bluuebunny/crossref_metadata_2025 huggingface dataset:
52-OR: Intrinsically Photosensitive Retinal Ganglion Cell Dysfunction in Diabetic Retinopathy Associates with Impaired Sleep and Circadian Rhythms
Authors: REUTRAKUL SIRIMON , PARK JASON C. , CHAU FELIX , BAYNARD TRACY , PRIYADARSHINI MEDHA , CROWLEY STEPHANIE , MCANANY J. JASON
Published: June 2019

Background: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control the pupillary light reflex (PLR) and synchronize sleep-wake cycles, melatonin secretion, and metabolic processes to the 24-h day. PLR abnormalities in diabetic retinopathy (DR) suggest ipRGC dysfunction. We explored whether ipRGC dysfunction in DR is associated with impaired sleep, circadian rhythms and metabolic functioning.

Methods: Healthy controls (n=6), type 2 diabetes (T2D) without DR (n=8), or T2D with at least moderate DR (n=11) participated. PLR inferred ipRGC function, HbA1c, and nocturnal urinary 6-sulfatoxymelatonin (aMT6s/creatinine ratio) were measured. Sleep was recorded by 7-day actigraphy. Dim light melatonin onset (DLMO) was assessed by sampling saliva in the 7 hours before self-reported bedtime.

Results: Mean age was 54.6±5.4 yr. The relative PLR was significantly smaller in T2D-DR (control vs. T2D-noDR vs. T2D-DR: 0.32(0.10) vs. 0.26 (0.09) vs. 0.13 (0.11), p=0.003). Nocturnal aMT6s [8.3 (3.1) vs. 14.6 (14.3) vs. 1.9 (2.1) ng/mg, p=0.001] was significantly lower in T2D-DR. Sleep was more disturbed in T2D-DR than others as reflected by higher wake time after sleep onset (p=0.024), higher fragmentation index (p=0.007) and lower sleep efficiency (p=0.030). HbA1c was similar between T2D groups. T2D-DR were more likely to have no detectable rise of salivary melatonin in the evening (normal 16% vs. DM-noDR 14% vs. DM-DR 67%, p=0.049). Smaller PLRs correlated with lower aMT6s (r=0.652, p=0.001). Among T2D, lower aMT6s and smaller PLR associated with lower sleep efficiency (p=0.029-0.046) and more fragmented sleep (p=0.028-0.066). There was no relationship between PLR or aMT6s with HbA1c in T2D. PLR was smaller in those without vs. with DMLO [0.11 (0.09) vs. 0.29 (0.09), p<0.001].

Conclusion: T2D with DR had dysregulated melatonin rhythm and disrupted sleep, which significantly correlated with the degree of ipRGC dysfunction.

Disclosure

S. Reutrakul: None. J.C. Park: None. F. Chau: None. T. Baynard: None. M. Priyadarshini: None. S. Crowley: None. J. McAnany: None.

Funding

University of Illinois at Chicago
520-P: Hyperglycemia-Induced Mitochondrial Dysfunction in Diabetic Kidney Disease May Be Mediated by Crabtree Effect in Kidney Proximal Tubule Epithelial Cells
Authors: DARSHI MANJULA , KIM JIWAN JOHN , DREL VIKTOR , MURPHY ANNE N.
Published: June 2019

Background: Recent studies indicate mitochondrial dysfunction is a dominant pathway in diabetic kidney disease (DKD), however underlying mechanisms are unclear. Here we examined if Crabtree effect by glucose is a cause of mitochondrial dysfunction in kidney.

Methods: Lactate was measured by by YSI biochemistry analyzer. TCA cycle metabolites were measured by gas chromatography mass spectroscopy in urine samples of type 1 and type 2 DKD mouse models. Changes in oxygen consumption (OCR) and extracellular acidification i(ECAR) were analyzed on a Seahorse extracellular flux analyzer. Immunohistochemical analysis was performed on FFPE-embedded mouse kidney sections. Western blot analysis was performed on kidney cortical sections and HK2 cells.

Results: Significantly increased urine and plasma lactate along with a decrease in several TCA cycle metabolites were observed in both type 1 and type 2 diabetic mice. Mitochondrial functional analysis in different kidney cells showed a profound respiratory inhibition and stimulation of lactate by glucose in proximal tubules, but not in mesangial cells and podocytes. Pyruvate at above physiological concentration reversed the glucose-induced inhibition of OCR. Western blotting of kidney cortical tissue sections showed a significant increase in phospho PDH in diabetic kidney tissues and in HK2 cells treated with high glucose. In normal conditions, phospho PDH was predominantly on distal tubules, however in diabetic conditions a significant increase in phospho PDH was noted in proximal tubule cells. Dichloroacetate, an inhibitor of PDK completely reversed the glucose induced respiratory inhibition in proximal tubule epithelial cells.

Conclusions: Mitochondrial dysfunction in proximal tubule epithelial cells may potentially be due to high-glucose induced PDH phosphorylation resulting in limited pyruvate oxidation into mitochondria and enhanced lactate production.

Disclosure

M. Darshi: None. J.J. Kim: None. V. Drel: None. A.N. Murphy: Advisory Panel; Self; Cytokinetics Inc. Consultant; Self; Agilent Technologies.

Funding

JDRF; U.S. Department of Veterans Affairs
521-P: Sodium Butyrate Alleviates High-Glucose-Induced Renal Glomerular Endothelial Cells Pyroptosis
Authors: GU JUNLING , HUANG WEI , XU YOUHUA , XU YONG
Published: June 2019

Caspase1-GSDMD canonical pyroptosis pathway is associated with pathogenesis of chronic inflammatory diseases. As the first layer of renal filtration barrier, whether high glucose triggers glomerular endothelial cells (GECs) pyroptosis in the pathogenesis of diabetic nephropathy (DN) is unclear. Previous research showed that the gut microbiota metabolites-butyrate, reversed high glucose induced IL-1β release in mesangial cells. However, the effects of butyrate on pyroptosis in GECs remain indistinct. Therefore, we hypothesized that high glucose may induce GECs pyroptosis and then trigger inflammatory, but sodium butyrate may alleviate it. In this study, human renal glomerular endothelial cells (HRGECs) were exposed to high glucose in vitro, exogenous sodium butyrate was used as an intervention reagent, and then caspase 1 inhibitor Ac-YVAD-CMK pre-treated or silencing GSDMD by siRNA on HRGECs. The expression of Caspase1-GSDMD signaling molecule were observed by confocal microscopy and western blotting. Propidium iodide (PI) staining-positive cells were determined using a flow cytometer. The release of IL-1β was detected and the release of lactate dehydrogenase (LDH) was assayed. Our results showed that high glucose increased the protein level of GSDMD, GSDMD-N and cleaved-caspase-1, and induced the release of IL-1β and LDH, PI positive staining cells also increased synchronously. Sodium butyrate co-treated, pretreatment with caspase-1 inhibitor or GSDMD siRNA alleviated high glucose-induced pyroptosis in HRGECs, respectively. Moreover, sodium butyrate-mediated anti-pyroptosis effect was facilitated by si-GSDMD. Overall, this is the first observation of the potential relationship between sodium butyrate and pyroptosis in the pathogenesis of DN, proved that sodium butyrate could inhibit high glucose-induced Caspase1-GSDMD canonical pyroptosis pathway, which may act as new therapeutic targets of DN.

Disclosure

J. Gu: None. W. Huang: None. Y. Xu: None. Y. Xu: None.
522-P: Long-Term Renal Outcomes in Young Onset Type 2 Diabetes
Authors: MIDDLETON TIMOTHY , CHADBAN STEVE , MOLYNEAUX LYNDA M. , D'SOUZA MARIO I. , CONSTANTINO MARIA I. , YUE DENNIS , MCGILL MARGARET , WU TED , TWIGG STEPHEN M. , WONG JENCIA
Published: June 2019

Young adult onset type 2 diabetes (YT2DM) is an aggressive disease. Cross-sectional studies have shown a higher prevalence of albuminuria in YT2DM compared to age-matched young adults with T1DM (YT1DM). Whether this translates to poorer long-term renal outcomes has not been widely studied. We aimed (i) to examine progression to renal replacement therapy (RRT) and renal-related death (RRD) in our young adult population, and (ii) to examine survival on RRT for those individuals who reached end stage renal disease. We performed probabilistic linkage of prospectively collected data from the RPA Diabetes Centre eMR to the Australian National Death Index and the Australian and New Zealand Dialysis and Transplant Registry up to 31/12/2015. In our patient cohort diagnosed between the ages of 15 and 35 years, 1,248 had YT1DM and 1,534 had YT2DM. After a median (IQR) observation of 13.6 (6.9-20.7) years, 56 (4.5%) of YT1DM vs. 98 (6.4%) of YT2DM reached the combined renal end-point of RRT/RRD. Analysis of Kaplan-Meier survival curves demonstrated a greater rate of progression of renal disease in YT2DM (Log-rank p=0.003). Cox proportional hazard modelling of RRT/RRD with adjustment for gender, ethnicity and duration of diabetes exposure was undertaken. The HR (95% CI) for an adverse renal outcome in YT2DM relative to YT1DM was 2.0 (1.4-2.9), p<0.001. This HR was attenuated when further adjustments were made for HbA1c, blood pressure, BMI and cholesterol. Similar results were obtained after multiple imputation for missing data. For the 80 young adults who commenced RRT, there were 19 deaths (70%) in the YT1DM subgroup and 26 deaths (49%) in the YT2DM subgroup after a median (IQR) observation time of 4.2 (2.2-9.1) years. KM survival analysis demonstrated equally poor survival in YT1DM and YT2DM. Cox regression with transplant as a time-varying covariate also showed non-significance. These data highlight the more rapidly progressive renal disease seen in YT2DM compared to YT1DM; however, survival on RRT appears to be equally poor for both diabetes types.

Disclosure

T. Middleton: Other Relationship; Self; AstraZeneca. S. Chadban: None. L.M. Molyneaux: None. M.I. D'Souza: None. M.I. Constantino: None. D. Yue: None. M. McGill: None. T. Wu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. S.M. Twigg: Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Board Member; Self; AstraZeneca. Research Support; Self; Abbott. Speaker's Bureau; Self; Abbott, AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. J. Wong: Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; AstraZeneca, Lilly Diabetes.
523-P: Axon Guidance Pathway (AGP) Proteins Associate with ESKD and Kidney Lesions in Type 2 Diabetes
Authors: SAULNIER PIERRE , SATAKE EIICHIRO , LOOKER HELEN C. , SKUPIEN JAN , KROLEWSKI ANDRZEJ , NELSON ROBERT
Published: June 2019

Seven AGP proteins associate with ESKD in Caucasians with diabetes. We explored the association of these proteins with ESKD and kidney lesions in Pima Indians with type 2 diabetes. EPHA1, EPHA2, EPHB6, EFNA4, EFNA5, UNC5Cand UNC5D were measured in serum of 162 Pimason a SOMAscan platform. Hazard ratio (HR) for ESKD for a 1 SD increase of each protein was computed by Cox regression after adjustment for age, sex, A1c, iothalamate glomerular filtration rate (GFR), and albumin:creatinine ratio (ACR). Serum samples obtained a median of 2.5 years later were measured in a subset of 67 Pimas who underwent kidney biopsy. Relationships between changes in protein concentrations and kidney lesions were explored by Spearman correlations. Baseline, mean age was 45±10 years, diabetes duration 15±6 years, GFR 155±53 ml/minute, and median ACR 54 (13-250) mg/g. During median follow-up of 12.5 years, 54 participants developed ESKD. Higher concentrations of 6 proteins (UNC5C HR1.51 [95CI 1.07-2.13]; EPHB6 1.67 [1.15-2.41]; EFNA4 1.72 [1.29-2.31]; UNC5D 1.73 [1.12-2.69] EFNA5 1.99 [1.36-2.91] and EPHA2 2.15[1.46-3.17]) were associated with ESKD. Increasing concentrations of these proteins were associated with structural lesions of diabetes (Figure). Proteins related to cell surface molecules of the Ephrin family were associated with kidney lesions and with progression to ESKD in Pima Indians with type 2 diabetes.

Disclosure

P. Saulnier: None. E. Satake: None. H.C. Looker: None. J. Skupien: None. A. Krolewski: None. R. Nelson: None.

Funding

American Diabetes Association (1-08-CR-42 to R.N.)
53-OR: Efficacy of Efpeglenatide in Patients with Obesity and Prediabetes: A Subanalysis of the BALANCE 205 Study
Authors: PRATLEY RICHARD E. , JACOB STEPHAN , KANG JAHOON , TRAUTMANN MICHAEL E. , HOMPESCH MARCUS , HAN OAKPIL , STEWART JOHN A. , OGBAA IKE , SORLI CHRISTOPHER H. , YOON KUN-HO
Published: June 2019

Once-weekly (QW), subcutaneous efpeglenatide (efpeg) is a long-acting GLP-1 RA being developed to improve glycemic control in T2D. In the 20-week BALANCE 205 study (NCT02075281), all doses of efpeg led to significant reductions in body weight (BW) vs. placebo (PBO) in patients with obesity without diabetes (p<0.0001; primary endpoint). This exploratory analysis investigated the effects of efpeg on glycemic, BW, BMI, waist circumference (WC) and cholesterol parameters in patients from BALANCE with prediabetes (HbA1c 5.7−6.4% or FPG 100−125 mg/dL) at baseline (n=140/295). At study end, percentages of patients with normoglycemia (i.e., no longer prediabetic) were higher with efpeg (4 mg QW, 64.3%; 6 mg QW, 46.2%; 6 mg once every 2 weeks [Q2W], 40.6%; 8 mg Q2W, 41.7%; pooled efpeg, 48.2%) than with PBO (10.0%; Table). All efpeg doses led to significant reductions vs. PBO in BW and HbA1c (p<0.0001 for all comparisons; −6.6 kg and −0.4%, respectively for pooled group), BMI, total cholesterol, FPG and WC (p<0.05 for all), except the 4 mg QW dose for WC. Adverse events (AEs) mirrored those known for GLP-1 RAs, with higher rates of gastrointestinal AEs vs. PBO, with no incidences of severe hypoglycemia.

In conclusion, treatment with efpeg led to significant improvements vs. PBO in HbA1c, BW, BMI, FPG, WC and cholesterol, and greater proportions of patients achieving normoglycemia, in patients with obesity and prediabetes.

Disclosure

R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. S. Jacob: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novartis AG, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. J. Kang: Employee; Self; Hanmi Pharm. Co., Ltd. M.E. Trautmann: Consultant; Self; CeQur Corporation, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Oramed Pharmaceuticals, ProSciento, Servier. Stock/Shareholder; Self; Lilly Diabetes. M. Hompesch: Stock/Shareholder; Self; ProSciento. O. Han: None. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. I. Ogbaa: Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. Other Relationship; Self; Sanofi. C.H. Sorli: Employee; Self; Sanofi. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited.

Funding

Hanmi Pharmaceutical, Co., Ltd.; Sanofi
536-P: Association between Uric Acid Level and Incidence of Macroalbuminuria in People with Type 2 Diabetes Mellitus: A 4.5-Year Cohort Study
Authors: LAI YUN-JU
Published: June 2019

Background: Using animal models and molecular biology researches, hyperuricemia has been shown to instruct renal arteriolopathy, arterial hypertension, and microvascular injury involving the renin-angiotensin system and resulting in renal function impairment. Nevertheless, the association between uric acid levels and the development of macroalbuminuria has been under-investigated in people with type 2 diabetes mellitus.

Methods: Patients with type 2 diabetes and regular outpatient visits were recruited from the Puli Branch of the Taichung Veterans General Hospital in Taiwan since January 2014. Demographics, lifestyle features, and medical history were gathered by well-trained interviewers. All participants underwent comprehensive physical examinations, including a biochemical assay of venous blood specimens and urine samples after an 8-hour overnight fast. Participants were followed until June 2018. The primary outcome was the macroalbuminuria incidence. Univariate and multivariate Cox regression analysis were employed to explore the relation between uric acid and incident macroalbuminuria. Uric acid cutoffs for incident macroalbuminuria were determined with the receiver operator characteristic curve.

Results: We included 247 qualified subjects (mean age: 64.78 years old [standard deviation=11.29 years]; 138 [55.87%] men). During a 4.5-year follow-up duration, 20 subjects with incident macroalbuminuria were recognized. Serum uric acid was significantly associated with an increased risk of incident macroalbuminuria (adjusted hazard ratio=2.39; 95% confidence interval: 1.53-3.75; p<0.001) with potential confounders adjustment. The uric acid cutoff point was 6.9 mg/dL (area under the curve 0.708, sensitivity 60.0%, specificity 84.58%) for incident macroalbuminuria.

Conclusions: Serum uric acid was associated with incident macroalbuminuria among people with type 2 diabetes.

Disclosure

Y. Lai: None.
542-P: One-Year eGFR Decline Rate Predicts Renal Outcome in High-Risk Japanese Patients with Hypercholesterolemia and Diabetic Retinopathy
Authors: MEGURO SHU , SATO YASUNORI , ITOH HIROSHI
Published: June 2019

Objective: The slope of eGFR decline is collecting attentions for earlier recognition of eGFR decliner. We analyzed the predictive value of maximum 1-year eGFR decline rate for the renal endpoint in prospective cohort.

Research Design and Methods: We analyzed the data from EMPATHY trial which was the multicenter randomized control trial to assess the benefits of intensive statin therapy for patients with hypercholesterolemia and diabetic retinopathy. We calculated 1-year eGFR decline rate in every 6 months and analyzed its relation to the renal endpoint defined as initiation of chronic dialysis or increase in serum creatinine level by at least twofold.

Results: The renal endpoint developed in 101 subjects out of 5,042 patients in mean follow-up 37 ± 13 months. The AUC of maximum 1-year eGFR decline rate by ROC was 0.960, that of albuminuria at baseline was 0.913, and that of eGFR at baseline was 0.809. When we defined the cut-off value of maximum 1-year eGFR decline rate as 20%, its sensitivity was 97.8% and its specificity was 80.2%. Time until the renal endpoint from the first demonstration of 1-year eGFR decline rate more than 20% was 353.1 ± 31.9 days.

Conclusions: One-year eGFR decline more than 20% was highly associated with the renal endpoint. The renal endpoint was predominantly observed in the subjects with albuminuria.

Disclosure

S. Meguro: Research Support; Self; Novartis Pharmaceuticals Corporation. Speaker's Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., NIPRO Medical Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Y. Sato: None. H. Itoh: None.
547-P: Utility of Galectin-3 as a Biomarker of Prediabetes and Complications of Type 2 Diabetes Mellitus
Authors: ABDELLA NABILA A. , MOJIMINIYI OLUSEGUN A.
Published: June 2019

Introduction: To determine its utility as a biomarker, this study explores the diagnostic usefulness of Galectin-3 (Gal3), in subjects with type 2 diabetes mellitus (T2D) and their first-degree relatives (FDR).

Methods: Gal3, glucose (FPG) and high-sensitivity C-reactive protein(hs-CRP) were measured in 217 T2D patients and 226 FDR. Clinical data were recorded and subjects were classified using homeostasis model assessment of insulin resistance (HOMA-IR). FDR were classified as normal, prediabetes or diabetic using HbA1c. T2D were classified by presence or absence of retinopathy, neuropathy (autonomic (AN) and sensory (SN) and as normo- (NAO) or micro-albuminuric (MIA)) using urine microalbumin to creatinine ratio. Binary logistic regression with determination of the Odds Ratio (OR) analyses were used to evaluate associations with T2D complications. Receiver-Operating Characteristic Curve (ROC) analysis was used to evaluate diagnostic utility of Gal3.

Results: Gal3 showed significant (p<0.05) correlations with waist circumference (r=0.21), HbA1c (r= 0.33); glucose (r=0.21) and hs-CRP (r=0.2). In FDR, mean Gal3 levels increased stepwise with worsening glucose tolerance - normal (7.6ng/ml); prediabetes (8.1ng/ml) and diabetes (9.1 ng/ml) and subjects with HOMA-IR >2 had significantly higher mean Gal 3 than subjects with HOMA-IR < 2 (10.2 vs. 9.3 ng/ml). In FDR, ROC analysis showed that Gal3 cut-off value of 8.7 ng/ml has 77% sensitivity and 67% specificity for detection of diabetes. In T2D, binary logistic regression analysis showed Gal3 was significantly associated with hypertension (HT), MIA, AN, SN and retinopathy. ROC analysis showed that Gal3 significantly detects HT, MIA, AS and SN. Gal3 >9.7 ng/ml was associated with presence of T2D complications with sensitivity and specificity >70%.

Conclusions: Gal3 is significantly associated with diabetes in FDR and is a strong predictor of associated complications in subjects with T2D.

Disclosure

N.A. Abdella: None. O.A. Mojiminiyi: None.

Funding

Kuwait Foundation for the Advancement of Science (2011-1302-01)
56-OR: Liraglutide for Perioperative Management of Hyperglycaemia in Cardiac Surgery Patients (GLOBE): A Multicentre, Prospective, Superiority Randomised Trial
Authors: HULST ABRAHAM H. , PRECKEL BENEDIKT , HOLLMANN MARKUS W. , DEVRIES J. HANS , HERMANIDES JEROEN
Published: June 2019

Background: Most cardiac surgery patients develop perioperative hyperglycaemia requiring intravenous insulin therapy. This is labour-intensive and carries a risk of hypoglycaemia. We hypothesised that preoperative administration of the GLP-1 receptor agonist liraglutide would reduce the number of patients requiring insulin during cardiac surgery.

Methods: In this randomised, blinded, placebo-controlled, parallel-group, balanced (1:1), superiority, multicentre randomised trial, adult patients undergoing cardiac surgery in four Dutch tertiary hospitals were randomised to receive 0·6 mg subcutaneous liraglutide on the evening before surgery and 1·2 mg after induction of anaesthesia, or matching placebo. Blood glucose was measured hourly and controlled using an insulin-bolus-algorithm. The primary outcome was insulin administration for blood glucose above 8·0 mmol/L in the operating theatre. Research pharmacists used centralised, stratified, variable-block, randomisation software. Patients, care providers, and study personnel were blinded to treatment allocation.

Findings: Between June 2017 and August 2018, 278 patients were randomised to liraglutide (139) or placebo (139). All patients receiving at least one study drug injection were included in the intention-to-treat analyses (liraglutide: 129, placebo: 132). In the liraglutide group, 55 patients (43%) required additional insulin compared to 80 patients (61%) in the placebo group, absolute difference: 18% (95% CI 5·9-30·0, p=0·003). Dose and number of insulin injections and mean blood glucose were all significantly lower in the liraglutide group. We observed no difference in the incidence of hypoglycaemia, nausea and vomiting, mortality, or postoperative complications.

Interpretation: Preoperative liraglutide reduces insulin requirements while improving peri-operative glycaemic control during cardiac surgery.

Disclosure

A.H. Hulst: Research Support; Self; Novo Nordisk A/S. B. Preckel: Research Support; Self; Novo Nordisk Inc. M.W. Hollmann: Consultant; Self; Eurocept BV. Other Relationship; Self; CSL Behring. J. DeVries: Advisory Panel; Self; Novo Nordisk A/S. Employee; Self; Profil Institute for Metabolic Research. Speaker's Bureau; Self; Novo Nordisk A/S. J. Hermanides: Consultant; Self; Julius Clinical (CRO). Research Support; Self; Novo Nordisk A/S.

Funding

Novo Nordisk A/S
57-LB: The Wellness Bus: Closing the Gap in Type 2 Diabetes Prevention and Promoting Population Health
Authors: MARCUS ROBIN L. , BANNON BRITTANY L. , DELANEY REBECCA K. , FAGERLIN ANGELA
Published: June 2019

More than 150,000 Utahns have diabetes, costing the state over one billion dollars each year. The risk for developing type 2 diabetes is significantly higher among members of minority racial or ethnic groups. The Wellness Bus is a mobile health unit that aims to reduce the burden of type 2 diabetes in Utah’s underserved communities. The program represents a unique partnership between researchers, community health workers, student volunteers, and community health partners.

Objective: To describe the characteristics and needs—both medical and social—of community members being served by the Wellness Bus in its first 6 months of implementation, and to discuss how the mobile health unit and its partners are addressing these critical gaps in access to care.

Methods: Participants included 501 individuals who visited the Wellness Bus’s weekly neighborhood sites between June and December of 2018. Participants were ages 18 to 88 years (Mean age = 46.8), 50% Female; 28% white; and 67% Hispanic/Latino. Descriptive data from routinely-collected assessments during Wellness Bus visits at the weekly sites including participant self-report surveys, biometric screenings, and social service referrals were analyzed with R statistical software.

Results: Of all individuals, 57% reported Spanish as their primary language, 67% were uninsured, and 61% did not have a primary care provider; 23% had been previously diagnosed with diabetes or prediabetes. More than half of high-risk individuals had HbA1c levels > 5.7. Mean BMI = 29.8, with 82% overweight or obese; more than half screened with elevated blood pressure. Service referrals were made for 160 individuals, most to community medical/dental services. In regard to the social risk assessment, 35% reported experiencing food insecurity. Through the first 6 months of the Wellness Bus program, we have gained an understanding of our communities’ needs and are addressing these gaps. We are developing strategies to increase the number of follow-up visits.

Disclosure

R.L. Marcus: None. B.L. Bannon: None. R.K. Delaney: None. A. Fagerlin: None.
580-P: Cardiovascular Autonomic Neuropathy Is Associated with Carotid Intima-Media Thickness and Arterial Stiffness in Patients with Type 2 Diabetes
Authors: SOHN TAE SEO
Published: June 2019

Cardiac autonomic neuropathy (CAN) is a frequent but underdiagnosed complication of diabetes mellitus. CAN represents a significant cause of morbidity and mortality in patients with diabetes and is associated with a high risk of cardiac arrhythmia and sudden death. The aim of this study is to evaluate the association between CAN and carotid intima-media thickness (CIMT) and arterial stiffness in patients with type 2 diabetes mellitus (T2DM). CAN, CIMT, ankle-brachial index (ABI) and pulse wave velocity (PWV) were evaluated in a cross-sectional sample of 321 patients (147 men and 174 women) with T2DM. CAN was assessed by Ewing’s method which employs five non-invasive tests of autonomic function. Among 321 patients, CAN was found in 87 patients (27%). Compared with the patients without CAN, those with CAN were significantly older and had significantly longer duration of diabetes, lower glomerular filtration rate, higher hs-CRP, mean CIMT, PWV, and ABI. The CAN scores correlated positively with mean CIMT and PWV (P<0.05). Using multivariate regression analysis, CAN score independently predicted mean CIMT in patients with T2DM after adjustment for age and DM duration.

In conclusion, CAN was associated CIMT and increased arterial stiffness in patients with T2DM. CAN might be associate with the development of cardiovascular disease through CIMT and arterial stiffness in T2DM.

Disclosure

T. Sohn: None.
60-OR: Sitagliptin for the Prevention and Treatment of Perioperative Hyperglycemia in Diabetic Patients Undergoing Cardiac Surgery
Authors: CARDONA SAUMETH , TSEGKA KATERINA G. , JACOBS SOL , ALBURY BONNIE S. , GALINDO RODOLFO J. , MIGDAL ALEXANDRA , HALKOS MICHAEL E. , KEELING WILLIAM B. , MILLER JEFFREY S. , MACHEERS STEVEN K. , GUYTON ROBERT A. , VELLANKI PRIYATHAMA , DAVIS GEORGIA , FAYFMAN MAYA , PENG LIMIN , PASQUEL FRANCISCO J. , UMPIERREZ GUILLERMO E.
Published: June 2019

Perioperative hyperglycemia (BG >180 mg/dl) is reported in more than 80% of patients with T2D after cardiac surgery and is associated with high morbidity and mortality. Continuous insulin infusion (CII), the recommended for treatment of perioperative hyperglycemia is labor intensive and is associated with hypoglycemia risk. Because, treatment with DPP-4is has been shown to improve glucose control without hypoglycemia in general surgery patients, we conducted a double-blinded randomized trial to test the hypothesis that sitagliptin could prevent and treat hyperglycemia after CABG. A total of 202 patients with T2D were randomized to sitagliptin (n=101) or placebo (n=101) once daily, starting the day prior to surgery and continued in the ICU and after transition to regular wards.

We observed no differences in BG prior to or during surgery, ICU stay or after transition to floor between groups. There were no differences in the number of patients requiring insulin therapy in the ICU or in regular floors, frequency of hypoglycemia or in hospital complications. Sitagliptin was associated with lower SQ insulin requirements without increased risk of hyper- or hypoglycemia compared to placebo after transition to regular floor.

Conclusion: Sitagliptin cannot be recommended for the prevention or treatment of perioperative hyperglycemia in patients with T2D undergoing cardiac surgery.

Disclosure

S. Cardona: None. K.G. Tsegka: None. S. Jacobs: None. B.S. Albury: None. R.J. Galindo: Advisory Panel; Self; Abbott, Novo Nordisk Inc., Sanofi US. Research Support; Self; Novo Nordisk Inc. A. Migdal: None. M.E. Halkos: Board Member; Self; Medtronic. W.B. Keeling: None. J.S. Miller: None. S.K. Macheers: None. R.A. Guyton: None. P. Vellanki: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. Research Support; Self; National Institutes of Health. G. Davis: None. M. Fayfman: None. L. Peng: None. F.J. Pasquel: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. G.E. Umpierrez: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc., Sanofi US.

Funding

Merck & Co., Inc.
607-P: Hyperhomocysteinemia Is Closely Associated with Macular Edema in Type 2 Diabetes
Authors: LI JIANBO , ZHANG HONGMAN , LV QING , LU HUAN , ZHOU JUN
Published: June 2019

Macular edema that impairs central vision is one of leading causes of blindness related to diabetes. Hyperhomocysteinemia is more common in type 2 diabetes, which may damage endothelium by excessive sulphation of connective tissues. In this study, we for the first time explored the relation of plasma total homocysteine concentration to diabetic macular edema in patients with type 2 diabetes. We enrolled 176 type 2 diabetic patients and 115 healthy subjects in a cross-sectional hospital-based study. Using fundus photographs documented retina statuses and using fluorescence polarization immunoassay measured homocysteine concentration. Risk factors for diabetic macular edema were obtained from fasting blood samples and interviewer- questionnaire. We found that diabetic patients had increased plasma homocysteine compared with normal control, and plasma homocysteine levels were higher in subjects with diabetic macular edema than without ((11.4 ± 2.7) vs. (8.5 ± 1.9) (μmol/l), p = 0.000). The association of homocysteine with diabetic macular edema was independent of major risk factors for diabetic macular edema (duration of diabetes, HbA1c, lipid) and determinants of higher homocysteine concentration (age, gender, serum folate and vitamin B12, renal status, and biguanide use) (OR: 1.63 (1.02-2.14), p = 0.018). Furthermore, a 1 μmol/l increase in plasma homocysteine concentration was associated with a 0.5% to 2.2% increase of diabetic macular edema and per increase of 5.0 μmol/l plasma homocysteine was significantly related to macular edema (OR: 1.64 (1.04-2.16), p = 0.019) after adjusting for duration of diabetes per 5 year increase, HbA1c per 1% increase, serum folate per 10 nmol/l increase, serum B12 per 100 pmol/l increase, serum creatinine per 10 μmol/l increase and urinary ACR per 5 mg/g increase. We concluded that hyperhomocysteinemia is independently associated with occurrence of macular edema in type 2 diabetes. Future prospective studies are warranted to clarify the relationship.

Disclosure

J. Li: None. H. Zhang: None. Q. Lv: None. H. Lu: None. J. Zhou: None.
625-P: Metallothionein Improves Angiogenic Function of Endothelial Progenitor Cells via HIF-1α/SDF-1/Akt Pathway in Diabetic Limb Ischemia
Authors: WANG KAI , DAI XIAOZHEN , HE JUNHONG , YANG CHENGKUI , CHEN JING , WINTERGERST KUPPER A. , EPSTEIN PAUL N. , CAI LU , TAN YI
Published: June 2019

Diabetes mellitus associated dysfunction of endothelial progenitor cells (EPCs) may contribute to dysregulation of endothelial regeneration. Metallothionein (MT) acts as an antioxidant in various pathophysiological processes. Whether MT in EPCs has positive angiogenic effects and the mechanisms involved remain unclear. Endothelial MT overexpression (JTMT) mice were made diabetic by high fat diet followed by STZ administration (HFD/STZ). Diabetic hind limb ischemia model was established by femoral artery ligation. Bone marrow derived mononuclear leucocytes (MNCs) collected from JTMT mice were transplanted into db/db mice with hind limb ischemia. Blood reperfusion was monitored and oxidative stress was measured. High glucose and hypoxia conditions in culture were adopted to mimic diabetic ischemia in vitro. MT improved blood perfusion of ischemic hind limb and promoted angiogenesis in HFD/STZ diabetes. Oxidative stress of ischemic muscles was aggravated under diabetic condition, which was reduced in JTMT mice. Compared with WT mice, the expression of HIF-1α, SDF-1, VEGF and p-Akt were all increased in JTMT mice, along with elevation of plasma SDF-1α and VEGF. Moreover, transplantation of MT overexpressed MNCs showed better therapeutic effect on db/db diabetic mice with hind limb ischemia than control or transplantation of normal MNCs. Transplantation was accompanied by elevated HIF-1α, SDF-1 and Akt signaling. Vitro studies demonstrated that MT overexpression reduced high glucose and hypoxia induced EPC dysfunction and preserved high glucose and hypoxia impaired HIF-1α, SDF-1, VEGF and Akt signaling, all of which were abolished by siRNA knockdown of HIF-1α.

In conclusion, elevated MT enhances angiogenic function and therapeutic efficacy of EPCs in diabetic limb ischemia. The benefits of MT are predominantly mediated by a HIF-1α/SDF-1/Akt pathway under diabetic ischemia conditions.

Disclosure

K. Wang: None. X. Dai: None. J. He: None. C. Yang: None. J. Chen: None. K.A. Wintergerst: None. P.N. Epstein: None. L. Cai: None. Y. Tan: None.

Funding

American Diabetes Association (1-15-BS-018, 1-18-IBS-082 to L.C.); 1-13-JF-53 (to Y.T.)
626-P: Association between Peripheral Neuropathy and Biomechanics Performance in Patients with Type 2 Diabetes Mellitus
Authors: DENG WUQUAN , DENG FANG , CHEN BING , MA YU , JIANG XIAOYAN , ARMSTRONG DAVID , ZHOU HE
Published: June 2019

Objective: To explore the effect of DPN on the gait and balance ability using new a biomechanical monitoring technology.

Methods: 176 subjects were divided into 4 groups: Group A (no DPN signs and symptoms, NCV negative, 48), group B (no DPN signs and symptoms, NCV positive, 45), group C (with DPN signs and symptoms, NCV positive, 51) and group D (normal control, 32). The gait, balance, timed up and go test were conducted using the LEGSys and BalanSens system. The difference of biomechanics parameters and their relationship with NCV were analyzed.

Results: The stride, stride to height ratio, walking speed, step height and swing (left) of diabetic groups were significantly lower than group D (P < 0.05). The support (left) and double support (right) of diabetic groups were significantly higher than group D (P < 0.05). In eyes-open hard surface stand test, the center of gravity (COG) sway range of side to side and front to back, the ankle sway range of side to side, the COG sway area, the ankle sway area, the COG sway index and the ankle sway index in group B and C were significantly higher than group D (P < 0.05). The stride length and stride to height ratio of group C were lower than group A (P < 0.05). The walking speed, step height and steps per minute of group C were significantly lower than group A and B (P < 0.05). In the eyes open or closed stand balance test, COG sway range of front to back and the sway index of group C were significantly higher than group A (P < 0.05). In the eyes open state, the ankle sway range of front to back, ankle sway index and COG sway velocity of group C were significantly higher than group A (P < 0.05). In the eyes closed state, the hip sway area of group C were higher than group A (P < 0.05). In the mCTSIB test, the COG sway index of group C were significantly higher than group A (P < 0.05).

Conclusion: The biomechanics performance in diabetic patients are impaired and further worse by DPN. These defects may achieve an early detection by the new biomechanical monitoring technology.

Disclosure

W. Deng: None. F. Deng: None. B. Chen: None. Y. Ma: None. X. Jiang: None. D. Armstrong: None. H. Zhou: None.

Funding

Cultivation Project of Chongqing Youth Medical High-End Reserve Talents (2017HBRC015)
631-P: Negative Pressure Wound Therapy May Affect Circulating Plasma MicroRNAs in Patients with Diabetic Foot Ulceration
Authors: KAPUSTA PRZEMYSłAW , HOHENDORFF JERZY , ZURANSKA JUSTYNA , BORYS SEBASTIAN , KONIECZNY PAWEL , KIEC-WILK BEATA M. , WOLKOW PAWEL P. , MALECKI MACIEJ
Published: June 2019

Background: Negative pressure wound therapy (NPWT) has been successfully used as treatment for diabetic foot ulceration (DFU). However, the molecular mechanisms of its action, especially outside of the wound bed, are not fully understood. We assessed the effect of NPWT on levels of circulating plasma microRNAs in patients with type 2 diabetes (T2DM) and DFU.

Methods: We included 33 patients with T2DM and DFU - 23 individuals were assigned to NPWT and 10 to standard treatment (ST). Assignment to NWPT was based on routine clinical recommendations and not random. MicroRNAs enriched RNA was extracted from plasma at two time points: before treatment and after 8±1 days of treatment. Prepared small RNA libraries were sequenced on the NextSeq 500 sequencer (Illumina). Generated reads were aligned to mirBase 21 using Bowtie and counted using miRDeep2 software. Statistical analysis of differentially expressed microRNAs was performed via the edgeR package in the R environment.

Results: The NPWT and ST groups were similar in terms of basic clinical characteristics, such as age (67.8 vs. 67.8 years, p=0.95) and HbA1c level (7% vs. 7.8%, p=0.15). We identified three miRNAs - miR-6842, miR-3690 and miR-11400 - that were expressed at a higher level post-treatment in the NPWT group as compared to the ST group. Interestingly, miR-3690 has been previously predicted to target mRNA of T-cell surface glycoprotein CD3 gamma chain (CD3G), therefore, it may be hypothesized that it affects the expression of CD3 and modulate the immune response. Additionally, in the NPWT group we observed a downregulation of miR-9 as compared to the initial level. MiR-9 is expressed in human monocytes and neutrophils upon activation. Thus, it may regulate the synthesis of proinflammatory mediators.

Conclusions: We found initial evidence that short-term NPWT use in T2DM patients with DFU may affect miRNA expression in plasma and act through promoting immune system factors in the wound bed.

Disclosure

P. Kapusta: None. J. Hohendorff: Other Relationship; Self; Abbott, Ascensia Diabetes Care, Novo Nordisk A/S, Sanofi-Aventis. J. Zuranska: None. S. Borys: None. P. Konieczny: None. B.M. Kiec-Wilk: None. P.P. Wolkow: None. M. Malecki: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Bioton, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Merck & Co., Inc.

Funding

National Science Centre of Poland (2013/11/B/NZ5/03298)
638-P: Innovative Diagnostic Tool for Assessment of Plantar Skin Temperature to Spot Diabetes-Related Foot Complications
Authors: SHAHADE ARATI A. , SHAHADE ANUJ A. , SHAHADE AMBRISH M. , WAGH SAGAR P. , OZARKAR SHOUNAK
Published: June 2019

Objective: Our aim was to measure plantar skin temperature using an innovative diagnostic device; thereby identifying early diabetes-related foot complications such as ulceration and Charcot foot.

Materials and Methods: The innovative portable device is a box with an inclination on upper side to place foot on a temperature sensitive mat connected to a microprocessor. Readings are recorded at 5 predefined areas, viz. ball of the great toe, 1st and 5th meta-tarsals, lateral arch and heel on both feet with patients in sitting position placing their feet on the mat for 30 seconds.105 patients; 83 diabetes [15 with diabetic neuropathy - symptoms or signs (DN) and 68 patients without DN] and 22 nondiabetes aged 24-80 years visiting Shahade Hospital OPD during last 6 months were included. Patients with skin diseases, edema, ulcer and known neurological illness were excluded.

Results: 78% of DN patients recorded higher temperature at the predefined areas. Diabetes patients with DN had 0.36°C higher plantar skin temperature (mean difference) compared to nondiabetes patients. Mean difference in temperature for DN patients on left foot was (0.20°C, 0.29°C, 0.52°C, 0.37°C, 0.53°C) and right (0.02°C, 0.44°C, 0.39°C, 0.29°C, 0.54°C), respectively. Diabetes patients without DN had 0.18°C higher temperature compared to nondiabetes patients. DN patients had diabetes of 9.67 ± 5.46 years with HbA1c of 9.8 ± 2.8%; duration of diabetes in patients without DN was 7.26 ± 5.64 years with HbA1c 7.23 ± 1.23%. The device also noted that 64.4% of diabetes patients without DN or any symptoms of DN were having higher temperature at predefined areas compared to nondiabetics, which warrants further monitoring.

Conclusions: The innovative device is precise for sensing plantar skin temperature change that could help clinicians in monitoring diabetes related foot complications. The device is handy, reliable, and gives instantaneous results that will aid self-monitoring by patients and care givers.

Disclosure

A.A. Shahade: None. A.A. Shahade: None. A.M. Shahade: None. S.P. Wagh: Employee; Self; Biocon. S. Ozarkar: None.
639-P: Pharmacological Mobilization and Recruitment of Bone Marrow Stem Cells Accelerates Diabetic Wound Healing in Rats with Diabetic Complications
Authors: QI LE , AHMADI ALI REZA , HUANG JINNY , LIN QING , CHEN MELISSA , KUWABARA HIROSHI , IWASAKI KENICHI , BURDICK JAMES , SUN ZHAOLI
Published: June 2019

Introduction: The lifetime incidence of foot ulcers has been estimated to be 19% to 34% among persons with diabetes. Diabetic wound healing(DWH) remains a challenge. Given the promising role of stem cells in wound healing, the current study proposed to improve DWH by mobilizing and recruiting bone marrow stem cells pharmacologically with combination of AMD3100 and low-dose FK506 (AF) in rats.

Methods: T2 GK rats and STZ induced T1DM SD rats were used. To determine the role of bone marrow stem cells, bone marrow from GFP tg Lewis were transplanted into wt Lewis rats and T1 rats were induced by STZ injection at 2 months following bone marrow transplantation. Full-thickness wounds were created in the dorsal skin or in the foot skin at 6 weeks after STZ injection or GK rats at 4 month old. Wounded rats were divided into two experimental groups and received saline or a combination of AMD3100 (1mg/kg) and FK506 (0.1mg/kg) immediately after wounding and every 2 days until complete healing.

Results: At the time of wounding, all animals developed peripheral artery disease and neuropathy. The back wound healing time was reduced from 27 to 19 days and the foot wound healing time was reduced from 25 to 20 days in T1DM rats treated with AF. Similarly, the back wound healing time was reduced from 26(S) to 21(AF) days in GK rats. Equally important, healing was accompanied by reduced scar and regeneration of hair follicles. Searching for the mechanisms, we found that AF therapy mobilized bone marrow stem cells to peripheral blood and recruited bone marrow-derived CD31+CD133+ endothelial progenitor cells, CD34+ stem cells and Ym1/2+ M2 macrophages into the wound sites and enhanced capillary and hair follicle neogenesis.

Conclusion: Combination of AMD3100 and low-dose FK506 results in better and faster healing of diabetic wounds in rats with diabetic peripheral artery disease and neuropathy. Our findings offer a significant therapeutic approach to healing of DFU.

Disclosure

L. Qi: None. A.R. Ahmadi: None. J. Huang: None. Q. Lin: None. M. Chen: None. H. Kuwabara: None. K. Iwasaki: None. J. Burdick: None. Z. Sun: None.
644-P: QTc Prolongation as a Risk Factor for Increased Mortality in People with Diabetes and Charcot Osteoarthropathy
Authors: SCHOUG JOHAN , FAGHER KATARINA , LONDAHL MAGNUS
Published: June 2019

Background: Charcot neuropathic osteoarthropathy (CN) is an uncommon but potentially serious complication of diabetes mellitus (DM). Aspects of morbidity and mortality in CN patients have not been fully described. The aim of this study was to evaluate the impact of QTc prolongation on long-term mortality in people with DM and CN.

Methods: All patients diagnosed with acute CN at a tertiary hospital based Diabetic Foot Unit between 2003 and 2017 were retrospectively studied. QTc prolongation was defined as ≥440 ms and confirmed with manual measurement. Patients with QTc-prolonging drugs and pacemakers were excluded. Data are given as median (IQR). Log Rank tests were used for survival analysis. A Cox regression model was performed for 10-year mortality, using age, DM duration, QTc interval, HbA1c and creatinine as continuous variables, and hypertension, ischemic heart disease, cerebrovascular disease, smoking history and proliferative retinopathy as categorical variables.

Results: In all, 81 patients (age 62 [52.5-68] years, 44% females, 38% type 1 DM, DCCT 7.5% [6.8-8.6%]) were included. QTc prolongation was associated with significantly higher mortality (Figure 1). In the Cox regression model, only age (HR 1.08, p<0.05) and QTc interval (HR 1.03, p<0.05) remained significant factors.

Conclusions: QTc prolongation seems to be associated with increased mortality in people with DM and CN.

Disclosure

J. Schoug: None. K. Fagher: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. M. Londahl: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.