bluuebunny/crossref_metadata_2025_split huggingface dataset:
495-P: Risk Factors for Incident T2DM in Patients with Prediabetes by CKD Status
Authors: HENNESSEY KELLY A. , ALICIC RADICA Z. , DARATHA KENN B. , JONES CAMI , NEUMILLER JOSHUA J. , DURU O. KENRIK , NICHOLAS SUSANNE , MCPHERSON STERLING M. , NORRIS KEITH C. , TUTTLE KATHERINE R. 
Published: June 2020

Longitudinal data are critical to inform prediction of transition to type 2 diabetes mellitus (T2DM) from prediabetes. This study aimed to ascertain T2DM incidence and risk factors, including chronic kidney disease (CKD), in patients with prediabetes. The CURE-CKD registry of electronic health record data includes &gt;2.6 million patients with and at-risk for CKD (T2DM, hypertension, prediabetes).
Adults with prediabetes were identified by established criteria for % A1C, random and fasting glycemia, and administrative codes. T2DM was defined by corresponding established criteria. CKD was defined by estimated glomerular filtration rate &lt;60 mL/min/1.73m2, urine albumin-to-creatinine ratio &gt;30 mg/g based upon 2 or more measurements &gt;90 days apart, and administrative codes. Cox proportional hazards regression was used to predict T2DM.
From 2006 to 2017, there were 678,493 patients with prediabetes and baseline A1C 5.9±0.3% (mean±SD). Incident T2DM occurred in 185,770 (27%) at a mean of 3.6 years. At baseline, 134,240 (20%) had CKD. Adjusted for age, gender, race/ethnicity, and hypertension, hazard ratios for T2DM were greater in patients with CKD (1.44, 95%CI [1.42, 1.47]) and with increases in 1% A1C (4.59 95%CI [4.47, 4.72]).
CKD was common in prediabetes and, along with higher A1C, demonstrated the greatest hazards for incident T2DM. Presence of CKD identifies patients with prediabetes who are high-risk for transition to T2DM.

Disclosure
K.A. Hennessey: None. R.Z. Alicic: None. K.B. Daratha: None. C. Jones: None. J.J. Neumiller: None. O. Duru: None. S. Nicholas: Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Centers for Disease Control and Prevention, George Institute for Global Health, Goldfinch Bio, Inc., National Institutes of Health. S.M. McPherson: None. K.C. Norris: None. K.R. Tuttle: Consultant; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Goldfinch Bio, Novo Nordisk Inc.
497-P: Abnormal ABI in Association with Nephropathy Is a Risk Factor for CAD in Type 2 Diabetic Patients: A Retrospective Real-World Evidence Study in Indian Population
Authors: TREHAN SIDDHANT , CHAWLA RAJEEV , JAGGI SHALINI , S ANUSHRITA , PALUKURI SRIVANI , DEKA SAURAV , MAKKAR BRIJ M. 
Published: June 2020

Objective: To study the association between ankle brachial index (ABI) and microvascular complications in type 2 diabetes (T2DM) patients with coronary arterial disease (CAD).
Methodology: A retrospective study was carried on 3,468 T2DM patients who gave ABI test between 2002 and 2019. ABI status was defined as normal (1.0-1.4) and abnormal (&lt;1.0 and &gt;1.4). The distribution of patients was given in percentages. The logistic regression was used to study ABI status, microvascular complications and CAD risk factors (hypertension, age, BMI, smoking etc) role on CAD, and the resulted odds ratio (OR) was given with 95% CI and p-value.
Results: Patients were classified based on history of CAD, with, G1 (334), and without, G2 (3134). In G1, 69% patients were normal ABI and 31% abnormal. Across G1 and G2, neuropathy was populated with 37% (1279), nephropathy, 8% (293), hypertension, 15% (507) and hypothyroidism, 8% (270). The ABI abnormality was high in nephropathy (G1: 41%; G2: 29%) than neuropathy (G1: 34%; G2: 27%). Age wise, 60 and 70% of patients in neuropathy and nephropathy, respectively, were &gt;60 years and shown increased ABI abnormality with age. The logistic model had revealed that patients with nephropathy, OR-1.8 [1.26-2.58], p-0.001 and abnormal ABI, OR-1.27 [95% CI, 0.99-1.63], p-0.059 were likely to have positive CAD outcome, i.e., both are associated. While neuropathy, OR-0.69, [0.54 - 0.90], and hypertension, OR-0.43 [0.33 - 0.57] were not contributing towards CAD in our study population.
Conclusion: T2DM patients with abnormal ABI were predicted to have 27% of increased odds of CAD outcome and this was increased to 80% in presence of nephropathy. Thus, following the onset of diabetes, albuminuria screening along with ABI measurement are suggested.

Disclosure
S. Trehan: None. R. Chawla: None. S. Jaggi: None. A. S: None. S. Palukuri: None. S. Deka: None. B.M. Makkar: Advisory Panel; Self; Abbott, AstraZeneca, Biocon, Boehringer Ingelheim Pharmaceuticals, Inc., Eris Lifesciences, Novartis AG, Novo Nordisk Inc., Sanofi, USV Private Limited. Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc.
51-OR: Loss of Critical ER Chaperone GRP78 Leads to Beta-Cell Death by a JNK Dependent Mechanism
Authors: SHARMA ROHIT B. , DARKO CHRISTINE O. , GABLASKI BRIAN , LEE AMY S. , ALONSO LAURA C. 
Published: June 2020

Endoplasmic reticulum (ER) health is an important determinant of pancreatic beta cell function or failure. Adaptive ER stress leads to expansion of beta cell number through proliferation, but decompensated ER stress results in beta cell loss and contributes to both T1D and T2D. Therefore, understanding the mechanisms of ER-stress-induced beta cell death could help identify novel strategies for the prevention or treatment of diabetes. Glucose responsive protein GRP78/HSPA5 is a key ER chaperone. Loss of GRP78 causes cell death in many cell types; including, in our own prior work, the beta cell. To study the mechanism by which GRP78 loss leads to beta cell death we devised an ex vivo model of GRP78 knockdown by transducing Grp78-flox mouse islets with adenovirus expressing Cre recombinase. To study human islets, we used adenovirus expressing shRNA against GRP78. Using these tools, we successfully reduced GRP78 RNA and protein in primary mouse and human islet cells. Loss of GRP78 strongly activated the ATF6, IRE1 and PERK pathways of the unfolded protein response (UPR). GRP78 knockdown decreased beta cell number due to increased cell death as measured by Annexin V and TUNEL staining. Probing the mechanisms of cell loss, we found that loss of GRP78 activated multiple death-related pathways, notably autophagy and apoptosis; cell death effectors Chop, caspase 9 and cleaved caspase 3 were increased. Additionally, GRP78 deletion increased stress kinase JNK (c-Jun-N-terminal kinase) which has been implicated in cellular proliferation as well as cell death. Inhibition of JNK kinase using JNK-IN-8 inhibitor during GRP78 loss conditions decreased phosphorylation of JNK and rescued beta cells from cell death as measured with Annexin V and TUNEL. Therefore, we conclude that ER stress related cell death induced by loss of GRP78 (ER stress) involves JNK activation, and that modulation of JNK under certain circumstances may help maintain beta cell mass to protect against diabetes.

Disclosure
R.B. Sharma: None. C.O. Darko: None. B. Gablaski: None. A.S. Lee: None. L.C. Alonso: Consultant; Self; Fairbanks Pharmaceuticals Inc. Research Support; Self; American Diabetes Association.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK113300-02)
523-P: Different Effect on UACR According to Predetermined Treatment Schedule Groups (GLP1RA or SGLT2i) Therapy in T2DM
Authors: GOMEZ JUANA CARRETERO , ENA JAVIER , SEGUI-RIPOLL JOSE MIGUEL , CARRASCO-SÁNCHEZ FRANCISCO JAVIER , AREVALO LORIDO JOSE CARLOS , TEMBRA MANUEL SUAREZ , VARELA JOSE MANUEL , GOMEZ-HUELGAS RICARDO 
Published: June 2020

Aim: To analyze changes on UACR in T2DM patients according to treatment schedule groups (GLP-1RA or SGLT2i).
Methods: Observational, prospective, multicenter study. Patients were stratified according to predetermined treatment schedule groups (successively vs.simultaneously).
Results: 178 patients (58.6% males, age 61.9+/-10.0 years). Table 1 shows baseline findings by groups. Initial UACR was 19.6+/-52.5 mg/g and initial UACR &gt;30 mg/g (n=68) was 95.1+/-222 mg/g. At 26 weeks significant % change in UACR and UACR&gt;30mg/g was found (4.35+/-30** and 48.8+/105.5**), greater when SGLT2i is added (90.5+/-276.5 *) (Table 2).
Discussion: Our results shows that the combination GLP-1ra-SGLT2i reduces UACR, especially if macroalbuminuria is present and is correlated to improvement in either HbA1c, weight and SBP.

Disclosure
J. Carretero Gomez: None. J. Ena: None. J. Segui-Ripoll: None. F. Carrasco-Sánchez: None. J. Arevalo Lorido: None. M. Suarez Tembra: None. J. Varela: None. R. Gomez-Huelgas: None.
53-LB: Health-Related Quality of Life and Its Associated Factors among Persons with Diabetes in Kathmandu, Nepal
Authors: ACHARYA SUJATA , DHAKAL AMRIT 
Published: June 2020

Health- Related Quality of Life (HRQoL) among persons with diabetes is an important public health issue throughout the world. As per the information available, no study has been conducted till date to determine HRQoL using EQ-5D-5L in person with diabetes in Nepal. Therefore, this study was conducted to assess HRQoL in persons with diabetes and to identify factors associated with it. Hospital based cross sectional study was conducted in two diabetes centers of Kathmandu district. Study population included persons already diagnosed with diabetes from diabetes centers. We recruited 225 participants and they were interviewed using the standard Nepali version of the EQ-5D-5L questionnaire and some additional questionnaire based on extensive literature review. Independent t-test was used to find the bivariate association of HRQoL and other factors. Variables with p-value&lt;0.05 in bivariate analysis were fitted into linear regression after fulfilling the assumptions. Ethical approval was obtained from the Institutional Review Board (IRB) of the Institute of Medicine. The study found that HRQoL among persons with diabetes was 0.53. Study found significant association with self-reported complications, age, insulin use, employment, education and duration of diabetes in bivariate analysis. In the multivariate analysis using the linear regression, study found that HRQoL was positively associated with education (β= 0.03), employment (β= 0.11). Similarly, study found that health related quality of life was negatively associated with self-reported complications (β= -0.10), insulin use (β= -0.11) and age (β= -0.09). Fitting the equation in linear regression revealed that 40% of change in HRQoL in persons with diabetes can be predicted by self-reported complications, employment, education, age, and insulin use. Our study findings were similar to other studies conducted in Southeast Asian region. HRQoL was lower compared to studies conducted in most of the developed countries.

Disclosure
S. Acharya: None. A. Dhakal: None.
53-OR: Deletion of YTHDF2 in Beta Cells Results in Glucose Intolerance
Authors: REN DECHENG , SUN JUAN 
Published: June 2020

N6-methyladenosine (m6A) is the most common and abundant mRNA modification. However, the role of m6A in regulating β-cell function is unclear. YTHDF2 is a ’reader’ protein that recognizes m6A-containing mRNAs and targets them for degradation. To address the functional role of YTHDF2 in β-cells, we generated an Ythdf2 β-cell knockout mouse using RIP-Cre transgenic mice. At the 3-month old age, the feeding and fasting glucose of βKO mice were similar to that in control mice (RIP-Cre mice). However, both male and female βKO mice are glucose intolerant after glucose challenge. The AUC was increased by 44.6% in male βKO mice and 71.1% in female mice, respectively (both P&lt;0.01). The response to insulin was similar between βKO and control mice. Interestingly, although the fasting insulin levels were comparable between βKO and control mice, the feeding insulin levels in both male and female βKO mice were increased. The serum insulin levels from βKO mice were significantly lower at 15 min after glucose challenge. In addition, the insulin secretion from βKO islets was less due to decreased insulin protein. Surprisingly, β-cell mass in βKO mice was significantly higher than that in control mice (P&lt;0.05). Both islets number and size were increased in βKO mice. To understand the molecular mechanism, we performed RNA-seq to detect the gene expression in βKO and control islets isolated from male mice. Among 626 altered genes in βKO islets, 421 genes were upregulated and 205 genes were downregulated. The genes response to ER stress were among the top up-regulated genes. The genes related to insulin secretion were downregulated. We applied m6A-seq in MIN6 cells and confirmed that Ire1α was indeed modified by m6A in its last exon and 3’ UTR region. We further confirmed that both mRNA and protein levels of Ire1α and spliced XBP-1 were significantly increased in βKO islets.
In conclusion, YTHDF2 plays an important role in regulating insulin secretion, and YTHDF2 deficiency in β-cells induces glucose intolerance by regulating insulin secretion and ER stress.

Disclosure
D. Ren: None. J. Sun: None.

Funding
The University of Chicago (P30-DK020595)
531-P: Metabolomics Identifies Novel Plasma Metabolomic Signatures Associated with Diabetic Neuropathy in a Cohort with Screen-Tested Type 2 Diabetes: ADDITION-Denmark
Authors: RUMORA AMY E. , ALAKWAA FADHL , ANDERSEN SIGNE T. , JØRGENSEN MARIT E. , CHARLES MORTEN , CALLAGHAN BRIAN C. , JENSEN TROELS S. , FELDMAN EVA L. 
Published: June 2020

Peripheral neuropathy (PN) is a common complication of diabetes that develops in up to 50% of people with diabetes. Obesity and the metabolic syndrome are risk factors for PN in patients with type 2 diabetes (T2D). However, the lipid metabolites associated with PN development are unknown. We compared the metabolomic profile of plasma from T2D patients with and without PN compared to lean control patients to identify metabolic changes that underlie PN associated with T2D. PN was evaluated in a cohort of T2D patients from the Danish portion of the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION). The Toronto criteria was used to assess PN based on symptoms of neuropathy and abnormal nerve conduction studies. To identify metabolomic signatures that associate with PN, plasma samples from 9 lean control, 49 T2D, and 48 T2D patients with PN were submitted to Metabolon® for a global metabolomics analysis. We used least absolute shrinkage and selection operator (LASSO) and Welch’s two-sample t-test to identify metabolites that differed between PN and non-PN subjects. Metabolomics identified plasma lipid metabolites that were dysregulated in T2D including cholesterol, sphingolipids, and acylcarnitines. Cholesterol and three classes of sphingolipid metabolites (dihydrosphingomyelin, glucosylceramide, and sphingomyelin) were significantly lower in plasma from T2D patients irrespective of PN compared to lean controls. Interestingly, long-chain and very long-chain acylcarnitines were also reduced in T2D patients while short-chain acylcarnitines were unchanged. Only a small number of metabolites were uniquely regulated by PN; of these, two very long-chain acylcarnitine species (C26:1 and C24) were significantly diminished in T2D patients with PN compared to those without. These results suggest an association with lipid markers of impaired mitochondrial β-oxidation and PN in T2D.

Disclosure
A.E. Rumora: None. F. Alakwaa: None. S.T. Andersen: None. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. M. Charles: Other Relationship; Self; Novo Nordisk A/S. B.C. Callaghan: None. T.S. Jensen: None. E.L. Feldman: Consultant; Self; Novartis Pharmaceuticals Corporation.

Funding
American Diabetes Association (7-12-BS-045 to E.L.F.); Novo Nordisk Foundation (NNF14OC0011633); National Institutes of Health (1R24082841, 1DP3DK094292); National Institute of Diabetes and Digestive and Kidney Diseases (T32DK101357, F32DK112642, K99DK119366); NeuroNetwork for Emerging Therapies; A. Alfred Taubman Medical Research Institute
532-P: The Longitudinal Determinants of Diabetic Complications in the Pima Indians of Arizona
Authors: REYNOLDS EVAN L. , NELSON ROBERT G. , AKINCI GULCIN , HENN ROSIE , PATTERSON ADAM , FELDMAN EVA L. , CALLAGHAN BRIAN C. 
Published: June 2020

The 5 components of the metabolic syndrome (MetS) increase the likelihood of developing diabetes, heart disease, and stroke, but their association with neuropathy and diabetic kidney disease (DKD) is less understood.
We examined the longitudinal association between the components of the updated National Cholesterol Education Program criteria for MetS, neuropathy and DKD in Pima Indians with type 2 diabetes, after substituting BMI for waist circumference. The primary outcome for neuropathy was the Michigan Neuropathy Screening Instrument index, for cardiovascular autonomic neuropathy (CAN) was the expiration/inspiration ratio, and for DKD was the Glomerular Filtration Rate. At baseline and during annual follow-up exams, participants underwent metabolic phenotyping and outcome measurements.
Linear mixed effects models with a random patient effect were used to evaluate the associations between the number of MetS components and neuropathy, CAN, and DKD outcomes. We also examined mixed models for each outcome with individual MetS components.
Between 11/1/2013 and 7/1/2019, we studied 141 Pima Indian subjects, who were followed an average of 3.2 years. The mixed effects models revealed a significant interaction between the number of MetS components and follow-up time for neuropathy (point estimate (PE): 0.07, CI: 0.02-0.11), indicating that the rate of neuropathy increases as the number of MetS components increases. Additionally, we found that neuropathy (year PE: 0.30, CI: 0.24,0.35) and DKD (PE: -14.2, CI: -16.8,-11.4), worsened over time, but CAN did not. The mixed models with individual MetS components revealed SBP was associated with each complication: neuropathy (PE: 0.23, CI: 0.07,0.39), CAN (PE: -0.02, CI: -0.03,-0.02) and DKD (PE: -10.2, CI: -15.4,-5.1).
Neuropathy progression was the complication most affected by the number of MetS components. Neuropathy and DKD worsened during follow-up, emphasizing how quickly these complications can change within this population.

Disclosure
E.L. Reynolds: None. R.G. Nelson: None. G. Akinci: Advisory Panel; Spouse/Partner; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. R. Henn: None. A. Patterson: None. E.L. Feldman: Consultant; Self; Novartis Pharmaceuticals Corporation. B.C. Callaghan: None.

Funding
National Institutes of Health (R24DK082841, T32NS0007222, R01DK115687); Program for Neurology Research & Discovery; Robert and Katherine Jacobs Environmental Health Initiative; Robert E. Nederlander, Sr. Program for Alzheimer’s Research; Sinai Medical Staff Foundation
54-OR: Nitric Oxide Attenuates Viral Replication in Pancreatic ß-Cells through an Inhibition of Mitochondrial Oxidative Metabolism
Authors: STAFFORD JOSHUA , CORBETT JOHN A. 
Published: June 2020

Viral infection has been identified as an environmental factor that may play a role in initiating the destruction of pancreatic β-cells during the development of autoimmune diabetes. We have identified a pro-inflammatory response activated in pancreatic islets in response to infection with encephalomyocarditis virus (EMCV). In response to the local production of cytokines such as IL-1 by resident islet macrophages, β-cells produce nitric oxide, a free radical with known antiviral activity. Nitric oxide has been characterized both as a potent antiviral molecule and as a mediator of β-cell dysfunction and damage and so we investigated the role of nitric oxide in controlling β-cell viability in the context of EMCV infection. We find that nitric oxide, either supplied exogenously with donor compounds or produced endogenously in response to cytokine treatment, attenuates EMCV replication and protects β-cells against EMCV-mediated death. These protective actions of nitric oxide are restricted to conditions in which nitric oxide is produced at low micromolar levels (consistent with the levels of nitric oxide generated by iNOS) and are associated with the ability of nitric oxide to impair mitochondrial oxidation and decrease ATP levels in β-cells. Treatment with rotenone, an inhibitor of complex I of the electron transport chain, likewise attenuates EMCV replication in β-cells, which are reliant on oxidative metabolism for ATP generation, but not in fibroblasts, which can sustain ATP levels via glycolysis alone. These findings suggest a mechanism of protection restricted to β-cells where nitric oxide production attenuates viral replication by inhibiting oxidative metabolism and depleting cellular stores of ATP, supporting a protective role for nitric oxide in the response of β-cells to viral infection.

Disclosure
J. Stafford: None. J.A. Corbett: None.

Funding
American Heart Association (17PRE3253000); National Institutes of Health (DK052194, AI44458)
545-P: Posttranslation Control Mechanisms (miRNAs) in Type 1 Diabetic Patients with and without Cardiac Autonomic Neuropathy
Authors: TOBOR EWA , POLUS ANNA , GASTOL JOANNA , MATEJKO BARTłOMIEJ , PAWLINSKI LUKASZ , KIEC-WILK BEATA 
Published: June 2020

Introduction: Type 1 diabetes (T1DM) is a chronic disease with multifactor pathogenesis. Large number of studies confirmed that epigenetic, microRNA (miRNA)- mediated, regulation mechanisms of gene expression are associated with both pathogenesis of T1DM and the progression of its complications. Cardiac autonomic neuropathy (CAN), the microvascular complication, is one of the strongest risk factor of cardiac mortality among T1DM patients. Circulating miRNA might be a prediction marker for development and progression of this diabetic complication but studies concerning connection between miRNA and CAN in T1DM patients are still missing.
Materials and methods: The study included 54 T1DM subjects with and without CAN and 27 healthy, age-correlated volunteers, as a control group. The CAN prevalence was assessed using Ewing test. Expression analysis of human miRNAs was performed using the TaqMan Low-Density Arrays (TLDAs) Panel v3.0 (Applied Biosystems). Differentially and significant (p&lt;0.05) expressed miRNA were uploaded into the DIANA-mirPath v.3, for Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis.
Results: Our study revealed a significantly upregulated expression of miR-190b, miR-520d-3p and miR-30a-5p in both CAN and T1DM groups comparing to control. Nevertheless, the miRNAs expression within T1DM group between CAN and T1DM groups did not differ.
Discussion: All of significantly altered miRNA are involved in axon guidance pathway, playing a role in neuron regeneration and, as a result of impaired function, neuropathy. Additional significantly regulated miR-30a-5p downregulates the expression of Beta/NeuroD gene, which role in the pathogenesis of diabetes mellitus is well documented.
Conclusion: Our study, for the first time, showed the potential correlation between epigenetic mechanisms and CAN, stressing that mi-30a-5p might be a new tool for early diagnosis and potentially therapeutic target of T1DM.

Disclosure
E. Tobor: None. A. Polus: None. J. Gastol: None. B. Matejko: Other Relationship; Self; Dexcom, Inc., Roche Diabetes Care. L. Pawlinski: Other Relationship; Self; Boehringer Ingelheim International GmbH. B. Kiec-Wilk: None.

Funding
National Science Centre in Poland (2014/13/B/NZ4/00149)