bluuebunny/crossref_metadata_2025_split huggingface dataset:
559-P: The Triglyceride Glucose Index (TyG Index), Surrogate Marker of Insulin Resistance and Dementia: Population-Based Study
Authors: HONG SANG MO , HAN KYUNGDO , PARK CHEOL-YOUNG 
Published: June 2019

Background: Recent several studies in both humans and animal models suggest that insulin resistance has negative effects on cognition, there were few evidences from large papulation study. In the current study, we evaluated the potential relationships between the triglyceride glucose index (TyG index), surrogate marker of insulin resistance, and dementia using a large-scale population dataset from the National Health Information Database (NHID).
Methods: We did a retrospective, observational, cohort study of 13,149,723 persons aged older than 40 years from 2009 to 2015 using NHID. We used the TyG index as a measures of insulin resistance and divided the subjects into quartiles groups based on TyG index. The incidence of demetia was assessed using the hazard ratios (HRs) estimated with cox proportional hazard modeling.
Results: During a median follow-up period of 5.26 years, dementia was diagnosed in 252,114 (1.92%) participants. Among them, Alzheimer disease (AD) were diagnosed 73% and vascular dementia (VD) were diagnosed 27%. Multivariate-adjusted hazard ratios (HRs) for patients in highest quartile of TyG index were higher for dementia (HRs =1.147; 95% confidence intervals [CI] 1.132-1.161), for AD (HRs =1.120; 95% CI 1.103-1.136), and for VD (HRs =1.220; 95% CI 1.177-1.264) compared with subjects in the lowest quartile of TyG index. These effects were independent of age, sex, smoking, physical activity, body mass index, systolic blood pressure, and total cholesterol.
Conclusions: In our large population study, TyG index, surrogate marker of insulin resistance was associated with an increased risk of dementia, even including AD, and it was independent of traditional cardiovascular risk factors.

Disclosure
S. Hong: None. K. Han: None. C. Park: None.
572-P: Lower Insulin Secretion Is Associated with Parahippocampal Gyrus Atrophy in Elderly Patients with Type 2 Diabetes Mellitus
Authors: ADACHI YUKO , OTA KAZUKI , ISHII RYOKO , CHO KEIHO , HIRAMATSU YUKI , MASUDA SEIZABURO , KOSEKI SAYO , HAYASHI TOMOHITO , KOMATSU NANA , UEDA ERI , MIZUGUCHI YASUFUMI , MINAMI ISAO , YAMADA TETSUYA , WATANABE TAKAYUKI 
Published: June 2019

Objectives: Alzheimer's disease (AD) is increasingly recognized as an important comorbidity of diabetes mellitus and is often accompanied by parahippocampal gyrus atrophy (PGA). But the associations between diabetes-related parameters and PGA are not well known. Voxel-based morphometry (VBM) recently became a popular tool for the early diagnosis of AD. One of the clinically useful tools using magnetic resonance imaging (MRI) is the Voxel-based Specific Regional Analysis system for AD (VSRAD) that evaluates the degree of volume loss of parahippocampal gyrus by comparing grey matter with the original normal database template. We examined the risk factors for PGA by using VSRAD in patients with type 2 diabetes mellitus (T2DM).
Methods: A total of 137 patients aged ≥ 50 years with T2DM (mean age 67.8 ± 9.8 years) underwent brain MRI scans and comprehensive health examinations. Volume of interest (VOI) was measured using VSRAD for each patient. We examined associations between the severity of VOI atrophy and diabetes-related parameters such as HbA1c, fasting plasma glucose (FPG), C-peptide (CPR) index (plasma CPR/FPG x 100) and Hasegawa Dementia Scale-Revised (HDS-R) score, consisting of 9 simple questions with a maximum score of 30. PGA was defined as the VOI atrophy more than 1.0.
Results: Mean HbA1c was 9.3 ± 2.2%. HDS-R (median (range)) score was 28 (12 - 30). CPR index (median (range)) was 1.29 (0.03 - 8.88). The severity of VOI atrophy was more than 1.0 in 36 patients. The VOI atrophy was negatively correlated with HDS-R score (R = - 0.261, p &lt; 0.02). By a using multivariate logistic regression analysis, age (OR 1.08, 95% CI 1.03 - 1.14) and CPR index (OR 0.477, 95% CI 0.233 - 0.977) were significantly associated with PGA.
Conclusions: The HDS-R score was significantly correlated with the VOI atrophy. Older age and lower insulin secretion were significantly associated with PGA in patients with T2DM.

Disclosure
Y. Adachi: None. K. Ota: None. R. Ishii: None. K. Cho: None. Y. Hiramatsu: None. S. Masuda: None. S. Koseki: None. T. Hayashi: None. N. Komatsu: None. E. Ueda: None. Y. Mizuguchi: None. I. Minami: None. T. Yamada: None. T. Watanabe: None.
583-P: Increase in Mitochondrial Ceramide Contributes to Diabetes-Induced Retinal Endothelial Cell Damage
Authors: PEGOUSKE DAVID , LEVITSKY YAN , HAMMER SANDRA , LYDIC TODD A. , MUCHNIK ARTEM , PROSHLYAKOV DENIS A. , BUSIK JULIA V. 
Published: June 2019

Mitochondrial damage precedes histopathological abnormalities in diabetic retinopathy (DR). Retinal endothelial cells (REC) have the highest level of Acid Sphingomyelinase (ASM) expression in the retina and the increase in ASM activity and ceramide production were shown to promote diabetes-induced pro-inflammatory and pro-apoptotic changes in the retina and REC. The role of diabetes-induced increase in ASM and ceramide production in mitochondrial damage in the retina and REC is not known.
Retinal mitochondria from control, STZ-induced diabetic and ASM-/- rodent models, as well as Bovine REC (BREC) treated with diabetogenic conditions were isolated by differential centrifugation. Sphingolipids were analyzed by eSI-MS. Respiration was measured using a novel custom designed microrespirometer. Mitochondrial sphingomyelin (mSM) decreased (62 ± 1% compared to control 72.5 ± 7%, P&lt;;0.05, n=3) and mitochondrial ceramide (mCer) increased (38 ± 4% compared to control 26.5 ± 6.5%, P&lt;0.05, n=3 in 7 weeks diabetic rat retina. ASM-/- mouse model showed increased mSM (85.0 ± 6.7%) compared to wild type (77.0 ± 2.8%) and decreased mCer (11.5 ± 3.6%) compared to wild type (17.6 ± 3.6%, P&lt;0.05, n=3), confirming that ASM is an essential contributor to mitochondrial ceramide regulation. Pre-treatment of BREC with an ASM inhibitor Desipramine revealed a 1.75-fold increase in maximal respiratory capacity compared to control cells. Diabetes results in decreased mitochondrial sphingomyelin and increased mitochondrial ceramide consistent with ASM-dependent ceramide production. Inhibition of ASM in BREC results in increased maximal, but not basal, respiratory rates. These results support the hypothesis that ASM activation and mitochondrial ceramide accumulation leads to inhibition of oxidative phosphorylation and REC damage in diabetic environment.

Disclosure
D. Pegouske: None. Y. Levitsky: None. S. Hammer: None. T.A. Lydic: None. A. Muchnik: None. D.A. Proshlyakov: None. J.V. Busik: None.

Funding
National Institutes of Health (R01EY028049, R01EY016077)
589-P: Could Diabetic Retinopathy Predict Cerebrovascular Disease? Evidence from Our Observation and Pooling Studies
Authors: ZHOU JIAN-BO , ZHANG RUI-HENG , ZHU XIAO-RONG , YANG JIN-KUI 
Published: June 2019

Background: Diabetic retinopathy (DR) is linked to cerebrovascular disease. However, the extent to which DR may confer the risk of incidence stroke is unclear.
Research Design and Methods: This study included two sets. Firstly, a prospective cohort set was performed to explore the relationship of proliferative diabetic retinopathy (PDR) to silent cerebral infarction (SCI). Then an accumulated evidence from cohort studies were evaluated to calculate adjusted hazard ratios of stroke events.
Results: During an average of 5.3 years follow-up, 39 (26 in PDR group and 13 in NDR group) SCI events occurred. After adjusted by covariates, the risk of SCI was significantly higher in the PDR group compared with NDR group (HR=2.69, 95% CI 1.24-5.84). Accumulated evidence from seven cohort studies with 20243 diabetic patients showed that DR was significantly associated with a higher risk of stroke (HR=1.73, 95% CI 1.30-2.16), even after adjusted by covariates (HR=1.54, 95% CI 1.14-1.93). Mild DR, macular edema and cotton wool spots in retina also conferred risk of stroke. There was an explainable low heterogeneity and no evidence of publication bias.
Conclusions: Different signs of DR predict incidence of asymptomatic and symptomatic stroke. Regular retinal examination has important clinical implications for the prevention of stroke in diabetic patients.

Disclosure
J. Zhou: None. R. Zhang: None. X. Zhu: None. J. Yang: None.

Funding
National Natural Science Foundation of China (81870556, 81670738)
59-OR: Liraglutide Preserved Insulin Secretion in Adults with Newly Diagnosed Type 1 Diabetes: The NewLira Trial
Authors: DEJGAARD THOMAS F. , FRANDSEN CHRISTIAN S. , KIELGAST URD , ANDERSEN HENRIK U. , THORSTEINSSON BIRGER , KRARUP THURE , HOLST JENS J. , MADSBAD STEN 
Published: June 2019

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion in adults with type 1 diabetes and residual beta-cell function. This randomized, double-blind, placebo-controlled, 52-week trial evaluated the efficacy of liraglutide 1.8 mg QD added to insulin treatment in adults diagnosed with type 1 diabetes within 6 weeks prior to screening. At randomization, at end-of-treatment (week 52) and at follow-up (week 58), a 240-min. liquid mixed meal test (237 kcal Nestlé BOOST) was conducted to evaluate the C-peptide response. In total, 65 adults (age 18-40 years) with newly diagnosed type 1 diabetes, stimulated C-peptide ≥200 pmol/L and BMI &gt;20 kg/m2 were randomized (1:1) to liraglutide or placebo added to insulin treatment. Baseline characteristics were similar between groups (mean±SD) age 27±5 years, fasting C-peptide 359±226 pM and diabetes duration 4.4±1.2 weeks. At end-of-treatment, liraglutide sustained stimulated C-peptide secretion and reduced insulin dose compared with placebo (Table). At 6 weeks post-treatment, stimulated C-peptide levels and total insulin dose did not differ between the groups. No difference was found between groups in HbA1c or BMI (Table). No events of severe hypoglycemia or ketoacidosis were reported. In conclusion, liraglutide preserved postprandial insulin secretion one year after diagnosis of type 1 diabetes. The effects had disappeared 6 weeks post-treatment.

Disclosure
T.F. Dejgaard: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim International GmbH. C.S. Frandsen: None. U. Kielgast: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Sanofi. H.U. Andersen: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Nordic Infucare. Stock/Shareholder; Self; Novo Nordisk Inc. B. Thorsteinsson: None. T. Krarup: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None.

Funding
Novo Nordisk
592-P: Diabetic Retinopathy Grade as Predictor of Outcomes in Patients with Type 2 Diabetes and Lower Extremity Amputations—Multicentric Longitudinal Seven-Year Study
Authors: SHAH KIRAN , NATARAJAN SUNDARAM , PARSEWAR VISHWANATH , SHIVANE VYANKATESH K. 
Published: June 2019

Lower Extremity Amputations (LEA) and Diabetic Retinopathy (DR) are debilitating complications in patients with T2DM. We prospectively explored the association of grades of DR with the outcomes and the risk factors in patients (n=2500) with LEA (January 2011 to December 2017) Goodness of fit was examined using Pearson Chi Square test. Severe neuropathy (n=1341, 53.6%), osteomyelitis (n=1274, 50.9%), and gangrene (n=1242, 49.6%), were the predominant comorbidities. DR was observed in 56% (n=1400) of patients (NPDR n=962, 38%; PDR n=438, 16%). DR and LEA were strongly related with the highest association observed for amputations of both lower limbs (n=640), followed by above knee (n=365), below knee (n=249) and toes (n=146) (p&lt;0.00001). 73.8% of patients with DR (n=1034) had HbA1c &gt;11%. The seven year follow-up was characterized by a high incidence of new diabetic ulcers and amputations (62.8% n=1571, p&lt;0.00001). The incidence of new ulcers was highest in the NPDR group (n=483, 50.2%) whereas the incidence of new amputations was highest in the PDR group (n=238, 54.3%). The all-cause mortality was 41.9% (n=1048, p&lt;0.00001). Patients with NPDR reported highest mortality (n=508, 48.4%). Myocardial Infarction (n=316, 30.01%) was leading cause of mortality in patients with NPDR (n=237, 42.3%) whereas Congestive Heart Failure (n=604, 57.6%), was predominant cause of mortality in patients with PDR (n=350, 70.5%) (p&lt;0.00001). The incidence of mortality 29.4% (n=308) was highest in the 7th year of follow-up. We observed that grades of DR had independent higher predictive values for new ulcers, new amputations and all-cause mortality. Patients with NPDR had worst outcomes. This long-term prospective study highlights the importance of grades of DR to predict outcomes beyond ocular morbidity and implement an integrated multidisciplinary approach for this composite complication, as a consequence of diabetes.

Disclosure
K. Shah: None. S. Natarajan: None. V. Parsewar: None. V.K. Shivane: None.
596-P: Previous Dramatic Reduction of HbA1c and Retinopathy in Type 2 Diabetes
Authors: LARROUMET ALICE , KOROBELNIK JEAN-FRANCOIS , FOUSSARD NINON , BLANCO LAURENCE , MOHAMMEDI KAMEL , MONLUN MARIE , RIGALLEAU VINCENT 
Published: June 2019

In type 2 diabetes, Diabetic Retinopathy (DR) can worsen with rapid glucose control in specific circumstances. We sought whether DR can be systematically related to a previous dramatic reduction of HbA1c. In patients hospitalized for uncontrolled or complicated type 2 diabetes, we collected values of HbA1c from the previous years. "Rapid declinors" were defined by a reduction of more than -3% between two consecutive HbA1c values, and "sustained moderate declinors" if the HbA1c always declined without reaching -3%. We compared the prevalences of DR according to the previous HbA1c courses, and adjusted the analysis for risk factors for DR. Our 680 patients were mainly men (56.8%), 62±10 years old, with 14±10 year duration of diabetes. Their BMI was 32.1±6.1 kg/m2. Sixty-seven percent had arterial hypertension, 67.5% were treated by a statin and 44.5% had a Diabetic Kidney Disease. They were poorly controlled: mean HbA1c at 8.7±1.7% at admission. One thousand and five hundred previous HbA1c values were available: 9.0±1.9% during the previous year (n=641, time -4±4 months before), 8.7±1.8% during the year before (n=363, time -16±4 months), 8.7±1.8% during the second year before (n=253, time -30±4 months), and 9.0±2.2% for the most ancient (n=243, time -65±27 months).One hundred and sixty-three subjects (24%) had a DR, associated to a longer duration of diabetes, higher previous HbA1c, arterial hypertension, Diabetic kidney disease, and dyslipidemia. A previous rapid decline of HbA1c was related to DR (OR=1.869, 95% CI:1.028-3.401) after adjustment for age, gender, BMI, arterial hypertension and DKD, blood lipids and statin treatment, duration of diabetes and the mean of previous available HbA1c. The relation between DR and a previous sustained moderate reduction of HbA1c as occurred in 193 other subjects (28.3%) was NS (OR=0.798, 95% CI:0.485-1.313). In subjects with poorly controlled T2D, a history of rapid decline of HbA1c was found to predispose to DR in our population, whereas a sustained moderate decline was safe.

Disclosure
A. Larroumet: None. J. Korobelnik: Board Member; Self; Novo Nordisk Inc. Consultant; Self; Allergan, Bayer AG, Novartis France, Roche Pharma. N. Foussard: None. L. Blanco: None. K. Mohammedi: None. M. Monlun: None. V. Rigalleau: None.
611-P: Berberine Prevented High-Fat Diet-Induced Metabolic Disorders via Inhibition of Whole Lipid Metabolism
Authors: YU MUYU , ALIMUJIANG MIRIAYI , YIN JUN 
Published: June 2019

Berberine, an alkaloid extracted from coptis and phellodendron, is known to alleviate lipid metabolism disorders, but the precise molecular mechanism remains unknown. This study aimed to investigate whether berberine regulated lipid metabolism by mitochondrial complex I suppression. In this study, the mitochondrial complex I inhibitor rotenone was used parallel to explore whether the lipid-lowering action of BBR was related to complex I. B6 mice were fed with high-fat diet (HFD) with or without berberine or rotenone for 20 weeks. Obesity, hepatic steatosis and insulin resistance were induced by HFD and reversed by berberine. Additionally, berberine reduced HFD induced complex I-dependent oxidative phosphorylation of gut and liver, citrate synthase activity, mtDNA copy number and ATP synthesis in liver. It also inhibited lipid synthesis, fatty acid uptake and oxidation. Furthermore, berberine increased the length and decreased the density of mitochondria to facilitate mitochondrial fusion. Berberine promoted the intestinal lipid excretion as well as reduced the abundance and diversity of gut microbiota remarkably. Nevertheless, no changes in metabolism and mitochondrial function of the recipient mice were observed after transplantation of fecal microbiota from the berberine treated mice. In vitro, berberine normalized oleic acid induced lipid deposition of mouse primary hepatocytes significantly. Oleic acid decreased AMPK activity, which was activated by berberine. The lipid-lowering effects of berberine were unaffected in the presence of compound C, an AMPK inhibitor. In all experiments, rotenone showed similar effects as berberine except for the little alteration of gut bacteria.
In conclusion, these results suggested that mitochondrial complex I of gut and liver is the target of berberine. Berberine and rotenone alleviates obesity and hepatic steatosis independently of gut microbiota and AMPK activity.

Disclosure
M. Yu: None. M. Alimujiang: None. J. Yin: None.

Funding
National Natural Science Foundation of China (81670790)
620-P: Novel Case of Diabetes Mellitus with VLCAD Deficiency
Authors: PRICE CATHERINE E. , MEKALA KAVYA , FAVREAU KACI 
Published: June 2019

Objective: To present a novel case of diabetes mellitus (DM) with hypertriglyceridemia in a patient with Very Long Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) Deficiency.
Case: A 37 year old man presented to ER with nausea, emesis, and abdominal pain. He also noted polyuria, polydipsia, and 23 pounds weight loss in the prior 2 weeks, during a rehab program for cocaine abuse. He reported non-adherence to very high carbohydrate, low fat diet prescribed for VLCAD Deficiency, myopathic episodic form. Labs on admission revealed Na 123 mmol/L, K 6.0 mmol/L, BG 1,065 mg/dL, Anion Gap 12 mmol/L, pH 7.377, Triglycerides 2,281 mg/dL, Lipase 46 IU/L, CK 326 IU/L, Urine negative for ketones, Serum Beta-Hydroxybutyrate 0.62 mmol/L, Serum Osmolality 337 mOsm/kg, and HbA1c 13.5%. IV insulin and IVF were used to treat hyperglycemia and hypertriglyceridemia. CK levels remained stable. He was transitioned off IV insulin to subcutaneous insulin once TGL&lt;1000 mg/dL.
Discussion: VLCAD Deficiency is a rare autosomal recessive disease that disables the breakdown of long-chain fatty acids into energy, which can be a significant issue during times of fasting. It is treated primarily with dietary modifications consisting of a high carbohydrate, low fat diet. Prolonged fasting is not recommended in this condition, to avoid risk of rhabdomyolysis. Given these concerns, caution was exercised to avoid hypoglycemia by adding dextrose to IV fluids and initiating complex carb diet thereafter. DM has been reported to occur in patients with medium-chain acyl-coenzyme A dehydrogenase deficiency, but to our knowledge, has not been described in VLCAD Deficiency in literature. In this case, the diagnosis of DM was established in the setting of elevated triglycerides and deviation from prescribed diet. Ketones were low, likely owing to limited fatty acid oxidation. GAD Antibody was undetectable and Tetradecenoylcarnitine, C14:1 elevated to 4.37 was consistent with deficiency of VLCAD. Further investigations will be pursued to determine potential underlying mechanism.

Disclosure
C.E. Price: None. K. Mekala: None. K. Favreau: None.
64-OR: Postprandial Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide in Type 2 Diabetes
Authors: STENSEN SIGNE , GASBJERG LÆRKE S. , KROGH LIVA S. , SPARRE-ULRICH ALEXANDER HOVARD , SKOV-JEPPESEN KIRSA , JENSEN METTE HØY , HARTMANN BOLETTE , VILSBØLL TINA , HOLST JENS J. , ROSENKILDE METTE MARIE , CHRISTENSEN MIKKEL B. , KNOP FILIP K. 
Published: June 2019

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is released from the small intestine following meal ingestion and potentiates glucose-stimulated insulin secretion. Exogenous GIP has a poor insulinotropic effect in patients with type 2 diabetes (T2D). We investigated postprandial effects of endogenous GIP in patients with T2D using the GIP receptor antagonist, GIP(3-30)NH2. In a randomized, double-blinded, placebo-controlled, cross-over study, 10 patients with T2D (mean±SD; HbA1c 6.9±3.2%; BMI 32.5±4.8 kg/m2) received 250-minute infusions of GIP(3-30)NH2 (1,200 pmol/kg/min) or placebo (saline) during two separate standardized liquid meal tests. Compared with placebo, GIP(3-30)NH2 infusion caused lower postprandial insulin (Δ%±SD; -19±15%, P=0.010) and C-peptide (-14±21%, P=0.021) responses (area under the curve) but had no effect on plasma glucagon (P=0.580) or glucose excursions (P=0.692). Postprandial inhibition of bone resorption (assessed by carboxy-terminal collagen crosslinks) was ∼50% lower during GIP(3-30)NH2 infusion compared with placebo (P=0.005; Figure 1).
In conclusion, endogenous GIP slightly reduced postprandial insulin secretion with no effect on postprandial glucagon or glucose concentrations in patients with T2D. In contrast, endogenous GIP was a major determinant of postprandial suppression of bone resorption in these patients.

Disclosure
S. Stensen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Krogh: None. A.H. Sparre-Ulrich: Other Relationship; Self; Antag Therapeutics. K. Skov-Jeppesen: None. M. Jensen: Employee; Self; Antag Therapeutics. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.

Funding
Novo Nordisk Foundation; European Foundation for the Study of Diabetes