bluuebunny/crossref_metadata_2025 huggingface dataset:
389-P: Ability for Detecting or Predicting Hypoglycemia with the Aid of Machine Learning Techniques: A Meta-analysis
Authors: KODAMA SATORU , YAMADA MAYUKO H. , YAGUCHI YUTA , KITAZAWA MASARU , KANEKO MASANORI , MATSUBAYASHI YASUHIRO , FUJIHARA KAZUYA , IWANAGA MIDORI , KATO KIMINORI , SONE HIROHITO
Published: June 2020

Hypoglycemia is a major barrier to maintaining optimal glycemic control. Machine learning (ML) approaches have been applied to improve the identification of unrecognized hypoglycemia. This meta-analysis assessed current detective or predictive ability for hypoglycemia using ML techniques. Electronic literature searches were conducted using MEDLINE and EMBASE for detecting real-time hypoglycemia or predicting hypoglycemia subsequent to several features, where an index test is a model constructed by ML algorithms and the reference standard is a blood test to confirm the occurrence of hypoglycemia. Included studies were restricted to sample-based studies that examined both the ability to discriminate non-hypoglycemia events from hypoglycemia events and the ability to discriminate hypoglycemia events from non-hypoglycemia events. The 2x2 contingency data (i.e., true-positive, false-positive, false-negative, and true-negative) were pooled with a hierarchical summary receiver operating characteristic model. Pooled sensitivity/specificity (95% confidence interval (CI)) of 6 eligible studies for predicting hypoglycemia and 5 eligible studies for detecting hypoglycemia were 0.78 (0.70-0.85)/0.81 (0.69-0.89) and 0.78 (0.72-0.83)/0.84 (0.63-0.94), respectively. Consequently, the positive likelihood ratio (PLR) calculated as [sensitivity/(1-specificity)] and the negative likelihood ratio (NLR) calculated as [(1-sensitivity)/specificity] with 95% CI were 4.03 (2.26-7.18)/0.27 (0.17-0.42) and 4.90 (1.92-12.51)/0.27 (0.21-0.33), respectively. Considering that PLR>5 moderately increases the probability of a disease given a positive test and NLR<0.2 moderately decreases the probability of a disease given a negative test, it is concluded that current models have not yet attained satisfactory performance and that the algorithm may need further development before being implemented.

Disclosure

S. Kodama: None. M.H. Yamada: None. Y. Yaguchi: None. M. Kitazawa: None. M. Kaneko: None. Y. Matsubayashi: None. K. Fujihara: None. M. Iwanaga: None. K. Kato: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.
396-P: Investigating the Risk of Severe Hypoglycemia in Elderly Patients with Type 2 Diabetes Mellitus
Authors: HORII TAKESHI , ATSUDA KOICHIRO
Published: June 2020

In Japan, The prevalence of type 2 diabetes mellitus (T2DM) is increasing, especially in the elderly population. Many of these patients have co-morbidities like renal insufficiency and personalized blood sugar goals, increasing the risk of hypoglycemia. This study was conducted to examine the associations of patients characteristics such as HbA1c level, BMI and use of glucose level-lowering medication with hypoglycemia-related hospitalizations.

This study was cross sectional study conducted over 6 years January 2014 and March 2019. We recruited 9,798 patients with elderly patients over 65 years with T2DM. To assess the odds ratio (OR) of hypoglycemia-related hospitalizations, we constructed a logistic regression analysis, having adjusting for age, gender, BMI, eGFR, baseline HbA1c levels, use of hypoglycemic agents.

Hypoglycemia was documented in 124 (1.27%) patients. In multivariate logistic regression analysis, age≧75years and gender were not significantly. DPP-4I (OR: 0.52, 95%CI: 0.28-0.96) showed lower odds ratio. BMI≦25kg/m2 (OR: 2.94, 95%CI: 1.26-6.86), baseline HbA1c<6.0% (OR: 4.43, 95%CI: 2.25-8.73), eGFR 15-≦30 mL/min(OR: 2.54, 95%CI: 1.05-6.10), <15mL/min(OR: 3.01, 95%CI: 1.26-7.16), Insulin (OR: 2.05, 95%CI: 1.22-3.43) showed higher odds ratio.

In this study of elderly patients with T2DM, the risk of hospitalization for hypoglycemia appeared to be highest among patients with too low Hba1c and BMI, decreased renal function, and sulfonylurea and/or insulin use. On the other hand, DPP-4I have been shown to reduce the risk of hospitalization for hypoglycemia. By leveraging the results of this study, at-risk elderly patients can benefit from individualized treatment plans to reduce the risk of hypoglycemia.

Disclosure

T. Horii: None. K. Atsuda: None.
399-P: Nurse-Driven Intervention Using Real-Time Data to Improve Hypoglycemia Rates in a Respiratory Care Unit
Authors: HASSE ANN MARIE , SCHULMAN RIFKA , CALDER TORI
Published: June 2020

Background: Hypoglycemia is a known cause of morbidity and mortality in the hospital setting. Nursing initiated interventions to reduce hypoglycemia rates have rarely been reported.

Methods: At our institution, hypoglycemia rate is defined as the percentage of patients with diabetes mellitus (DM) with one or more blood glucose (BG) < 70mg/dl after 24 hours of admission. Nursing units are given monthly hypoglycemia rates, retrospectively. An electronic hypoglycemia tracker tool was developed for hypoglycemia monitoring. This tool prompted nursing staff on the Respiratory Care Unit (RCU) to assess for causes of hypoglycemia. This study was a unit based quality improvement project.

Results: RCU’s baseline monthly hypoglycemia rates before intervention were: 23%, 38%, and 25% in January-March 2019, respectively. Hypoglycemia tracker results after 1 month of use demonstrated that > 50% of hypoglycemia occurrences were preceded by BG < 100mg/dl before becoming overtly hypoglycemic. Staff nurses accessed real-time data using the inpatient diabetes dashboard, beginning in April 2018, to assess BG trends on RCU patients currently admitted. Patients deemed at risk for hypoglycemia had the provider notified to intervene with reduced insulin dosage or another intervention if appropriate. Three months after intervention, monthly hypoglycemia rates decreased to 0%, 4% and 7% in April- June 2019, respectively. The RCU has been able to sustain improvement with an average hypoglycemia rate April-December 2019 of 9%.

Conclusion: Causes of hypoglycemia in the hospital setting need to be assessed in order to determine successful prevention strategies. Tools, like hypoglycemia tracker tool, has helped units assess the causes of hypoglycemia so that some events can be prevented. Traditionally providers are tasked with managing DM in the hospital. This quality improvement project showed that nurses can have an impact on preventing hypoglycemia.

Disclosure

A. Hasse: None. R. Schulman: None. T. Calder: None.
40-LB: The Effect of Continuous Diffusion of Oxygen (CDO) Treatment on Cytokines and Healing in Patients with Diabetic Foot Ulcers
Authors: LAVERY LAWRENCE A. , KILLEEN AMANDA L. , FONTAINE JAVIER LA , AKGUL YUCEL , CRISOLOGO PETER
Published: June 2020

Objective: To evaluate the effect of topical oxygen therapy on cytokines and healing in patients with diabetic foot ulcers.

Methods: This prospective cohort study evaluated 23 patients with diabetic foot ulcers that received Continuous Diffusion of Oxygen treatment over four visits. Wound size, hyperspectral imaging, transcutaneous oxygen measurements, cytokines (CXCL8, PDGF, IGF-1β, TGF-β, IL6, VEGF, and TNF-α), and bacterial cultures were obtained weekly. We used analysis of variance to test for differences in continuous variables. For this pilot study we used an α = 0.10.

Results: The results of this study show there is no significant difference between transcutaneous oxygen on plantar and dorsal foot (53.91 ± 13.97) and (57.81 ± 13.59), oxygenated or deoxygenated hemoglobin (Hgb) (64.50 ± 33.94) and (61.86 ± 23.80), or quantitative cultures at the time points. 60% of people had percent wound area reduction There is a significant difference between the levels of TGF-β and TNF-α between visits 1 and 2, p values 0.006 and 0.01 respectively. For VEGF p=0.00508 and IL6 p=0.11. The results were analyzed by patients with percent wound area reduction >50% (healers N=12, 52%) and non-healers (N=11, 48%). The median concentrations of cytokines between healers and non-healers for the four visits are shown in Figure 1.

Disclosure

L.A. Lavery: Advisory Panel; Self; Acelity, Bayer AG. Consultant; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Cardinal Health, EO2 Concepts, Integra LifeSciences, MedImmune, Smith & Nephew. A.L. Killeen: None. J. La Fontaine: None. Y. Akgul: None. P. Crisologo: None.

Funding

EO2 Concepts (19069)
405-P: Relationship between NAFLD and Cardiac Complications and Function in T2DM
Authors: LAVRYNENKO OLGA , ZEMLIANITSYNA OLHA , DUNAEVA INNA , KRAVCHUN NONNA , SINAIKO VADYM , DEFRONZO RALPH A.
Published: June 2020

NAFLD is common in T2DM patients and has been proposed to be part of the cardiometabolic syndrome.

Aim: To determine the relationship between hepatic fibrosis and cardiovascular abnormalities in T2DM.

Subjects: 72 T2DM patients with NAFLD and 38 T2DM without NAFLD were studied. Based upon liver elastography and Bonacini and Metavir scores T2DM patients with NAFLD were divided into 3 groups: (I) NAFLD with hepatic fibrosis ≥F2 (n=29); (II) NAFL without fibrosis/inflammation (n=11); (III) NASH (n=32). All subjects had cardiac echo to quantitate ventricular volumes, ejection fraction, and diastolic function.

Results: Incidence of cardiovascular complications was higher in patients with hepatic fibrosis: prevalence of arterial hypertension was 40% in T2DM without NAFLD vs. 44 % in NAFL, 69 % in NASH (p<0.01) and 70 % in hepatic fibrosis (p<0.001). Coronary heart disease was present in 20% of T2DM patients without NAFLD, 37% with NAFL, 36 % with NASH and 53 % with hepatic fibrosis (p<0.001). No patient with T2DM without NAFLD had non-fatal myocardial infarction; MI was present in 3.7% of patients with NAFL, 1.7 % with NASH and 15 % with hepatic fibrosis. 3.2% of patients with hepatic fibrosis had stroke; no other patient had stroke. Ejection fraction was decreased (p<0.05) in patients with NASH (57 ±3%) and hepatic fibrosis (54 ±2%) vs. NAFL patients (66 ±2%) and T2DM without NAFLD (63 ±1%). End-diastolic volume was increased in patients with NAFL (189 ±6 ml) and NASH (125±8 ml) vs. hepatic fibrosis (106±3ml) and T2DM patients without NAFLD (110±6 ml). End-systolic volume was increased in patients with NAFL (58±5 ml), NASH (55±3 ml) and hepatic fibrosis (48±4 ml) vs. T2DM without NAFLD (42±4 ml).

Conclusion: Liver fibrosis in T2DM is associated with impaired cardiac function and increased cardiovascular complications. The results demonstrate that hepatic inflammation and fibrosis in T2DM patients with NAFLD is an important risk factor for cardiovascular disease and is associated with cardiac dysfunction.

Disclosure

O. Lavrynenko: None. O. Zemlianitsyna: None. I. Dunaeva: None. N. Kravchun: None. V. Sinaiko: None. R.A. DeFronzo: None.
41-OR: Single Cell RNA-Sequencing Reveals the Developmental Heterogeneity of Brown Adipocytes
Authors: SHAMSI FARNAZ , PIPER MARY , HO LI-LUN , HUANG TIAN LIAN , TSENG YU-HUA
Published: June 2020

Brown adipose tissue (BAT) is the major thermogenic organ, which promotes energy expenditure through a process called adaptive thermogenesis. Central to the inherent thermogenic activity of brown adipocytes is uncoupling protein 1(UCP1). Other than mature adipocytes, several other cell types form the adipose niche and play important roles in BAT function and remodeling. Prolonged cold exposure increases BAT mass and activity through de novo recruitment of brown adipocytes as well as coordinated expansion of other cells within the adipose niche to enable maximal thermogenic activity. However, the source of cold-induced brown adipocytes and the molecular mechanism regulating BAT expansion is not known. To determine the cellular composition of BAT and its remodeling in response to ambient temperature, we performed single-cell RNA-sequencing (scRNA-seq) of the stromal vascular fraction of BAT from mice housed at different temperatures. The unsupervised clustering identified 19 major cell types, including several sub-populations of adipose progenitors, endothelial cells, immune cells, vascular smooth muscles, and Schwann cells. The transcriptional profile of each cell type in mice housed at different temperatures revealed the dynamic remodeling of brown adipocyte niche in response to environmental challenges. Among them, we identified a novel population of brown adipose progenitors derived from BAT endothelium. These endothelial-derived adipose progenitors have a distinct gene expression profile, which distinguishes them from the previously known Pdgfra-expressing adipose progenitors. Using an inducible genetic reporter, we validated the induction of UCP1 and other thermogenic gene program in the endothelial-derived adipose progenitors upon cold exposure.

In summary, scRNA-seq of BAT provides a high-resolution map of brown adipose niche and suggests the critical contribution of each cell type to BAT functions, homeostasis, and turn-over.

Disclosure

F. Shamsi: None. M. Piper: None. L. Ho: None. T. Huang: None. Y. Tseng: Consultant; Self; Boehringer Ingelheim International GmbH.

Funding

American Diabetes Association (1-18-PDF-169 to F.S.); National Institutes of Health (R01DK077097, R01DK102898, P30DK036836); Harvard Stem Cell Institute
410-P: Effects of Palmitate and Oleate on Apoptosis, Autophagy, Stress, Kinase Phosphorylation, and Enzymes of Fatty Acid Oxidation in Human Cardiac Progenitor Cells from Control and Diabetic Subjects
Authors: LAVIOLA LUIGI , SCHIPANI ROSSELLA , DORIA ROSSELLA , CACCIOPPOLI CRISTINA , LEONARDINI ANNA , NATALICCHIO ANNALISA , PERRINI SEBASTIO , CIGNARELLI ANGELO , GIORGINO FRANCESCO
Published: June 2020

Elevated circulating levels of palmitate are associated with high cardiovascular risk in diabetes. In contrast, oleate prevents palmitate-induced cytotoxic stress in multiple cell types. The viability of cardiac progenitor cells (CPC) is essential for tissue renewal in the heart. In this study, the ability of palmitate and oleate to induce apoptosis, autophagy and stress kinase phosphorylation, as well as the effects on enzymes involved in fatty acid oxidation, were investigated in human CPC isolated from control subjects or type 2 diabetic patients. Palmitate, but not oleate, induced apoptosis in control and diabetic CPC, as assessed by caspase-3 cleavage and ELISA assay (p<0.05). Exposure of control and diabetic CPC to 0.25 mM palmitate for 16 h also resulted in increased autophagy, evidenced by light chain 3-II immunoblotting (p<0.05). In contrast, oleate did not induce autophagy. Palmitate, but not oleate, also induced p38 MAPK and c-Jun phosphorylation (p<0.05), in control and diabetic CPC. Importantly, the palmitate effects on apoptosis and autophagy, as well as stress kinase activation, were prevented in control and diabetic CPC co-treated with 0.1 mM oleate for 16 h (p<0.05). However, palmitate, alone or with oleate, increased the mRNA levels of carnitine palmitoyltransferase 1B (CPT1B) (p<0.05), one of the enzymes of mitochondrial fatty acid oxidation, in control CPC but not in diabetic CPC.

In conclusion, oleate prevents palmitate-induced apoptosis, autophagy and p38 MAPK and JNK signaling in CPC from control subjects and diabetic patients. Since palmitate increases CPT1B expression only in control CPC, a selective impairment in metabolic signaling appears to occur in diabetic CPC. Hence, oleate supplementation might preserve the viability of cardiac progenitors from the lipotoxic damage in both control and diabetic subjects.

Disclosure

L. Laviola: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Medtronic. R. Schipani: None. R. Doria: None. C. Caccioppoli: None. A. Leonardini: None. A. Natalicchio: Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. S. Perrini: None. A. Cignarelli: None. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd.
412-P: Lipoprotein(a) and Vascular Risk in Patients with Established Cardiovascular Disease
Authors: SAELY CHRISTOPH H. , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , PURIN DANIELA , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2020

Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor especially in young individuals. However, data on the vascular risk conferred by Lp(a) in patients with established cardiovascular disease (CVD) are controversial. In particular, the power of Lp(a) as a predictor of cardiovascular events in CVD patients with type 2 diabetes (T2DM) is unclear and is addressed in the present study. Lp(a) was measured in a cohort of 1543 patients with established CVD, 1246 patients with angiographically proven CAD and 297 patients with sonographically proven PAD. Vascular events were recorded over a mean follow-up of 9.6±4.6 years. At baseline, 517 patients had T2DM and 1026 did not have diabetes. During follow-up, 49.8% of our patients suffered vascular events. Lp(a) proved to be a strong and independent predictor of vascular events in the total study cohort (standardized adjusted HR=1.12 [1.04-1.20]; p=0.002). In subgroup analyses by diabetes status Lp(a) significantly predicted vascular events both in T2DM patients (HR=1.16 [1.02-1.31]; p=0.021) and in nondiabetic patients (HR=1.10 [1.01-1.20]; p=0.021). We conclude that over a mean follow-up of 9.6 years, Lp(a) among CVD patients predicts cardiovascular events both among those with T2DM and among those who do not have diabetes.

Disclosure

C.H. Saely: None. L. Sprenger: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. M. Maechler: None. D. Purin: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
418-P: Chronic Kidney Disease Is a Type 2 Diabetes Risk Equivalent in Patients with Established Coronary Artery Disease
Authors: SAELY CHRISTOPH H. , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , PURIN DANIELA , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2020

Both type 2 diabetes (T2DM) and chronic kidney disease (CKD) confer a high risk of cardiovascular disease (CVD). We aimed at investigating the single and joint effects of T2DM and of CKD on cardiovascular event risk in high-risk patients with established coronary artery disease (CAD). We prospectively investigated 1460 patients with angiographically proven CAD over 10.3±4.8 years. Cardiovascular events occurred more frequently in T2DM patients (n=449) than in nondiabetic subjects (56.2% vs. 44.5%; p<0.001) and in patients with CKD (eGFR <60ml/min/1.73m²; n=264) than in those with an eGFR ≥60ml/min/1.73m² (61.7% vs. 45.1%; p<0.001). When both, T2DM and CKD were considered, 856 subjects had neither T2DM nor CKD, 340 had T2DM but not CKD, 155 did not have diabetes but had CKD, and 109 had both T2DM and CKD. When compared with the cardiovascular event rate among patients with neither T2DM nor CKD (42.5%), cardiovascular risk was significantly higher in patients with T2DM who did not have CKD (51.5%; p=0.002) as well as in nondiabetic patients with CKD (55.2%; p=0.009) and was highest in patients with both, T2DM and CKD (71.0%; p<0.001), in whom the event risk was higher than in those with T2DM but no CKD (p<0.001) or those without T2DM but with CKD (p=0.005); event risk however was did not differ significantly between nondiabetic CKD patients and T2DM patients who did not have CKD (p=0.692). We conclude that CKD is a T2DM risk equivalent in patients with established CAD.

Disclosure

C.H. Saely: None. L. Sprenger: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. M. Maechler: None. D. Purin: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
42-OR: The Impact of GSNOR-Mediated Nitroso-Redox Signaling on Immuno-Metabolic Interaction in the Brown Adipose Tissue
Authors: SEBAG SARA , QIAN QINGWEN , ZHANG ZEYUAN , LI MARK , LIRA VITOR A. , POTTHOFF MATTHEW J. , YANG LING
Published: June 2020

The thermogenic function of brown adipose tissue (BAT) is tightly regulated by cellular redox status, however, the molecular mechanism underlying this regulation is largely unknown. S-nitrosoglutathione reductase (GSNOR, Adh5) is a major denitrosylase that balances intracellular nitroso-redox status. Although GSNOR dysregulation has been implicated in the pathogenesis of many chronic diseases, the pathophysiological role of GSNOR in the BAT is completely unknown. We found cold exposure increased murine BAT GSNOR while diet-induced obesity (DIO) suppressed it, indicating a potential role for GSNOR in metabolic adaptation in the BAT. Mechanistically, we found that the transcription factor heat shock factor 1 (HSF1) occupies the Adh5 promoter activating Adh5 expression, while DIO inhibited the HSF1-GSNOR axis in the BAT. Notably, administration of a HSF1 enhancer to mice with DIO significantly improved glucose intolerance and BAT mitochondrial dysfunciton. Furthermore, GSNOR deletion in the BAT (GSNORBKO) suppressed UCP1-dependent respiration under both thermoneutral and cold acclimation conditions, as well as elevated immune cell infiltration in the BAT. This was in part mediated by increased BAT nitrosative stress and UCP1 S-nitrosylation induced by GSNOR deletion. Moreover, GSNORBKO mice have worsened DIO-induced glucose intolerance and decreased UCP1-mediated oxygen consumption. In contrast, gain-of GSNOR function in the BAT improved DIO-associated glucose intolerance, increased UCP1-dependent oxygen consumption and decreased DIO-induced inflammation. These data provide novel evidence that GSNOR plays a protective role in BAT against metabolic stressors. Ultimately, insights into the mechanisms by which dysregulation of nitroso-redox signaling impairs BAT metabolic homoestasis and drives the pathologies associated with obesity are expected to accelerate the development of novel therapeutic targets for metabolic diseases.

Disclosure

S. Sebag: None. Q. Qian: None. Z. Zhang: None. M. Li: None. V.A. Lira: None. M.J. Potthoff: None. L. Yang: None.

Funding

American Diabetes Association (1-18-IBS-149 to L.Y.)
420-P: Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists: A Systematic Review and Meta-analysis
Authors: ALEXANDER JASON , STAAB ERIN M. , WAN WEN , FRANCO MELISSA , KNITTER ALEXANDRA C. , THOMAS CELESTE C. , PRESS VALERIE G. , ZEYTINOGLU MELTEM , SKANDARI REZA , GUNTER KATHRYN E. , BINDON BRITTANY , JUMANI SANJAY , BOLEN SHARI D. , MARUTHUR NISA M. , HUANG ELBERT , PHILIPSON LOUIS H. , LAITEERAPONG NEDA
Published: June 2020

Background: Several large randomized trials suggest GLP-1RAs may reduce mortality in addition to lowering A1c in patients with T2D. Treatment algorithms from the ADA/EASD now recommend a GLP-1RA be initiated in patients with T2D who either have or are at high risk of atherosclerotic cardiovascular (CV) disease, regardless of A1c level. To better quantify the efficacy and safety of GLP-1RAs, we conducted a systematic review and meta-analysis of all randomized trials of this drug class.

Methods: We searched PubMed and Scopus (inception to June 2019) for randomized trials of at least 52 weeks duration enrolling adults with T2D that compared GLP-1RAs with placebo. Outcomes included microvascular/macrovascular complications, mortality, change in cardiovascular risk factors, and adverse events. Continuous outcomes were calculated with standardized mean differences, and binary outcomes were calculated using odds ratios. Pooled analyses were performed with fixed and random effects models. Heterogeneity was assessed using the I2 statistic.

Results: See Table for results.

Conclusions: Patients with T2D who received GLP-1RAs when compared to placebo had a significantly lower rate of major adverse CV events and A1c. These findings support the current ADA/EASD treatment recommendations. Subsequent cost effectiveness analyses will help further inform healthcare policy decisions.

Disclosure

J. Alexander: None. E.M. Staab: None. W. Wan: None. M. Franco: None. A.C. Knitter: None. C.C. Thomas: None. V.G. Press: Consultant; Self; Humana, Vizient Inc. M. Zeytinoglu: None. R. Skandari: None. K.E. Gunter: None. B. Bindon: None. S. Jumani: None. S.D. Bolen: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. E. Huang: None. L.H. Philipson: None. N. Laiteerapong: None.

Funding

American Diabetes Association (1-18-JDF-037 to N.L.); National Institutes of Health (P30DK092949)
421-P: Efficacy and Safety of Sodium–Glucose Cotransporter-2 Inhibitors: A Systematic Review and Meta-analysis
Authors: ALEXANDER JASON , STAAB ERIN M. , WAN WEN , FRANCO MELISSA , KNITTER ALEXANDRA C. , THOMAS CELESTE C. , PRESS VALERIE G. , ZEYTINOGLU MELTEM , SKANDARI REZA , GUNTER KATHRYN E. , BINDON BRITTANY , JUMANI SANJAY , BOLEN SHARI D. , MARUTHUR NISA M. , HUANG ELBERT , PHILIPSON LOUIS H. , LAITEERAPONG NEDA
Published: June 2020

Background: Several large randomized trials suggest SGLT2Is may reduce mortality in addition to lowering A1c in patients with T2D. Treatment algorithms from the ADA and EASD now recommend a SGLT2I be initiated in patients with T2D who have chronic kidney disease or heart failure, regardless of A1c level. To better quantify the efficacy and safety of SGLT2Is, we conducted a systematic review and meta-analysis of all randomized trials of this drug class.

Methods: We searched PubMed and Scopus (inception to June 2019) for randomized trials of at least 52 weeks duration enrolling adults with T2D that compared SGLT2Is with placebo. Outcomes included microvascular/macrovascular complications, mortality, change in cardiovascular (CV) risk factors, and adverse events. Continuous outcomes were calculated with standardized mean differences, and binary outcomes were calculated using odds ratios. Pooled analyses were performed with fixed and random effects models. Heterogeneity was assessed with the I2 statistic.

Results: See Table for results.

Conclusions: Patients who received SGLT2Is when compared to placebo had significantly lower rates of heart failure and A1c. These findings support the current ADA/EASD treatment recommendations. Subsequent cost effectiveness analyses will help further inform healthcare policy decisions.

Disclosure

J. Alexander: None. E.M. Staab: None. W. Wan: None. M. Franco: None. A.C. Knitter: None. C.C. Thomas: None. V.G. Press: Consultant; Self; Humana, Vizient Inc. M. Zeytinoglu: None. R. Skandari: None. K.E. Gunter: None. B. Bindon: None. S. Jumani: None. S.D. Bolen: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. E. Huang: None. L.H. Philipson: None. N. Laiteerapong: None.

Funding

American Diabetes Association (1-18-JDF-037 to N.L.); National Institutes of Health (P30DK092949)
428-P: Fatty Liver Disease Is Associated with Arterial Stiffness in Type 2 Diabetic Patients
Authors: HIGA MARIKO , HIJIKATA MAI , YAMASHITA KAORU , SUZUKI TAKAYUKI , SAITO MANABU , MICHISHITA MOE , IKEHARA KAYOKO , ICHIJO TAKAMASA
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD), which is currently the most prevalent liver disorder, not only leads to chronic liver disease but is also associated with cardiovascular mortality. Several studies have conclusively established that increased arterial stiffness is an independent risk factor for cardiovascular events and that the brachial-ankle pulse velocity (baPWV) is a useful clinical indicator of arterial stiffness for early evaluation of functional and structural changes in vessel walls. The aim of this study was to assess whether ultrasonographically diagnosed fatty liver disease is associated with arterial stiffness and carotid intima-media thickness (CIMT) in type 2 diabetic patients. The subjects were 294 type 2 diabetic patients (age: 66.4±10.3 years). Patients with and without fatty liver (FL) were categorized into the FL group (n=155), and non-FL group (n=139), respectively. The baPWV was measured as an index of arterial stiffness, and structural changes in vessel walls were assessed using the CIMT obtained with B-mode ultrasonography. BMI, waist circumference, blood pressure, serum LDL-C, triglyceride (TG), and HbA1c levels, as well as the baPWV and CIMT levels were significantly higher in the FL than in the non-FL group. Serum levels of TG, hepatic AST, age, waist circumference and systolic blood pressure showed significant positive correlations with baPWV, respectively. However, no significant association was observed between the CIMT and serum hepatic AST levels. Multiple regression analysis showed that serum hepatic AST and ALT were independently associated with increased baPWV. Our findings suggest that NAFLD is associated with increased arterial stiffness. This is a clinically significant observation because it implicates arterial stiffness in the pathogenesis of NAFLD, suggesting that abdominal obesity and low-grade inflammation might be key etiopathogenetic contributors to both hepatic steatosis and macrovascular disease in type 2 diabetic patients.

Disclosure

M. Higa: None. M. Hijikata: None. K. Yamashita: None. T. Suzuki: None. M. Saito: None. M. Michishita: None. K. Ikehara: None. T. Ichijo: None.
430-P: Macrovascular Complications and the Diabetes Early Readmission Risk Indicator (DERRI) Predict Risk for Hospital Readmission at 90 Days
Authors: PINKHASOVA DIANA , SWAMI JANYA , PATEL NEETI , DONIHI AMY , SIMINERIO LINDA M. , DELISI KRISTIN , HLASNIK DEBORAH S. , RUBIN DANIEL J. , KORYTKOWSKI MARY T.
Published: June 2020

Several risk factors for hospital readmission in patients with diabetes (DM) have been identified. The Diabetes Early Readmission Risk Indicator (DERRITM) is a tool that identifies patients at high risk for readmission within 30 days of hospital discharge, but does not incorporate several DM specific factors such as type of DM and pre-discharge glycemic measures. The purpose of this investigation was to prospectively examine DM specific factors and DERRI scores as predictors of readmission risk at 90 days in participants in the Readmission and Comprehension of Discharge Education in Diabetes (RECODED) study. Among the 126 patients, (age mean (STD) 61(12) yrs, BMI 32.9 (9.6) kg/m2, A1c 8.0 (2.2%), 45% women, 22% Black, 85% type 2 DM), readmission occurred in 54 (42.9%) of patients within 90 days of discharge. Factors identified as predicting risk for hospital readmission included the presence of known macrovascular (CAD, p = 0.039; CHF, p = 0.029; CVA, p = 0.054) but not microvascular complications. DERRI scores were higher in those with a readmission compared to those without (27 ± 12% vs. 20 ± 11%, p = 0.006).No differences were observed for age, BMI, type of diabetes, eGFR, history of DM self-management education, inpatient DM service consultation, education level, employment history, A1c, pre-discharge hypoglycemia, hyperglycemia or glycemic variability, or hospital length of stay among those with and without a readmission.

In summary, these results reinforce the complexity of identifying risk factors for hospital readmission in DM patients. Certain macrovascular complications, which are collectively components of the DERRI, individually demonstrate an association with readmission risk at 90 days, as does DERRI. This is the first demonstration of DM related macrovascular complications and DERRI score as a predictor of readmission beyond 30 days of hospital discharge.

Disclosure

D. Pinkhasova: None. J. Swami: None. N. Patel: None. A. Donihi: None. L.M. Siminerio: Research Support; Self; Becton, Dickinson and Company. K. Delisi: None. D.S. Hlasnik: None. D.J. Rubin: None. M.T. Korytkowski: None.

Funding

National Institutes of Health (UL1TR001857)
458-P: Resveratrol Attenuates Diabetic Cardiomyopathy by Inhibiting Asymmetric Dimethylarginine-Induced PGC-1a Acetylation
Authors: XIONG YAN , FANG WEI-JIN , HE ZHI-MIN
Published: June 2020

The cardiac protection of resveratrol may due to improvement of mitochondrial function through SIRT1 activation and PGC-1α deacetylation. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, is associated with diabetic cardiovascular complications and reported to have cross-talk with lysine acetylation in cells. This study was to determine the role of ADMA in the pathogenesis of diabetic cardiomyopathy, whether resveratrol could revise ADMA-induced pathological changes and elucidate the underlying mechanisms in rat model of type 2 diabetes mellitus (T2DM). Resveratrol was orally administered (50mg/kg/d) to T2DM rats for 16w. Echocardiography was performed to detect cardiac function. Contents of myocardial ATP and mitochondrial DNA were measured to evaluate mitochondrial function and biogenesis. Elevated endogenous ADMA content and its signal disorders were associated with cardiac and mitochondrial dysfunction in the myocardium of T2DM rats compared with control rats. Treatment with resveratrol significantly attenuated endogenous ADMA accumulation and cardiac dysfunction, increased myocardial mitochondrial DNA and ATP contents, as well as upregulated PGC-1α expression in the myocardium of resveratrol-treated diabetic rats compared with untreated diabetic rats. A positive feedback was observed in vitro that elevated ADMA return promoting its synthetic enzyme PRMT1 expression, reducing its metabolic enzymes DDAH2 expression, reproducing myocardial hypertrophy and mitochondrial dysfunction. Resveratrol treatment could reverse these pathological changes. More importantly, ADMA could enhance PGC-1α acetylation and reduced SIRT1 expressions, all of which were antagonized by resveratrol in cardiomyocytes. These results suggest that ADMA-induced PGC-1α hyperacetylation may serve as potential therapeutic targets for resveratrol to improve diabetic cardiomyopathy.

Disclosure

Y. Xiong: None. W. Fang: None. Z. He: None.

Funding

National Natural Science Research Foundation of China (81570751); Natural Science Foundation of Guangdong Province (2016A030311050)
459-P: Liver-Targeted Mitochondrial Uncoupling by CRMP Improves Whole-Body Insulin Sensitivity and Attenuates Atherosclerosis in A LDLR-/- Mouse Model of Metabolic Syndrome
Authors: GOEDEKE LEIGH , ROTLLAN NOEMI , TOUSSAINT KESHIA , NASIRI ALI , ZHANG XINBO , LEE JI EUN , ZHANG XIAN-MAN , FERNÁNDEZ-HERNANDO CARLOS , SHULMAN GERALD I.
Published: June 2020

Progress in preventing cardiovascular disease (CVD) has been stalled by the growing epidemic of type 2 diabetes, which increases the relative risk of developing atherosclerosis four-fold compared to nondiabetic individuals. We recently developed an orally available, liver-targeted controlled release mitochondrial protonophore (CRMP) that promotes oxidation of hepatic triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency and shown that this agent safely reverses dyslipidemia, fatty liver, and insulin resistance in rodents and nonhuman primates. While these studies suggest that CRMP may be a novel therapy for the major components of metabolic syndrome, its therapeutic utility for the treatment of CVD remains unknown. To assess the effect of CRMP on atherogenesis, we performed progression studies in Ldlr-/- mice fed a high-fat cholesterol diet and treated with CRMP (30 mg/kg-day) or vehicle control for 12 weeks. Here, we show that CRMP-treated mice display a 30% reduction in fasting plasma triglycerides (which could be attributed to a 20% decrease in VLDL-production) and a significant improvement in both hepatic and peripheral insulin sensitivity, due to reductions in hepatic and muscle ectopic lipid content. Importantly, CRMP-mediated decreases in hypertriglyceridemia and improvements in whole-body insulin sensitivity were associated with a 30% reduction in aortic root plaque area and neutral lipid accumulation (P<0.05). More detailed analysis of these plaques revealed that CRMP treatment also significantly lowered markers of plaque vulnerability, as evidenced by a 30% reduction in necrotic core area and increase in fibrous cap area (P<0.05).

Conclusion: Taken together, these results support an anti-atherogenic role for CRMP and suggest the therapeutic potential of liver-targeted mitochondrial uncouplers for the treatment of cardiometabolic disorders.

Disclosure

L. Goedeke: None. N. Rotllan: None. K. Toussaint: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. X. Zhang: None. J. Lee: None. X. Zhang: None. C. Fernández-Hernando: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, LLC, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Consultant; Self; Novo Nordisk A/S. Consultant; Spouse/Partner; Novo Nordisk A/S. Other Relationship; Self; Gilead Sciences, Inc., iMetabolic Biopharma Corporation. Other Relationship; Spouse/Partner; iMetabolic Biopharma Corporation. Other Relationship; Self; Maze Therapeutics.

Funding

National Institutes of Health (R01DK119968, R01DK116774, P30DK045735 to G.I.S.), (K99 HL150234 to L.G.)
46-OR: The Transcriptional Coregulator Ldb1 Directly Regulates Brown Adipose Thermogenic Function
Authors: KEPPLE JESSICA , LIU YANPING , KIM TEAYOUN , HABEGGER KIRK M. , YOUNG MARTIN , HUNTER CHAD S.
Published: June 2020

Brown adipose tissue (BAT) is critical for mammalian thermogenesis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling and is thus an attractive therapeutic target for combatting obesity. Exploiting the energy uncoupling capacity of this tissue will require a greater understanding of underlying BAT transcriptional mechanisms. Our prior work using a global deficiency model supported a novel role for the LIM domain-binding protein 1 (Ldb1) transcriptional co-regulator in regulating BAT function. However, direct roles for Ldb1 expressed in brown adipocytes has not been tested. Ldb1 acts as a scaffold to promote the assembly of transcriptional complexes and is important for the development and function of several metabolic tissues. We hypothesized that Ldb1 maintains BAT thermogenic function through direct regulation of thermogenic genes, like Ucp1. Loss of Ldb1 in primary brown adipocytes resulted in reduced expression of BAT-selective genes including Ucp1 and Elovl3 and the inability to induce Ucp1 expression upon Beta-3 adrenergic receptor agonism. This result was replicated using a siLdb1-transfected Ucp1-expressing cell line. To test Ldb1 roles on systemic thermogenesis, we developed a mouse model, termed Ldb1ΔBAT, where Ldb1 was reduced in thermogenic adipocytes using a Ucp1-driven Cre recombinase. Similar to our in vitro observations, Ldb1ΔBAT mice had reduced mRNAs of key BAT genes, including Ucp1 and Cidea. Through indirect calorimetry and a cold challenge, we uncovered significant impairments in energy expenditure and cold intolerance in Ldb1ΔBAT mice. To assess the transcriptional mechanisms underlying Ldb1 impacts on BAT thermogenesis, we conducted chromatin immunoprecipitation and found Ldb1 occupied upstream regulatory domains of Ucp1 in chromatin prepared from a BAT cell line and primary tissue. Overall, this work supports that Ldb1 is required for the thermogenic function of brown adipocytes.

Disclosure

J. Kepple: None. Y. Liu: None. T. Kim: None. K.M. Habegger: Consultant; Self; Glyscend, Inc. Research Support; Self; Daiichi Sankyo, Novo Nordisk Inc. M. Young: None. C.S. Hunter: None.

Funding

National Institutes of Health (R01DK111483, F31DK121414, T32GM109780)
471-P: Transplantation of Apoptosis Resistant Endothelial Progenitor Cells (EPC) May Improve Renal Function in Both Type 1 and 2 Diabetic Kidney Disease (DKD)
Authors: KUNDU NABANITA , ASICO LAUREANO D. , JOSE PEDRO A. , SEN SABYASACHI
Published: June 2020

Introduction: DKD is associated with glomerulosclerosis and poor perfusion. Transplanting apoptosis resistant p53 silenced (p53sh) EPCs may help to increased vascularization and renal perfusion. EPCs are known to improve perfusion and could be more beneficial than mouse mesenchymal stromal cell (mMSC) transplantation.

Method: Hyperglycemia and proteinuria were confirmed at 10 weeks in STZ induced type 1 diabetic C57BL mice and db/db mice for type 2 diabetes mellitus (DM). We transplanted 0.3 million p53sh-EPCs, Null EPCs (control), MSC or saline under each kidney capsule. For type 2 DM model, we also transplanted supernatant of p53sh EPC. Urine was collected weekly for creatinine and protein estimation. Perfusion was measured by renal ultrasound at week 4 post transplantation. Kidneys were harvested for qRT PCR.

Results: In type 1 DM model, reduction of protein/creatinine was observed in p53sh EPC transplantation group compared to null and mMSC (1.8 and 1.6 folds, p=0.03. 0.04 respectively) significantly. KDR expression was increased (1.2 fold, p=0.04) on p53sh EPC transplantation compared to null. We observed increased mean and peak renal blood velocity (1.3 folds, p= 0.01, 1.3 fold p=0.001 respectively) in p53sh EPC transplant group compared to null. In type 2 model, 2 fold reduction of protein concentration was noted in p53sh transplanted group compared to null and mMSC groups. Reduction of plasma TNFa, a marker for systemic inflammation was decreased by 2.7 and 1.6 folds in p53sh EPC group in comparison to null-EPC and mMSC respectively. We also noticed that blood glucose level decreased post treatment in all cell therapy groups including the supernatant group, compared to saline, indicating a possible paracrine systemic effect of the cell and supernatant therapy.

Conclusion: Transplantation of p53sh EPC improves renal perfusion and renal function in both type 1 and type 2 DM and it is more beneficial than transplantation of mMSC.

Disclosure

N. Kundu: None. L.D. Asico: None. P.A. Jose: None. S. Sen: None.
476-P: Predicting the Risk of Chronic Kidney Disease in People with Diabetes (PWD) from Electronic Health Care Records (EHRs): A Validation Study
Authors: HUSCHTO TONY , KÖNIG HELENA , MARRIOTT CLAIRE E. , MILITZ DANIEL , RINGEMANN CHRISTIAN
Published: June 2020

Chronic kidney disease (CKD) is one of the most frequent complications faced by people with diabetes mellitus.

The ability to accurately predict the onset of this disease at an early stage and adjust the individual therapy and lifestyle appropriately has the potential to prevent or at least slow down the progression of the disease significantly.

We have previously published a 3-year CKD risk engine based on longitudinal U.S. EHRs data (Indiana Network for Patient Care and IBM Explorys) from more than 600,000 PwDs and have demonstrated a superior performance compared to previously published risk algorithms developed solely on clinical trial data (AUC = 0.794 vs. AUC = 0.718 for the best benchmark algorithm). Nevertheless, our previous analysis was limited to healthcare data from the U.S. and the risk prediction was only tested for patients at the time point of the initial diabetes diagnosis. To prove that our algorithm has a broader applicability, we have independently validated our risk engine on a dataset of general practitioners from the UK (Clinical Practice Research Datalink) including longitudinal data from more than 140,000 PwDs, thereby showing the transferability of our algorithm into a European context (AUC = 0.763 +/- 0.005 vs. AUC = 0.594 +/- 0.006 for the best benchmark). Moreover, we used this analysis to apply our risk engine at variable time points after the initial diabetes diagnosis within the U.S. and European data and could thereby demonstrate that our algorithm is not limited to the initial time of diagnosis (average AUC = 0.79 irrespective of the time after diagnosis).

This validation analysis further corroborates the external validity of our approach to use Real-World-Data from EHRs in the development of CKD risk prediction algorithms and thereby supports a broader use of those algorithms in standard clinical practice.

Disclosure

T. Huschto: Employee; Self; Roche Diabetes Care. H. König: Employee; Self; Roche Diabetes Care. C.E. Marriott: Employee; Self; Roche Diabetes Care. D. Militz: Employee; Self; Roche Diabetes Care. C. Ringemann: Employee; Self; Roche Diabetes Care.
48-OR: Pancreatic ß Cell SERCA2 Deficiency Leads to Impaired Proinsulin Processing and Reduced ER to Golgi Protein Trafficking
Authors: KONO TATSUYOSHI , IIDA HITOSHI , JARVELA TIMOTHY S. , LEE CHIH-CHUN , TONG XIN , ARVAN PETER , LINDBERG IRIS , EVANS-MOLINA CARMELLA
Published: June 2020

Impaired proinsulin processing is observed in both type 1 and type 2 diabetes. We have previously shown that reductions in endoplasmic reticulum (ER) calcium (Ca2+) in the pancreatic β cell arising from impaired activity of the Sarcoendoplasmic Reticulum Ca2+ ATPase (SERCA) pump are associated with increased proinsulin secretion. However, the mechanisms responsible for reduced proinsulin processing in the context of SERCA2 deficiency remain incompletely understood. To test this, we developed mice with β cell specific SERCA2 deletion (βS2KO mice) and S2KO INS1 cells. βS2KO mice exhibited age-dependent glucose intolerance and reduced glucose-stimulated insulin secretion without evidence of impaired insulin sensitivity. ER Ca2+ levels in islets from βS2KO mice were significantly reduced, while serum proinsulin/insulin (PI/I) ratios and whole pancreas PI/I content were elevated. Immunoblot analysis of βS2KO islets and S2KO INS-1 cells revealed reduced active forms of the proinsulin processing enzymes, PC1/3, PC2 and CPE. Restoration of SERCA2b via adenoviral transduction in S2KO INS1 cells was sufficient to restore PC1/3 and PC2 maturation and enzyme activity. Brefeldin A treatment in INS1 cells recapitulated the impairments in PC1/3 and PC2 maturation observed in S2KO cells, suggesting a disturbance in protein trafficking between the ER and Golgi. Consistent with this, trafficking assays were performed using a vesicular stomatitis virus G (VSVG) protein construct and revealed a significantly slower rate of VSVG movement from the ER to the Golgi in S2KO INS1 cells. Moreover, pancreas sections from βS2KO mice showed increased co-localization of proinsulin and ProPC2 in the early compartments of the secretory pathway. Taken together, these data suggest that loss of SERCA2 activity and ER Ca2+ loss in the pancreatic β cell leads to impaired proinsulin processing via reduced maturation and trafficking of proinsulin processing enzymes.

Disclosure

T. Kono: None. H. Iida: None. T.S. Jarvela: None. C. Lee: None. X. tong: None. P. Arvan: None. I. Lindberg: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb.

Funding

National Institutes of Health (R01DK093954); U.S. Department of Veterans Affairs (2-I01BX001733)