bluuebunny/crossref_metadata_2025_split huggingface dataset:
386-P: Chronic and Acute Consumption of a Ketogenic Diet Leads to Deficits in Hypoglycemic Counterregulation in Mice
Authors: DUVALL MARINA A. , COULTER CAROLYN , HILL CRISTAL M. , MORRISON CHRISTOPHER , SIKAFFY HUNTER X. , MCDOUGAL DAVID 
Published: June 2019

Background: Due to their metabolic benefits, ketogenic diets (KDs) are growing increasingly popular as a dietary strategy for augmenting treatment of type 1 and type 2 diabetes. Although much is known regarding the metabolic benefits of KDs, little is known about their effect on hypoglycemic counter-regulation. We tested whether mice fed a KD have normal hypoglycemic counter-regulation.
Methods: B6 mice were fed a KD (Bio-Serv; F3666) ad lib for either 28 days (chronic) or 7 days (acute). On the final day of the diet, hypoglycemic counter-regulation was assessed via glucoprivic challenge (ICV 2DG, 1 mg/mouse, or saline) in the chronic KD group or via a hypoglycemic insulin tolerance test (ITT) in the acute KD group. Deficits in the counter-regulatory response were determined by comparing glucose and glucagon levels to control mice simultaneously fed a standard chow diet (LabDiet; 5001). ITTs consisted of a variable dose of IP insulin which produced equivalent hypoglycemia in all groups (∼45 mg/dL).
Results: As expected, mice fed a KD either acutely or chronically had lower fasting blood glucose levels relative to controls (chronic KD: 132.4 and 167.5mg/dL respectively, p = 0.0011, n= 12-17/group; Acute KD: 167.3 and 200.7 mg/dL respectively, p = 0.026; n = 7-10/group). In response to glucoprivic challenge, chronic KD mice had a blunted rise in both glucose and glucagon relative to chow fed mice (Delta glucose: 84.2 and 135.8 mg/dL respectively, p = 0.017; Glucagon: 32.7 and 73.8 pg/mL respectively, p = 0.027; n = 5-8/group). Acute KD mice also had reduced serum glucagon levels in response to the ITT (28.8 and 50.1 pg/mL respectively, p = 0.044).
Conclusions: We show that consuming a KD reduces glucose counter-regulation in mice. If a similar effect exists in persons with diabetes it could blunt a homeostatic response which is critical for counteracting treatment-induced hypoglycemic crises. Further characterization of the effects of KDs on glucose counter-regulation is warranted.

Disclosure
M.A. DuVall: None. C. Coulter: None. C.M. Hill: None. C. Morrison: None. H.X. Sikaffy: None. D. McDougal: None.

Funding
American Diabetes Association (1-15-JF-37 to D.M.)
39-OR: VPS41 Contributes to Insulin Granule Biogenesis
Authors: BURNS CHRISTIAN H. , YAU BELINDA , KEBEDE MELKAM A. , ASENSIO CEDRIC S. 
Published: June 2019

Insulin secretory granules (ISGs) mediate the regulated secretion of insulin. The basic machinery responsible for this regulated exocytosis consists of specific membrane proteins present both at the plasma membrane and on ISGs. The protein composition of ISGs thus dictates their release properties, yet the mechanisms controlling ISG budding from the trans-Golgi network (TGN), which partly determines this molecular composition, remain poorly understood. The cytosolic protein VSP41 was recently identified as a potential coat protein at the TGN involved in the formation of neuroendocrine/neuronal granules. To test whether this protein might contribute to ISG biogenesis, we have generated VPS41 KO Ins1 cells using CRISPR/Cas9. Loss of VPS41 leads to reduced cellular insulin content with a defect in regulated insulin secretion. We also find, using live-imaging and a pHluorin based reporter, that VPS41 KO cells exhibit less stimulated exocytotic events. At the cellular level, insulin appears to be retained in a perinuclear compartment, and cell fractionation and electron microscopy analysis further reveal a change in ISG protein composition and number. Finally, mice with a beta-cell specific deletion of VPS41 are glucose intolerant and display a defect in insulin secretion in response to glucose. Altogether our data suggest that VPS41 is an important player in the formation or maintenance of ISG.

Disclosure
C.H. Burns: None. B. Yau: None. M.A. Kebede: None. C.S. Asensio: None.

Funding
American Diabetes Association (1-17-JDF-064 to C.S.A.); National Institutes of Health (R15GM116096, R01GM124035)
394-P: Nonsevere Hypoglycemia Treatment in Adults with Type 1 Diabetes: A Validation Study of Carbohydrate Intake at Different Glucose Thresholds
Authors: TALEB NADINE , MESSIER VIRGINIE , PARENT VALERIE , BOVAN DANIJELA , BRAZEAU ANNE-SOPHIE , RABASA-LHORET RÉMI 
Published: June 2019

Background: For nonsevere hypoglycemia (NS-H), treatment guidelines recommend 15-20g of rapidly absorbed carbohydrates (CHO) and repeat intake at 15 min until recovery (glucose above 70 mg/dL). The adequacy of this one size fits all approach is questioned. Our group reported an average intake of 32 ± 24g CHO in a type 1 diabetes (T1D) outpatient study. We aim to validate N-SH treatment guidelines in the context of modern therapies.
Methods: Randomized four way cross-over trial to assess treatment with 16g vs. 32 g CHO (glucose tablets) for fasting subcutaneous insulin induced NS-H at two glucose thresholds: a) below 54 mg/dL and b) between 54 to 63 mg/dL. Plasma glucose is measured every 5 min till recovery then at 15-30 min intervals.
Results: Preliminary data was collected for 12 of 33 subjects (53.2 ± 16.8 years old, 58.3% females, HbA1c 56 ± 7.7 mmol/mol, diabetes duration 31.9 ± 15.8 years). Comparison of 16 vs. 32g CHO for each threshold revealed the following change in glucose 15 min post treatment (primary outcome): a) below 54 mg/dL: 12.0 ± 21.8 vs. 17.6± 28.4 mg/dL, p=0.4; b) between 54 to 63 mg/dL: -1.6 ± 19.7 vs. 12 ± 22.7 mg/dL, p=0.06; time needed to recovery (above70 mg/dL): a) below 54 mg/dL: 30 ± 13.6 vs. 29.6 ±14.4 min, p= 0.9; b) between 54 to 63 mg/dL: 37.5 ±14.4 vs. 28.7 ± 17.2 min, p= 0.1 and time needed for disappearance of symptoms: a) below 54 mg/dL: 27.8± 22.3 vs. 22.8 ± 9.5 min, p=0.8; b) between 54 to 63 mg/dL: 24.2 ± 10.7 vs. 16.7± 11.5 min, p=0.5. Regression analysis will be conducted to study response predictors (plasma insulin and catecholamines levels, body composition, etc.)
Conclusion: The response to nonsevere hypoglycemia treatment is extremely variable. A one size fits all recommendation is unlikely to be appropriate. Data of this trial will add to the knowledge of hypoglycemia treatment in T1D.

Disclosure
N. Taleb: None. V. Messier: Other Relationship; Self; Eli Lilly and Company. V. Parent: None. D. Bovan: None. A. Brazeau: None. R. Rabasa-Lhoret: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk A/S.

Funding
Canadian Institutes of Health Research (354024); JDRF (4-SRA-2018-651-Q-R)
396-P: SGLT2 Inhibition Suppresses Glucagon Response to Hypoglycemia in Male but Not Female Rats with Streptozotocin-Induced Type 1 Diabetes
Authors: GREENBERG CAYLEE A. , MANDEL ERIN R. , PASIEKA AOIBHE M. , JAHANGIRIESMAILI MAHSA , TREMBLAY JULIE , RIDDELL MICHAEL 
Published: June 2019

Sodium glucose co-transporter 2 inhibitors (SGLT2i) show promise as an add-on to insulin therapy in patients with type 1 diabetes (T1D), however their effect on glucagon secretion in T1D is not yet known. Increases in glucagon have the potential to protect against hypoglycemia that may develop from insulin overtreatment or exercise. We investigated whether 8 days of SGLT2i treatment (10mg/kg empagliflozin, 2x/day) altered plasma glucagon concentrations in response to voluntary running wheel activity and insulin-induced hypoglycemia in male and female Wistar rats with streptozotocin-induced T1D. SGLT2 inhibition did not alter basal or post-exercise glucagon concentrations and did not affect exercise-associated changes in blood glucose (BG) levels. Additionally, SGLT2 inhibition did not alter voluntary activity levels. However, in males, SGLT2 inhibition lowered plasma glucagon response during an insulin tolerance test (+22.7±30.8 pg/mL vs. +40.4±48.6 pg/mL, p=0.02) and decreased the time taken to reach hypoglycemia (30±13.4 min vs. 63.8±17.2 min, p&lt;0.0001), as compared to placebo. We also observed novel sex differences in the response of BG and glucagon concentrations to voluntary exercise. In female rats alone, voluntary exercise decreased BG concentrations (-2.9±2.6 mM vs. +1.7±1.8 mM, p=0.0003) and led to lower post-exercise glucagon concentrations (37.3±47.9 pg/mL vs. 117.9±86.0 pg/mL, p=0.01), as compared to inactive animals. On average, voluntary activity levels were higher in females than in males (539.2±199.4 m vs. 308.4±215.6 m, p=0.02), however running distances were not correlated with changes in BG levels during exercise (r2=0.02). Our finding of increased hypoglycemia risk with SGLT2i has concerning implications for its use as an adjunct to insulin therapy in T1D. The novel sex differences that we observed should be investigated in individuals with T1D to determine their human applicability and potential mechanisms.

Disclosure
C.A. Greenberg: None. E.R. Mandel: None. A.M. Pasieka: None. M. Jahangiriesmaili: None. J. Tremblay: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc.
40-LB: Association between Complement and Severe Retinal Complications in Type 1 Diabetes—An 18-Year Follow-Up Study
Authors: HOLT CHARLOTTE B. , HOFFMANN-PETERSEN INGEBORG TORP , øSTERGAARD JAKOB A. , PARVING HANS- HENRIK D. , THIEL STEFFEN , HOVIND PETER , TARNOW LISE , ROSSING PETER , HANSEN TROELS K. 
Published: June 2019

Introduction: Diabetic retinopathy (DR) remains the leading cause of preventable vision loss in developed countries. Adverse activation of the complement system plays an essential role in development of complications in diabetes and has been demonstrated in eyes from patients with DR. We hypothesized that complement proteins of lectin pathway can predict severe DR, defined as proliferative DR and macular edema, in newly diagnosed type 1 diabetes.
Methods: In this explorative study, incidence of severe DR was monitored in a cohort of newly diagnosed type 1 diabetes patients (n=270) with median follow-up time of 18 years (range 1-22 years). Baseline complement proteins MBL, M-ficolin, H-ficolin, MASP-1, MASP-2, MASP-3, MAp44, and MAp19 were quantified using immunoassays. A cox proportional hazards regression model was applied to test for difference between quantile groups and adjusted for age and HbA1c.
Results: During follow-up, 28 patients developed severe DR. A tendency arose when testing association between MAp44 levels and severe DR in an unadjusted model (HR, 4th quartile vs. the remaining, 1.3; 95% CI 0.99, 1.6), p = 0.06), which became significant in the adjusted model (HR, 1.33; 95% CI 1.0, 1.7), p = 0.04), Fig. 1.
Conclusion: MAp44 was significantly associated with development of severe DR, whereas other complement factors were not. Further analysis in a larger cohort is warranted.

Disclosure
C.B. Holt: None. I.T. Hoffmann-Petersen: None. J.A. østergaard: None. H.D. Parving: None. S. Thiel: None. P. Hovind: None. L. Tarnow: Stock/Shareholder; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk Foundation. P. Rossing: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novartis AG, Novo Nordisk A/S. T.K. Hansen: None.

Funding
Aarhus University; Foundation of Skibsredder Per Henriksen
40-OR: The Role of TALK-1 K+ Channels in Pancreatic ß-Cell Insulin Secretion, Mitochondrial Function, and the ER Stress Response
Authors: GRAFF SARAH M. , DADI PRASANNA , IBSEN CHLOE E. , DICKERSON MATTHEW , JORDAN KELLI L. , JACOBSON DAVID 
Published: June 2019

During Glucose-Stimulated Insulin Secretion (GSIS), β-cells exhibit oscillations in cytosolic Ca2+ ([Ca2+]c) and endoplasmic reticulum (ER) Ca2+ ([Ca2+]ER), which are regulated by the two-pore domain K+ channel, TALK-1. TALK-1 is the most abundant β-cell K+ channel and it controls Ca2+ homeostasis by modulating K+ permeability at both the plasma and ER membrane. However, how TALK-1 modulates ER stress and β-cell failure during the pathogenesis of diabetes has not been determined. To understand how TALK-1 controls β-cell function under diabetic conditions, we assessed how a mutation in TALK-1 (ND) which causes neonatal diabetes, impacts TALK-1 channel activity and [Ca2+]ER handling. While plasmallemal TALK-1 activity was inhibited with the ND mutation, [Ca2+]ER storage was significantly reduced by the ND mutation compared to control TALK-1. This suggests that TALK-1 ND enhances TALK-1 activity on the ER membrane leading to reduced [Ca2+]ER storage. Reducing [Ca2+]ER enhances ER stress, which would be expected to cause β-cell dysfunction. Indeed, TALK-1 ND significantly reduces β-cell insulin secretion compared to control. To further investigate the role of TALK-1 we developed a β-cell-specific TALK-1 KO mouse model (β-TALK1-KO). On a high fat diet, β-TALK1-KO mice show improved glucose tolerance compared to controls. Mitochondrial calcium ([Ca2+]mito) was also examined because it is modulated by [Ca2+]ER; we found that β-TALK1-KO mice have increased [Ca2+]mito. As reactive oxygen species (ROS) production is a byproduct of mitochondrial respiration, we investigated if TALK-1 affects ROS production. TALK1 KO islets were found to have reduced ROS production compared to wild type islets. Together, these data indicate that increased TALK-1 channel activity reduces [Ca2+]ER, [Ca2+]mito, and increases ROS; suggesting that TALK-1 plays an important role in modulating the β-cell responses to stress associated with diabetic conditions.

Disclosure
S.M. Graff: None. P. Dadi: None. C.E. Ibsen: None. M. Dickerson: None. K.L. Jordan: None. D. Jacobson: None.
411-P: PRMT1 Upregulation and ADMA Accumulation Contribute to the High Sensitivity of Zucker Diabetic Fatty Rats to Myocardial Ischemia/Reperfusion Injury
Authors: XIONG YAN , LIN YUAN , LEI YANPING , HE ZHI-MIN , ZHOU XIN-KE 
Published: June 2019

Diabetic patients show a high sensitivity to myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism has remained obscure. Increasing evidence indicates that protein arginine methyltransferase1 (PRMT1) is implicated in modulation of cellular processes including gene transcription, energy metabolism, apoptosis and generation of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS). ADMA as an intermediate of protein arginine methylation catalyzed by PRMT1 is associated with diabetic cardiovascular complications. This study was to examine whether PRMT1-ADMA disorder is involved in the high sensitivity to myocardial I/R injury in Zucker diabetic fatty (ZDF) rats. Myocardial I/R injury was induced by 30min of ligation in left anterior descending coronary artery followed by 2∼24h reperfusion. Cardiac function was measured by M-echocardiography, and ADMA signaling pathway was evaluated by expressions, activities or contents of signal molecules. ZDF rats showed severer cardiac dysfunction and larger area of infarction after myocardial I/R injury compared with Zucker-control rats. Expression and activity of PRMT1 and ADMA content were higher while expression and activity of NOS and nitric oxide (NO) content were lower in ZDF rats. Treatment with PRMT1 inhibitor TC-E or knockdown of PRMT1 with shRNA-PRMT1-LV reduced myocardial ADMA accumulation and protected cardiac function of ZDF rats from I/R injury. Exogenous ADMA perfusion of isolated heart from control rats could induce similar cardiac dysfunction to that of I/R injury. Treatment with TC-E or NO donor protected the isolated heart from I/R injury or ADMA-induced impairment. These results indicate that PRMT1 upregulation and ADMA accumulation contribute to the high sensitivity of ZDF rats to myocardial I/R injury and reveal the novel target for prevention and treatment of myocardial I/R injury in diabetes mellitus.

Disclosure
Y. Xiong: None. Y. Lin: None. Y. Lei: None. Z. He: None. X. Zhou: None.

Funding
National Natural Science Foundation of China (81570751); Guangdong Province (2016A030311050)
413-P: SIRT1 Overexpression Restores the Protective Effects of Ischemic Post-conditioning in Diabetic Mice via Modulating Akt Signaling Pathway
Authors: DING MINGGE , ZENG KE , YU MINGZHE , LIU CHAOYANG , FU FENG 
Published: June 2019

Ischemic post-conditioning (IPO) activates Akt signaling to confer cardioprotection. The responsiveness of diabetic hearts to IPO is impaired. We hypothesized that decreased cardiac SIRT1, a positive regulator of Akt, may be responsible for the impaired responsiveness of diabetic hearts to IPO-mediated cardioprotection. High-fat diet and streptozotocin-induced diabetic mice were subjected to myocardial ischemia/reperfusion (MI/R, 30 minutes ischemia and 180 minutes reperfusion) or IPO (three cycles of 10 s of reperfusion and ischemia at the onset of reperfusion). Adenoviral vectors encoding GFP or SIRT1 (Ad-SIRT1) were administered by direct injection into the left ventricular. IPO activated the Akt signaling pathway and reduced MI/R injury in nondiabetic hearts but not in diabetic hearts, in which reduced expression of SIRT1 and increased Akt acetylation were observed. Delivery of Ad-SIRT1 into the diabetic hearts reduced Akt acetylation and restored the cardioprotective effects of IPO. In in vitro study, transfection with wild type SIRT1 but not inactive mutant SIRT1 reduced the expression of Akt acetylation and restored the protective effects of hypoxic post-conditioning in high glucose-incubated primary cardiomyocytes. Moreover, the cardiomyocytes transfected with Akt acetylation-defective mutant (K20R) showed increased Akt phosphorylation and enhanced protective effects against hypoxia/reoxygenation injury. These findings demonstrate that SIRT1 up-regulation restores IPO-mediated cardioprotection in diabetic mice via deacetylation-dependent activation of Akt signaling pathway. It is suggested that targeting up-regulation of SIRT1 may be a potential therapeutic strategy to restore myocardial responsiveness to post-conditioning in diabetic patients.

Disclosure
M. Ding: None. K. Zeng: None. M. Yu: None. C. Liu: None. F. Fu: None.

Funding
National Natural Science Foundation of China (81600235, 81670354); Natural Science Foundation of Shaanxi (2018JM7061)
427-P: The Prevalence of Asymptomatic Cardiac Dysfunction Diagnosed by Tissue Doppler Echocardiography in Subjects with Type 2 Diabetes
Authors: TAKATA YASUNORI , TAKAKADO MISAKI , HADATE TOSHIMI , KAWAMURA RYOICHI , OSAWA HARUHIKO 
Published: June 2019

Background: The sodium-glucose transporter 2 inhibitors have been found to reduce the risk of hospitalization for heart failure (HF). However, in the majority of clinical studies of diabetes, HF is usually defined as administration to hospital with typical symptoms without measurements of cardiac-function using tissue Doppler echocardiography (TDE). Therefore, the incidence of cardiac-dysfunction in diabetic subjects would be underestimated, leading to a delay in the initiation of treatment. Thus, we analyzed the prevalence of asymptomatic cardiac-dysfunction (ACD) diagnosed by TDE in subjects with diabetes.
Methods: We recruited inpatients or outpatients with type 2 diabetes at university hospital. Subjects with symptomatic HF, atrial fibrillation, myocardial infarction, valvular disease, and hypertrophic cardiomyopathy were excluded from this study. Finally, 343 diabetic subjects were enrolled. Cardiac-dysfunction was defined as left ventricular ejection fraction &lt;50% (systolic dysfunction) and/or the ratio of early transmitral flow velocity to TDE diastolic mitral annular velocity&gt;15 (diastolic dysfunction). To determine optimum cut-off values for BNP and eGFR associated with ACD, we performed ROC curve analyses.
Results: Twenty-four % of subjects had ACD. Seventy-eight % of these subjects had diastolic dysfunction. Age, the proportion of females, pulse wave velocity and BNP were higher, and eGFR was lower in subjects with cardiac-dysfunction than those without cardiac-dysfunction. ROC curve analyses revealed that AUCROC for BNP was 0.66 with a sensitivity of 57% and a specificity of 70% at a cut-off value of 32 mg/gCr, and eGFR was 0.53 with a sensitivity of 74% and a specificity of 70% at a cut-off value of 62 mL/min/1.73m2 (both p&lt;0.001).
Conclusions: About a quarter of diabetic subjects had ACD, and the majority of them were diastolic dysfunction. Therefore, TDE would be needed to accurately assess ACD in subjects with diabetes.

Disclosure
Y. Takata: None. M. Takakado: None. T. Hadate: None. R. Kawamura: None. H. Osawa: None.
43-LB: Characteristics of Statin Initiation and Its Association with Mortality in Diabetic and Nondiabetic U.S. Elderly Veterans
Authors: SOOHOO MELISSA , STREJA ELANI 
Published: June 2019

Background: Trials examining statin benefit often exclude elderly patients over age 75 years; thus specific guidelines on statin initiation for this group are lacking. Among U.S. veterans, there is a growing elderly population with a high prevalence of diabetes and cardiovascular (CV) disease. We sought to characterize which elderly diabetic and nondiabetic U.S. veterans initiated a statin and the related all-cause mortality risk.
Methods: We identified 204,217 veterans who were not on statin at baseline (2004-2006) and were more than 75 years old at the time of initial lipid measurement between 2006-2008. Cox models were used to examine associations of statin initiation within 6 months of lipid measurement with all-cause mortality after adjustment for demographics, Charlson Index, CV comorbidites, liver disease, cancer, smoking, and kidney disease.
Results: Cohort mean age was 81±4 years, and comprised 2% female, 8% blacks, 20% diabetics, and 43% with CV disease. Statin initiation was more common in diabetics vs. nondiabetics (11% vs. 7%, respectively) and decreased with higher age. Among diabetics, there was little difference in CV comorbidities for statin initiation vs. not; whereas in nondiabetics, statin initiators were more likely to have ischemic heart disease. For both groups, statin initiators had higher triglyceride and LDL levels. Simvastatin was the most frequently prescribed statin in both groups (over 80%), followed by atorvastatin (3%) in diabetics. Over median follow-up of 9 (7,10) years, statin initiation was associated with a lower adjusted all-cause mortality risk in diabetics (HR: 0.91, 95% CI: 0.88, 0.95), with a similar association in nondiabetics (HR: 0.95, 95% CI: 0.92, 0.97).
Conclusions: Elderly U.S. veterans with diabetes who initiated statin therapy had a moderately lower risk of all-cause mortality. Further analyses will examine considerations for additional predictors and differences in cause of death.

Disclosure
M. Soohoo: None. E. Streja: None.

Funding
U.S. Department of Veteran Affairs