (TrCD20) to make the effect more sustained.

Methods: Thirty-six children with newly diagnosed T1DM were randomized 1:1:1 into the following groups: Tr, TrCD20 and control. The treatment in Tr group consisted of autologous expanded CD3+CD4+CD25highCD127- Tregs in the two doses (30x106 of Tregs/kg b.w. each), three months apart. TrCD20 group received additionally 4 doses of rituximab (375 mg/m2, each) between the first and second dose of Tregs. Control group was left without the treatment and all patients were followed for 2 years.

Results: The best results were found in TrCD20 group, who was characterized by stable serum levels of both fasting C-peptide and stimulated C-peptide in glucagon and MMT tests throughout the entire trial (for fasting C-peptide only 20% decrease at +24months when compared to baseline). Tr group was characterized by stable levels of fasting and stimulated C-peptide up to +12months and then it dropped gradually until the end of the trial. As compared to control group, there was a better glycemic control measured as HbA1c and mean fasting glucose in both interventional groups throughout the whole follow up. TrCD20 group was in partial remission defined as insulin dose below 0.5IU/kg up to +21 months. The longest insulin independent follow up lasted 18months. The end of the remission in Tr group was noted at +18month and in controls at +12months. At the +24months daily insulin requirement and HbA1c levels were significantly lower in TrCD20 as compared to control group.

Conclusions: The combined immunotherapy with Tregs and anti-CD20 antibody prolonged the most significantly survival of pancreatic islets in T1DM children. Trial registration: EudraCT: 2014-004319-35.

Disclosure

M. Zielinski: None. M. Zalinska: None. D. Iwaszkiewicz-Grzes: None. M. Gliwinski: None. M. Hennig: None. A. Jazwinska-Curyllo: None. H. Kaminska: None. J. Sakowska: Employee; Self; Poltreg S.A. R. Owczuk: None. W. Mlynarski: None. P. Jarosz-Chobot: None. A. Bossowski: None. A. Szadkowska: None. J. Siebert: None. M. Mysliwiec: Stock/Shareholder; Self; POLTREG SA. N.M. Marek-Trzonkowska: Stock/Shareholder; Self; Poltreg SA. P. Trzonkowski: Board Member; Self; Poltreg S.A. Stock/Shareholder; Self; Poltreg S.A.

Funding

National Centre for Research and Development in Poland (STRATEGMED1/233368/1/NCBR/2014)