bluuebunny/crossref_metadata_2025_split huggingface dataset:
256-OR: Costarting Sitagliptin with Metformin Is Associated with a Lower Likelihood of Disease Progression in Newly Treated Patients with Type 2 Diabetes
Authors: CAMPBELL SCOTT A. , LIGHT PETER E. , SIMPSON SCOT H. 
Published: June 2019

Aim: Sitagliptin can potentially preserve beta cell function by promoting local action of GLP-1 in the pancreas. This study examined if early addition of sitagliptin to metformin is associated with a delay in the progression of type 2 diabetes.
Methods: Administrative health records from Alberta, Canada between April 1, 2008 and March 31, 2015 were used to conduct a retrospective cohort study. New metformin users were identified and included if they added sitagliptin during follow-up. Patients costarting therapy with sitagliptin and metformin were compared to those who added sitagliptin after initial metformin therapy. Potential confounding variables included age, sex, comorbidities, and cardiovascular medications at baseline. A multivariable logistic regression model was used to evaluate the association between sitagliptin addition (costart versus delayed) and insulin initiation. Change in A1c 1 year after adding sitagliptin was evaluated using a multivariable linear regression model.
Results: Mean (SD) age of the 8,746 included patients was 52.1 (11.1) years, 5,655 (64.7%) were men, and 1,149 (13.1%) costarted treatment with metformin and sitagliptin. Insulin was added to the therapy of 192 (16.7%) costarters and 1,640 (21.6%) of delayed sitagliptin users (adjusted odds ratio 0.73; 95% CI: 0.62 to 0.86). The A1c change 1 year after starting sitagliptin was greater in the costarters (-2.1%; SD 2.8%) compared to delayed sitagliptin users (-1.0%; SD 1.9%). After adjusting for baseline A1c and other covariables, costarters had a greater reduction in A1c -0.56% (95% CI: -0.74% to -0.38%).
Conclusions: Costarting sitagliptin with metformin is associated with a lower likelihood of disease progression in newly treated patients with type 2 diabetes compared with adding sitagliptin later in therapy.

Disclosure
S.A. Campbell: None. P.E. Light: None. S.H. Simpson: None.

Funding
Canadian Institutes of Health Research
258-OR: Use of High Sensitivity Cardiac Troponin T and I for Risk Classification in Type 2 Diabetes
Authors: TANG OLIVE , MATSUSHITA KUNIHIRO , CORESH JOSEF , MCEVOY BILL , SHARRETT A. RICHEY , BALLANTYNE CHRISTIE M. , HOOGEVEEN RON C. , SELVIN ELIZABETH 
Published: June 2019

Introduction: ADA guidelines recommend costly cardioprotective medications as second-line therapy for patients with diabetes and prevalent cardiovascular disease (CVD). High sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) may identify those at high risk in the absence of CVD and inform prioritization for treatment with newer classes of medications.
Methods: We conducted a prospective cohort analysis of middle-age adults (mean age 63, 52% female, 30% black) in the Atherosclerosis Risk in Communities (ARIC) Study with diabetes (1996-1998, n=1,415). Participants were followed &gt;20 years for heart failure (HF), coronary heart disease, and death. We used Cox models to evaluate the risk associated with independent and joint elevations (&gt;90th percentiles) in hs-cTnT and hs-cTnI.
Results: Elevations in hs-cTnT (26%) or I (19%) were common, with 10% of those without CVD having elevations in both. Elevated hs-cTnT and hs-cTnI were independently associated with all three outcomes (and jointly improved C-statistics). For HF and death, those with elevations in both troponins in the absence of CVD showed similar risk as those with prevalent CVD (Table).
Conclusions: Hs-cTnT and I are independently prognostic of cardiovascular risk and mortality among adults with diabetes. These biomarkers may help identify patients for novel cardioprotective anti-hyperglycemics, even in the absence of pre-existing CVD.

Disclosure
O. Tang: None. K. Matsushita: Consultant; Self; Akebia, Kyowa Hakko Kirin Co., Ltd. Research Support; Self; Fukuda Denshi, Kyowa Hakko Kirin Co., Ltd. J. Coresh: None. B. Mcevoy: None. A. Sharrett: None. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Gilead Sciences, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., Esperion, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Other Relationship; Self; Roche Diagnostic USA. R.C. Hoogeveen: Consultant; Self; Denka Seiken. Research Support; Self; Abbott, American Heart Association, National Heart, Lung, and Blood Institute, SomaLogic, Inc. E. Selvin: None.

Funding
National Institutes of Health
263-LB: Functional Inactivation of Mast Cell Enhances Subcutaneous Adipose Tissue Browning through Decreasing Serotonin Release in Mice
Authors: ZHANG XIAN 
Published: June 2019

Introduction: Therapeutic targeting of brown adipocyte-mediated thermogenesis to increase energy expenditure may offer a viable alternative approach to combat obesity and metabolic disease. Several immune signaling regulated beige fat thermogenic circuits were established in adipose tissues. Genetic deficiency and pharmacological stabilization of Mast Cells (MCs) increased metabolic rate and UCP1 expression in BAT in western diet-fed mice in concert with their obesity and insulin resistance improvement. Serotonin is an important regulator of energy balance. Yet, it remains unknown whether MCs play a direct role in energy homeostasis or the above-mentioned changes in energy expenditure are merely a consequence of mouse body weight reduction.
Methods and Results: We compared metabolic rate differences between WT and MC-deficient Kitw-sh/w-sh mice. In the context of mice on a chew diet, norepinephrine (NE)-stimulated metabolic rate is increased in MC-deficient Kitw-sh/w-sh mice and MC-stabilized wide-type (WT) mice. Histological staining, qPCR and western blot showed UCP1 and other thermogenic genes also increased in these mice. Such functional inactivation of MCs enhances thermogenesis and browning in subcutaneous adipose tissues (SAT), but not in brown (BAT) and epididymal adipose tissues (EAT). MC reconstitution to SAT blocks the aforesaid changes in Kitw-sh/w-sh mice. Mechanistic studies demonstrate that functional inactivation of MCs not only elevates the numbers and proliferation of PDGFRα+ bipotential adipocyte precursors but also accelerates beige adipocyte differentiation in SAT. Using tryptophan hydroxylase 1 inhibitor and Tph1-/- mast cells, we show that MC-derived serotonin inhibits SAT beige adipocyte biogenesis and systemic energy expenditure.
Conclusions: Together, functional inactivation of MCs or inhibition of MC serotonin synthesis in SAT promotes adipocyte browning and systemic energy metabolism in mice.

Disclosure
X. Zhang: None.

Funding
American Heart Association
271-LB: Intranasal Insulin Treatment Causes Sex-Specific Differences in Metabolism and Behavior in Mice
Authors: CHUDOBA CHANTAL , KLEINRIDDERS ANDRE 
Published: June 2019

Brain insulin action regulates metabolism and behavior. Conversely in diabetes, brain insulin resistance associates with obesity and behavioral abnormalities. Intranasal insulin (INI) treatment activates brain insulin signaling in rodents and humans with a more prominent effect on metabolism in males. Recently, we have shown that INI treatment reduces diet-induced high fat diet (HFD) weight gain in males. Here, we investigated whether INI treatment reduces metabolic and behavioral abnormalities in males and females fed a HFD.
We investigated the effect of 1h 1.75U INI treatment on metabolism and behavior in 12 weeks old C57BL/6N male and female mice fed a normal chow diet (NCD) and HFD for two weeks. We analyzed brain insulin signaling using ELISA, qPCR and western blot technique and assessed metabolic parameters as well as behavior using a dark-light box and novelty-suppressed feeding test.
We show that acute INI treatment activates the insulin cascade in a region-dependent manner with highest activation in olfactory bulbus, caudate putamen and hypothalamus in males. INI treatment caused a two-fold increase in insulin levels in the cerebrospinal fluid (CSF) without altering blood glucose and insulin levels. INI reduced anxiety in males fed a NCD using a dark-light box test and novelty-suppressed feeding test. Yet, INI treatment did not alter insulin signaling and behavior in mice fed a HFD. Though male and female mice exhibited equal amounts of insulin receptor signaling proteins in the brain, INI treatment did not alter food intake, body weight gain or behavior in females fed a NCD or a HFD. In females, basal insulin levels in the CSF were comparable to insulin levels of INI-treated males and did not drastically increase further after INI treatment indicating optimal insulin action under basal conditions. Overall, we show that INI treatment activates the insulin signaling throughout the brain and improves in a sex-dependent manner metabolism and behavior only in healthy conditions.

Disclosure
C. Chudoba: None. A. Kleinridders: None.

Funding
German Federal Ministry of Education and Research; State of Brandenburg (82DZD00302)
274-LB: The Anti-inflammatory Effects of Insulin and Hydrocortisone Combination in Obese Subjects
Authors: DANDONA PARESH , GHANIM HUSAM , BATRA MANAV , GREEN KELLY , ABUAYSHEH SANAA , KATKAR RUJUTA 
Published: June 2019

Glucocorticoids have been used as the major class of anti-inflammatory agents for over 60 years. However, they have well known side effects including weight gain, adiposity, muscle loss, osteoporosis and diabetogenicity. We have recently described the induction of specific pro-inflammatory genes by a single large dose of hydrocortisone (HC) in normal weight subjects. Since our group discovered the anti-inflammatory actions of insulin, we have now hypothesized that a combination of insulin with a high dose of a HC may neutralize the proinflammatory effects of HC and offer a safe anti-inflammatory combination. Eight obese subjects (BMI:31-46 kg/m2, age: 29-63 years, 3 females) were randomized into a cross over study to be injected in two separate visits (a week apart) with 300 mg of HC (?60 mg prednisolone) intravenously with or without an infusion of 2U/h of insulin with 5% dextrose for 8 hours. HC injection alone induced a significant anti-inflammatory effect including suppression of CCR-2 (by 54±8%), IL-4 (by 68±14%) and TNF-α (by 35±10%) expression in mononuclear cells (MNC). However, the HC injection also induced an increase in the expression of HMG-B1, TLR2, TLR4, TLR9, JNK-1 and RANK-L (by 43±12%, 57±9%, 62±17%, 69±15%, 89±19% and 61±11% over the baseline, respectively, P&lt;0.05 for all). Plasma glucose and FFA concentrations also increased significantly following the HC injection alone. Insulin infusion along with the HC injection further suppressed the expression of CCR-2, TNF-α and IL-4 in MNC and completely inhibited the HC induced increases in FFA concentrations and in HMG-B1, TLR-2, TLR-9 and RANK-L expression (p&lt;0.05 vs. HC alone). In addition, insulin infusion not only inhibited the HC induced increases in JNK-1 and TLR4 expression but also suppressed levels below baseline (by 27±14% and 22±10%, p&lt;0.001 vs. HC alone). Thus, the infusion of insulin at a low dose with a high dose of HC or other corticosteroids may constitute an ideal anti-inflammatory cocktail in the in- patient setting.

Disclosure
P. Dandona: Advisory Panel; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. H. Ghanim: None. M. Batra: None. K. Green: None. S. Abuaysheh: None. R. Katkar: None.
285-OR: Conversations and Reactions around Severe Hypoglycemia (CRASH): U.S. Results from a Global Survey of People with T1DM or Insulin-Treated T2DM and Caregivers
Authors: SNOEK FRANK J. , JILETCOVICI ALINA , BUSHNELL DONALD M. , CHILD CHRISTOPHER J. , BAJPAI SANJAY K. , SPAEPEN ERIK , THOMAS JOSH , BALANTAC ZANETA , PEYROT MARK , MITCHELL BETH 
Published: June 2019

The CRASH study examines the experience and treatment of a severe hypoglycemia event (SHE) among people with T1DM (ppl w/T1DM) or insulin-treated ppl w/T2DM and caregivers. The online survey was conducted in 8 countries. To be eligible in the global study, ppl had experienced or cared for a person who had ≥1 SHE in the last 3 years. SHE was defined as low blood glucose requiring assistance for recovery. Here, we report U.S. data for 220 ppl with diabetes (n=110 T1DM; n=110 T2DM). Sixty-five (59.1%) ppl w/T2DM used insulin for &gt;5 years, while mean (SD) duration of diabetes was 30.6 (16.6) years for ppl w/T1DM and 16.0 (8.7) years for ppl w/T2DM. Forty (36.4%) ppl w/T1DM and 22 (20.0%) ppl w/T2DM reported impaired awareness (Gold score ≥4). During the last SHE, glucagon use was low (T1DM [8.2%]; T2DM [3.6%]); reasons for not using glucagon were not having a prescription (T1DM [40.0%]; T2DM [59%]) or it was unavailable (T1DM [20.0%]; T2DM [17.1%]). Also, ppl w/T1DM (75.5%) and ppl w/T2DM (83.6%) reported using oral glucose only for treatment; use of healthcare provider assistance was low. The main causes reported for a SHE were eating less than planned (T1DM [27.3%]; T2DM [47.3%]) or exercising more than planned (T1DM [21.8%]; T2DM [20.0%]). Results indicate that treatment of a SHE mainly occurred outside the healthcare system with fewer ppl having glucagon as an option for recovery.

Disclosure
F.J. Snoek: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk A/S, Roche Diabetes Care. Research Support; Self; Sanofi. Speaker's Bureau; Self; Lilly Diabetes. A. Jiletcovici: Employee; Self; Eli Lilly and Company. D.M. Bushnell: None. C.J. Child: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. S.K. Bajpai: Employee; Self; Eli Lilly and Company. E. Spaepen: Consultant; Self; Eli Lilly and Company. J. Thomas: Employee; Self; Eli Lilly and Company. Z. Balantac: Other Relationship; Self; Eli Lilly and Company. M. Peyrot: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Calibra Medical. Research Support; Spouse/Partner; Eli Lilly and Company. B. Mitchell: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
296-OR: Diminished Sensor Performance of the Abbott Freestyle Libre Intermittently-Viewed Continuous Glucose Monitoring System (ICGMS) during Hypoglycemia and Acute Exercise in People with Type 1 Diabetes
Authors: MOSER OTHMAR , ECKSTEIN MAX L. , MCCARTHY OLIVIA , DEERE RACHEL , PITT JASON , WILLIAMS DAVID M. , HAYES JENNIFER , BAIN STEPHEN C. , BRACKEN RICHARD M. 
Published: June 2019

Aim: To determine the sensor performance of the Abbott Freestyle® Libre iCGMS during glycemic challenges and acute exercise during multiple 23-hours inpatient phases.
Methods: 17 people with T1D (4 women, age 34.9 ± 15.5 years, BMI 25.9 ± 3.0 kg/m2, HbA1c 7.3 ± 1.4% (56 ± 15 mmol/mol)) on multiple daily injections were included in the study, consisting of four 23-hours inpatient phases with meal-induced glycemic disturbances and 45-minutes moderate-intensity cycle ergometer exercises. iCGMS was compared to reference blood glucose by median absolute relative difference (MARD), Clarke Error Grid (CEG) and Bland-Altman (intention-to-treat).
Results: The overall MARD (IQR) during the inpatient phases (excluding exercise) was 12.9% (6.1-21.5%), during hypoglycemia 31.6% (14.0-46.8%), euglycemia 14.5% (7.0-22.5%) and hyperglycemia 8.7% (4.6-14.6%). The overall Bland-Altman analysis showed a bias (95% LoA) of 19.8 mg/dL (-78.37-118 mg/dL) and CEG is illustrated in the Figure. The overall MARD during exercise was 29.8% (17.5-39.8%), during hypoglycemia 45.1% (35.2-51.1%), euglycemia 30.7% (18.7-39.2%) and hyperglycemia 16.3% (10.0-22.8%).
Conclusion: iCGMS interstitial glucose readings should be used cautiously during hypoglycemia and exercise and need confirmatory blood glucose measurements.

Disclosure
O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. McCarthy: None. R. Deere: None. J. Pitt: None. D.M. Williams: None. J. Hayes: None. S.C. Bain: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S, Sanofi. R.M. Bracken: None.

Funding
Novo Nordisk A/S
297-LB: Dietary Fructose Increases Plasma Angiopoietin-Like Protein-3 Concentrations in Rhesus Macaques: Prevention with Fish Oil Supplementation
Authors: BUTLER ANDREW , GRAHAM JAMES L. , STANHOPE KIMBER L. , HAVEL PETER J. 
Published: June 2019

Homozygous loss-of-function ANGPTL3variants are associated with familial combined hypolipidemia, suggesting the dual LPL/EL inhibitor is a promising target for treating atherogenic dyslipidemia. However, nothing is known regarding the dietary regulation of ANGPTL3, including effects of dietary sugar or n-3 fatty acids. We investigated plasma ANGPTL3 concentrations in a rhesus macaque model of high sugar diet-induced dyslipidemia. Animals provided fructose beverages (300 kcal/d) rapidly gain weight (∼10%) and develop insulin resistance and fasting hypertriglyceridemia within 1 month. Fasting plasma ANGPTL3 concentrations increased by 30-40% with fructose consumption after 1 and 3 months (mean±SD in ng/ml; baseline, 60.6±17.4; 1 month, 83.1±25.3; 3 months, 76.9±23.2; both p&lt;0.001 vs. baseline, n=59). Fish oil supplementation (4 g/d) prevents fructose-induced dyslipidemia and completely prevented the increases of ANGPTL3 (-3% vs. +33% over 6 months, p&lt;0.05). Regression modeling to identify lipid/lipoprotein parameters (TG, TC, HDL-C, LDL-C, VLDL-C, APOA1, APOB, APOC3, APOE) explaining variation in ANGPTL3 levels indicated strong correlations with APOC3 at baseline (p=0.002), and APOC3 and APOE after 3 months of fructose (both p&lt;0.05). Regression modeling also examined whether changes (?) of APOC3, APOE, and ANGPTL3 predict ?TG, explaining 41% of variation after 1 month. (R2=0.41, p&lt;0.001). ?APOC3 (B=0.588, p&lt;0.001) and ?ANGPTL3 (B=0.292, p&lt;0.05) were significant predictors in the model. After 3 months, modeling explained 36% of ∆TG (R2=0.36, p&lt;0.001), with all variables contributing significantly (?APOC3, B=0.616, p&lt;0.001; ?ANGPTL3, B=0.245, p&lt;0.05; ?APOE, B= -0.281, p&lt;0.05). Modeling predicted variation of ∆TG before and during fructose consumption (R2=0.294, p=0.033 at baseline; R2=0.438, p&lt;0.001 at 3 months).
In summary, these are the first findings reporting effects of diet composition (sugar and n-3 FAs) on circulating ANGPTL3.

Disclosure
A. Butler: None. J.L. Graham: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc. K.L. Stanhope: None. P.J. Havel: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc.

Funding
National Institutes of Health
300-LB: FGF21 and a ß3-Adrenergic Agonist Synergistically Lower Blood Glucose in Obese Mice at Thermoneutrality
Authors: ZOUHAR PETR , SPILAKOVA BLANKA , ANDERSEN BIRGITTE , NEDERGAARD JAN , KOPECKY JAN 
Published: June 2019

Fibroblast growth factor 21 (FGF-21) treatment is known to lower body weight and to increase insulin sensitivity in rodent models of obesity, probably via increased energy expenditure. Stimulation of non-shivering thermogenesis by FGF-21 was hypothesized to be the crucial antiobesogenic action. Thermogenesis is normally driven by stimulation of β3-adrenergic receptors. FGF-21 has been shown to inhibit lipolysis, while β3-adrenergic agonists are pro-lipolytic. In lean mice, acute β3-adrenergic stimulation results in drop in blood glucose, which is believed to be caused by a rise in non-esterified fatty acid (NEFA) and (subsequently) increase in plasma insulin. Thus, the effects of FGF-21 and β3-adrenergic agonists on thermogenesis could be synergistic, while their effects on NEFA seem opposite. Here we investigate the effect of combination of FGF-21 and the β3-adrenergic agonist CL316.243 on blood glucose level in mice. Dietary obese C57Bl/6 mice were housed at thermoneutral temperature (i.e., at 30 °C) in order to minimize basal adrenergic tone. Animals were treated twice daily with 65 µg FGF-21 or its vehicle for 8 days. This treatment was not sufficient to significantly decrease body weight and non-fasted blood glucose, but it lowered insulin (indicating increase in insulin sensitivity). Subsequently, the mice were injected with 35 µg of the β3-adrenergic agonist CL316.243. CL316.243 increased NEFA and insulin in control mice, but surprisingly (in contrast to earlier observations in lean mice) it acutely increased blood glucose as well. In FGF-21-treated mice, CL316.243 altered neither NEFA nor insulin levels, but it dramatically decreased blood glucose. In contrast to earlier works, our result demonstrates a complex nature of the glucose-lowering effects of β3-adrenergic agonists which does not simply correlate to changes in insulin and NEFA levels. We also show that FGF-21 has a potential to restore the glucose-lowering action of β3-adrenergic stimulation in obese mice.

Disclosure
P. Zouhar: None. B. Spilakova: None. B. Andersen: Employee; Self; Novo Nordisk A/S. J. Nedergaard: None. J. Kopecky: None.

Funding
Czech Science Foundation (19-05356Y)