bluuebunny/crossref_metadata_2025_split huggingface dataset:
382-P: Insulin Requirements after Hospital Discharge in Patients with Type 2 Diabetes
Authors: FAYFMAN MAYA , LEROITH DEREK , PASQUEL FRANCISCO J. , ANZOLA ISABEL , URRUTIA MARIA A. , WANG HEQIONG , UMPIERREZ GUILLERMO E. 
Published: June 2019

Changes in insulin requirements after hospital discharge in insulin-treated patients with type 2 diabetes (T2D) are not known. We conducted a pooled analysis of 4 randomized clinical trials with 3-month follow-up data to determine changes in insulin requirement after discharge. These studies followed a discharge algorithm based on admission HbA1c to guide outpatient insulin therapy. A total of 255 insulin-treated patients (age: 55.6 year, BMI 34.6 kg/m2, duration DM: 11.2±8 year) were discharged on glargine + oral antidiabetic (OAD) agents (75%), glargine + exenatide (4%), or basal bolus (21%). Patients with HbA1c &lt;7% (11.4%) were discharged on the same outpatient therapy. Those with an HbA1c between 7% and 9% (37.2%) were discharged on glargine at 50% of hospital TDD + their outpatient OAD agents. Those with an HbA1c &gt;9% (51.4%) were discharged on glargine at 80% of hospital TDD in combination to OAD or with basal bolus regimen. Treatment was adjusted to achieve a target HbA1c level &lt;7%. The primary outcome was change in insulin total daily dose (TDD) at 3 months after discharge. Changes in HbA1c, hypoglycemia, insulin TDD, and change in insulin requirements at 3 months of follow-up are shown in Table.
In summary, insulin TDD requirements vary greatly after hospital discharge in patients with T2D. Most patients required frequent insulin adjustments to maintain glycemic control and to avoid hypoglycemia after hospital discharge.

Disclosure
M. Fayfman: None. D. LeRoith: Advisory Panel; Self; AstraZeneca, MannKind Corporation. F.J. Pasquel: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc. I. Anzola: None. M.A. Urrutia: None. H. Wang: None. G.E. Umpierrez: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca, Merck 0026 Co., Inc., Novo Nordisk Inc., Sanofi US.
389-P: Comparison of Hormonal Response to a Mixed-Meal Challenge in Individuals with Hypoglycemia after Sleeve Gastrectomy vs. Gastric Bypass
Authors: LEE CLARE , BROWN TODD , SCHWEITZER MICHAEL , MAGNUSON THOMAS , CLARK JEANNE 
Published: June 2019

Objective: Exaggerated post-prandial incretin and insulin responses are well-documented in post-bariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). Thus, we sought to compare meal-stimulated hormonal response in those with PBH after SG vs. RYGB.
Methods: We enrolled 20 RYGB (7 with and 13 without PBH) and 23 SG (12 with and 11 without PBH) who underwent bariatric surgery at our institution. PBH was defined as a postprandial interstitial or plasma glucose &lt;55 mg/dl on continuous glucose monitor (5-days as outpatient, Dexcom) or 4-hour mixed meal tolerance test (MTT). Plasma samples from MTT were used to measure glucose, insulin, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). We used Kruskal Wallis Test to compare the difference in glucose or hormones across 4 groups (with and without PBH after SG or RYGB).
Results: Participants (N=43) were on average 5 years since surgery, with mean age of 50 years, mean preoperative BMI of 48 kg/m2, 81% female, 61% Caucasian, 53% post SG. There were no differences in fasting glucose (p=0.38) or fasting insulin (p=0.34) across the 4 groups. Among those with PBH, the SG group showed a lower peak glucose (131.8 mg/dl, p&lt;0.01), similar nadir glucose (59.6 mg/dl, p=0.18), peak insulin (68.7 mU/L, p&lt;0.01) and peak GLP-1 (15.3 pM, p&lt;0.01) and differed in overall hormonal response (AUC 0-240min) with lower insulin (3956.1 mU/L/min, p&lt;0.01), lower GLP-1 (2498.9 pM/min, p&lt;0.01) and higher GIP (51335.4 pM/min, p=0.05) compared to RYGB with PBH group.
Conclusion: Among those with PBH, the SG group showed less glycemic excursion and different hormonal profiles including lower insulin, GLP-1 and higher GIP responses to MTT compared to the RYGB group. Future studies are needed to better understand the differential contribution of insulin and non-insulin mediated mechanisms behind PBH after SG vs. RYGB.

Disclosure
C. Lee: Consultant; Self; XOMA Corporation. Research Support; Self; Eiger BioPharmaceuticals. T. Brown: None. M. Schweitzer: Consultant; Self; Ethicon, Inc. T. Magnuson: None. J. Clark: None.

Funding
National Institutes of Health
391-P: Hypoglycemia Reductions with the Dexcom G6 CGM System’s Predictive Alert
Authors: DERDZINSKI MARK , WELSH JOHN , PUHR SARAH , WALKER TOMAS C. , PARKER ANDREW , JIMENEZ ANNIKA 
Published: June 2019

Background: The Dexcom G6 continuous glucose monitoring (CGM) system differs from Dexcom’s earlier G5 system in that G6 includes a predictive “Urgent Low Soon” (ULS) alert that notifies users when an estimated glucose value (EGV) ≤55 mg/dL is predicted in the next 20 minutes. The effect of the ULS alert on the distribution of EGVs was evaluated in the context of traditional threshold alerts.
Methods: We identified individuals who had used G5 and transitioned to G6 between 5/1/2018 and 10/31/2018. Evaluable data were from a subset of 4083 users who had maintained low threshold alerts at either 70 or 80 mg/dL, who used a smartphone to view and upload ≥30 days of data from each system, and who maintained the G6 ULS alert in its default (enabled) state.
Results: Use of the 80 mg/dL low threshold alert was associated with higher mean EGVs, less hypoglycemia, and more hyperglycemia than use of the 70 mg/dL low threshold alert (Table). Over 97% of the G6 systems were used with the ULS feature enabled, and the ULS alert was activated less than once daily. At either low threshold setting, the transition to G6 was associated with reductions in hypoglycemia (&lt;55 and &lt;70 mg/dL) and severe hyperglycemia (&gt;250 mg/dL).
Conclusions: When used in the context of traditional low threshold alerts, the predictive ULS alert may enable timely and appropriate interventions that contribute to further reductions in hypoglycemia among CGM-experienced users.

Disclosure
M. Derdzinski: Employee; Self; Dexcom, Inc. J. Welsh: Employee; Self; Dexcom, Inc. S. Puhr: None. T.C. Walker: Employee; Self; Dexcom, Inc. A. Parker: Employee; Self; Dexcom, Inc. A. Jimenez: Employee; Self; Dexcom, Inc.
399-P: Deintensification of Diabetes Treatment in Elderly Patients with Type 2 Diabetes Mellitus
Authors: PIRELA DANIELA V. , GARG RAJESH 
Published: June 2019

The prevalence of type 2 diabetes mellitus (T2DM) is increasing, especially in the elderly population. Many of these patients have co-morbidities like renal insufficiency, cognitive impairment and lack of social support, increasing the risk of hypoglycemia. Moreover, the benefits of tight glycemic control have not been established in the elderly. Therefore, the American Diabetes Association recommends relaxed glycemic goals (HbA1c ∼8%) in the elderly population. De-intensification of diabetes treatment is recommended to prevent potential harm. We conducted a retrospective study to evaluate the rate of de-intensification of antidiabetic treatment in patients aged ≥75 years with HbA1c ≤7% at the time of their clinic visits. All patients with ≥2 clinic visits over 1-year period at a major academic diabetes center were included. Out of 1,417 unique patients treated during 2017, 174 were ≥75 years old on the day of their last clinic visit. Out of these, 80 patients had an HbA1c ≤7%. Medical records of these 80 patients were manually reviewed for comorbidities, hypoglycemic episodes and drug therapy. A mention of de-intensification of antidiabetic treatment was found in physicians’ notes in only 12 cases. After excluding those with type 1 diabetes, inadequate documentation or controlled on medications without hypoglycemia potential, we found 36 patients treated with a sulfonylurea drug or insulin. Only 10 (27%) patients were advised to reduce the dose of sulfonylurea drug or insulin after an HbA1c &lt;7% was noted. Out of patients receiving a sulfonylurea drug or insulin, 17 had at least one episode of hypoglycemia before the visit. Even among patients with documented hypoglycemia, only 7 (41%) were advised to de-intensify therapy. Our study suggests that de-intensification of antidiabetic medications is infrequent despite the potential harm of hypoglycemia in elderly patients with T2DM. Strategies need to be developed to prevent overtreatment of diabetes in the elderly patients.

Disclosure
D.V. Pirela: None. R. Garg: None.
401-P: Acute Low Glucose Alters Human Primary Astrocyte Expression of Endoplasmic Reticulum Stress and Mitochondrial Associated Genes, Which Is Blunted after Recurrent Low Glucose
Authors: WEIGHTMAN POTTER PAUL G. , WASHER SAM J. , JEFFRIES AARON , DEMPSTER EMMA L. , BEALL CRAIG 
Published: June 2019

Astrocytes are important regulatory cells in the brain that support neuronal function. However, their role in hypoglycemia counterregulation is poorly understood. Moreover, astrocytic transcriptional responses to hypoglycemia and the mechanisms by which recurrent hypoglycemia (RH) suppresses counterregulation are not understood. Using human primary astrocytes (HPA) in vitro we tested whether recurrent low glucose (RLG), to model RH, would regulate differential gene expression (DGE). HPA cells were exposed to 3-hour bouts of 2.5 or 0.1 mM glucose over 4 days and mRNA expression was quantified using RNA-sequencing and DGE measured using DESeq2. Acute low glucose (LG) differentially expressed 31 genes including the downregulation of mitochondrial genes (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2, subunit 4 and subunit 4L; MT-ND2, MT-ND4 and MT-ND4L) and endoplasmic reticulum stress associated genes (X-box binding protein 1; XBP1, and heat shock protein family A; Hsp70, member 1A, and member 5; HSPA1A and HSPA5). However, neither antecedent RLG (aRLG) nor RLG treated cells have significantly altered gene expression compared to control. LG treatment decreased the expression of XBP1 and increased thioredoxin interacting protein (TXNIP) and exostosin Like glycosyltransferase 3 (EXTL3) which were also similarly altered by low glucose compared to aRLG.MT-ND2, MT-ND4 and MT-ND4L genes are associated with diabetes and neurodegeneration. Furthermore, LG-induced reduction of XBP1 may also increase fatty acid oxidation by disinhibiting inositol-requiring kinase 1α. This corroborates previous work indicating low glucose increases fatty acid utilisation in astrocytes and the hypothalamus. While the functional impact of differential gene expression needs assessing, this provides evidence that these genes may be important in astrocytic responses to hypoglycemia.

Disclosure
P.G. Weightman Potter: None. S.J. Washer: None. A. Jeffries: None. E.L. Dempster: None. C. Beall: None.

Funding
Novo Nordisk UK Research Foundation; Diabetes UK; Mary Kinross Charitable Trust
407-P: Growth Differentiation Factor 15, Coronary Atherosclerosis and Diabetic Kidney Disease in Adults with Type 1 Diabetes (T1D)
Authors: BJORNSTAD PETTER , SIPPL RACHEL M. , REWERS MARIAN , SNELL-BERGEON JANET K. 
Published: June 2019

Objective: In health, circulating growth differentiation factor (GDF)-15 is low, and concentrations are thought to increase rapidly in response to cardiac and renal injuries. GDF-15 is secreted in response to inflammation, oxidative stress and hypoxia, and therefore may be a biomarker of subclinical vascular disease. Yet, the relationships between GDF-15, coronary artery disease and diabetic kidney disease (DKD) remain incompletely understood. Accordingly, the objective of this study was to delineate these relationships in adults with T1D.
Methods: Participants with (n=377, HbA1c 7.8±1.3%, duration 37.1±8.6 years) and without T1D (n=456) in the Coronary Artery Calcification in type 1 diabetes (CACTI) study were assessed for serum GDF-15, coronary artery calcification (CAC) measured using 128-slice spiral CT, urinary albumin-to-creatinine ratio (UACR) and eGFR calculated by CKD-EPI creatinine. Impaired GFR was defined as eGFR &lt;60mL/minutes/1.73m2, albuminuria as UACR ≥30 mg/g, high and very high CAC score as ≥100 and ≥300 AU. Multivariable (age, sex, HbA1c, and antihypertensive medication use) logistic models were applied to examine the relationships.
Results: Participants with T1D had greater GDF-15 concentrations than nondiabetics (666.4 [95% CI 633.9-700.5] vs. 579.1 [558.7-600.4] ng/l, p&lt;0.0001). In participants with type 1 diabetes, higher GDF-15 was associated with greater odds of impaired GFR (OR: 4.40, 95% CI 2.51-7.73, p&lt;0.0001), albuminuria (2.47, 1.60-3.80, p&lt;0.0001), high CAC (1.67, 1.16-2.41, p=0.006) and very high CAC (1.62, 1.01-2.58, p=0.04) in multivariable models (per 1 SD increase in natural log GDF-15).
Conclusion: In this cross-sectional analysis, GDF-15 was strongly associated with DKD and coronary atherosclerosis in adults with T1D, independent of glycemic control. As a biomarker, GDF-15 holds promise to aid in risk stratification and clinical trial enrichment.

Disclosure
P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. R.M. Sippl: None. M. Rewers: None. J.K. Snell-Bergeon: None.

Funding
National Institutes of Health; JDRF
41-LB: Lipoprotein Subfractions Are Associated with Diabetic Microvascular Disease among 9,795 Patients in the FIELD Trial
Authors: TOTH PETER P. , KEECH ANTHONY C. , JANUSZEWSKI ANDRZEJ S. , OCONNELL RACHEL L. , LI LIPING , SULLIVAN DAVID , TASKINEN MARJA-RIITTA , DRURY PAUL L. , WATTS GERALD FRANCIS , BEST JAMES D. , ANSQUER JEAN CLAUDE , JONES STEVEN R. , JENKINS ALICIA J. 
Published: June 2019

Background: In the FIELD trial, a 5-year randomized double-blind placebo-controlled trial of fenofibrate vs. placebo in 9,795 adults with type 2 diabetes (T2D), the only standard lipid parameter correlating with microvascular (renal) events was triglycerides. Given the high prevalence of diabetic microangiopathy, we explored associations between lipoprotein subfractions and nephropathy, retinopathy, microvascular amputations (MiAmp) and neuropathy.
Methods: We performed ultracentrifugation using the vertical autoprofile (VAP, Atherotech) on plasma (baseline and after 6 weeks of fenofibrate). Analyses were performed using Cox proportional hazards and logistic regression for new on-study events. Results were adjusted for gender and fenofibrate or placebo allocation.
Results: HDL related analytes (HDL-C, HDL3-C, apo A1, apoA2) correlated with reduced risk for neuropathy, nephropathy, and MiAmp. Buoyant LDL (LDL1-C) and densest LDL (LDL4-C) correlated negatively with neuropathy and positively for MiAmp, respectively. Triglycerides and apo C3 increased neuropathy and nephropathy risk. VLDL species correlated with increased MiAmp and retinopathy risk.
Conclusions: VAP identifies multiple lipoprotein subclasses and VAP subclass/apoprotein ratios associated with diabetic microangiopathy. Many were improved with fenofibrate.

Disclosure
P.P. Toth: Consultant; Self; Amarin Corporation, Amgen Inc., AstraZeneca, Kowa Pharmaceutical Europe Co. Ltd., Novo Nordisk Inc. Speaker’s Bureau; Self; Amarin Corporation, Amgen Inc., Merck & Co., Inc., Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi US. A.C. Keech: None. A.S. Januszewski: None. R.L. OConnell: None. L. Li: None. D. Sullivan: None. M. Taskinen: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Akcea Therapeutics, Chiesi USA, Inc. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; Amgen Inc. P.L. Drury: None. G.F. Watts: None. J.D. Best: Consultant; Self; Abbott. J. Ansquer: Research Support; Self; Abbott, Mylan. S.R. Jones: None. A.J. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.
410-P: An Impaired Mitophagy-Lysosome System Contributes to Hyperglycemia Cardiotoxicity
Authors: KOBAYASHI SATORU , HUANG YUAN , KOBAYASHI TAMAYO , LI CAIRONG , CAI FEI , LIANG QIANGRONG 
Published: June 2019

Mitochondrial dysfunction plays an important role in diabetic heart damage. A healthy pool of mitochondria is maintained through a number of quality control mechanisms including mitophagy that degrades dysfunctional mitochondria through the lysosome. In the present study, we investigated the function of mitophagy-lysosome system in the diabetic heart and in cardiomyocytes cultured under high glucose. Streptozotocin-induced diabetes initiated mitophagy in the mouse heart but did not lead to its completion in the lysosome. Overexpression of the E3 ligase Parkin accelerated mitophagy flux and reduced diabetic cardiac injury. In contrast, Parkin gene deletion had the opposite effects, suggesting an essential role for mitophagy in maintaining cardiac homeostasis in diabetes. Lysophagy is the degradation of injured lysosomes by healthy lysosomes which is extremely important for all forms of autophagy. Using a novel dual fluorescent lysosome reporter, we showed that diabetes triggered lysosomal injury but reduced lysophagy flux, leading to the accumulation of injured lysosomes and the release of lysosomal enzymes such as cathepsin D. High glucose had similar effects in cultured cardiomyocytes. Enhancing lysophagy not only reduced high glucose toxicity but also accelerated mitophagy flux. Together, these results suggest that lysosomal dysfunction accounts at least partially for the reduced mitophagy flux and increased diabetic heart damage and that restoring lysosomal function may enhance mitochondrial quality control and reduce hyperglycemia cardiotoxicity.

Disclosure
S. Kobayashi: None. Y. Huang: None. T. Kobayashi: None. C. Li: None. F. Cai: None. Q. Liang: None.

Funding
National Institutes of Health
421-P: Documentation of Heart Failure in Outpatients with Type 2 Diabetes and Evidence of Volume Overload: A Report from the Diabetes Collaborative Registry (DCR)
Authors: ARNOLD SUZANNE V. , KOSIBOROD MIKHAIL N. , JONES PHILIP , BEASLEY MICHAEL H. , GOYAL ABHINAV , CORDOVA JEANINE M. , FONAROW GREGG C. , SEMAN LEO J. 
Published: June 2019

Background: Heart failure (HF) is one of the most common and morbid complications of T2D. Prompt recognition of early signs of HF may avert HF hospitalization and may also impact T2D meds (e.g., TZDs or possibly SGLT2i). We determined the rate and factors associated with HF diagnosis in T2D patients with evidence of volume overload requiring loop diuretics.
Methods: DCR is a U.S. registry of outpatient T2D patients from 3074 cardiology, endocrinology, and primary care providers. Among T2D patients receiving loop diuretics, we examined the rate of documentation of HF. We excluded patients with chronic liver disease, as they may have a non-HF indication for loop diuretics.
Results: Among 931,361 adults with T2D, 215,957 (23%) were on a loop diuretic of whom 110,809 (51%) had documentation of HF. Patients seen by cardiologists and PCPs were more likely have HF documented vs. endocrinologists (52% and 50% vs. 22%; p&lt;0.001). Younger age, male sex, lower BMI, afib, CKD, and CAD were associated with greater odds of HF diagnosis (Figure).
Conclusions: Among U.S. outpatients with T2D, 23% had evidence of volume overload of whom half had a diagnosis of HF. While there may be non-HF indications for loop diuretics, our data suggest that a substantial proportion of T2D patients may have unrecognized HF and therefore could be missing therapies that could alter the clinical course of HF.

Disclosure
S.V. Arnold: None. M.N. Kosiborod: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eisai Co., Ltd., GlaxoSmithKline plc., Glytec, LLC, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. P. Jones: None. M.H. Beasley: None. A. Goyal: None. J.M. Cordova: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. G.C. Fonarow: Consultant; Self; Abbott, Amgen Inc., Bayer US, Janssen Pharmaceuticals, Inc., Medtronic, Novartis Pharmaceuticals Corporation. L.J. Seman: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc.
43-OR: Post-transcriptional Regulation of Slc16a1 mRNA Is Essential for Maintaining Normal ß-Cell Function
Authors: MOSTAFA DINA , TAKAHASHI AKINORI , YAMAMOTO TADASHI 
Published: June 2019

Slc16a1 gene belongs to a family of genes that are selectively silenced in mature β-cells as compared to other mammalian cell types and thereby named “β-cell disallowed genes.” Forced expression of Slc16a1 in β-cells interfered with insulin secretion and normal β-cell function. Slc16a1 is previously shown to be regulated by promoter methylation transcriptionally and miRNA post-transcriptionally. Here, we show deadenylation by CCR4-NOT complex is involved in silencing of Slc16a1 and maintaining normal β-cell function. We have previously shown that β-cell specific knockout of CNOT3 (CNOT3βKO), a CCR4-NOT complex and a positive modulator of its function causes upregulation of β-cell disallowed genes among them is Slc16a1 alongside with the decreased expression of β-cell specific genes and loss of normal β-cell function. In this study, we demonstrate the molecular mechanism by which CCR4-NOT complex is involved in silencing Slc16a1. Slc16a1 mRNA is stabilized in CNOT3βKO islets compared to wild type islets as assessed by calculating the relative amounts of introns and exons for Slc16a1 using total RNAseq data. RNA immunoprecipitation revealed Slc16a1 mRNA binds to CCR4-NOT complex. Expression of luciferase constructs bearing the 3′-untranslated regions (3’UTR) of Slc16a1 mRNA in wild type or CNOT3 knockdown HEK293T cells demonstrated that Slc16a1 mRNA is a direct target of CNOT3. CCR4-NOT complex binds to its target genes through interaction with RNA binding proteins that bind to special motifs in 3’UTR. We identified Roquin, an mRNA binding protein that binds to stem-loop structure in Slc16a1 3’UTR. Thus, CCR4-NOT complex -Roquin axis inhibits Slc16a1 expression in β-cells maintaining normal β-cell function.

Disclosure
D. Mostafa: None. A. Takahashi: None. T. Yamamoto: None.