bluuebunny/crossref_metadata_2025_split huggingface dataset:
191-LB: Comorbid Diabetes and Cancer: Differences by Patient Characteristics and Symptom Outcomes
Authors: SCARTON LISA , WILKIE DIANA J. , FITCHETT GEORGE , EMANUEL LINDA , HANDZO GEORGE , YAO YINGWEI , CHOCHINOV HARVEY M. 
Published: June 2020

Co-morbid Diabetes and Cancer: Differences by Patient Characteristics and Symptom Outcomes
More than 32 million Americans have diabetes and 1.8 million new cancer diagnoses are expected in 2020. Epidemiologically, a strong link exists between diabetes and several forms of cancer including pancreatic, colorectal, lung, and liver cancers. As a result of early cancer diagnosis and improved treatment modalities cancer survivors are living longer with other chronic diseases including diabetes. Since knowledge gaps exist regarding potential effects of having both diabetes and cancer, we examined demographic characteristics and Edmonton Symptom Assessment Scale-revised scores of 306 adult palliative care patients with cancer, 42 of whom had diabetes. The mean age of those with and without diabetes did not differ significantly (67.3±5.4 vs. 66.3±7.8, respectively; p=.35). Among these 306 patients, the prevalence of diabetes was 16% among males versus 12% among females (p=.40); 20% among African Americans, 11% among non-Hispanic Whites, and 23% among other races (p=.04). Those with diabetes reported significantly lower pain (2.7±2.6) than those without diabetes (3.6±2.9, p=.05). However, there were no significant differences between those with and without diabetes in depression (2.3±2.6 vs. 2.1±2.6, p=.69) and well-being (3.2±2.6 vs. 3.6±2.5, p=.32). Prevalence differed significantly for patients with diabetes versus those without diabetes for pancreatic cancer (14% vs. 5%, p=.04) but not for lung (26% vs. 17%, p=.20), colorectal (10% vs. 5%, p=.29), or liver (7% vs. 2%, p=.08) cancers. Findings revealed few differences across demographic characteristics and pain, depression and well-being among palliative care patients with and without diabetes. Additional prospective research is needed to investigate the effects of comorbid diabetes and cancer in a larger sample of subjects with a focus on specific cancer subtypes.

Disclosure
L. Scarton: None. D.J. Wilkie: None. G. Fitchett: None. L. Emanuel: None. G. Handzo: None. Y. Yao: None. H.M. Chochinov: None.
1910-P: Effects of Glucagon Concentrations on Splanchnic and Leg Glucagon Extraction in Healthy Humans
Authors: RUCHI FNU , YADAV YOGESH R. , ROMERES DAVIDE , SAWLEH SAFIA , BENSON LINDA M. , JOHNSON KENNETH L. , MAN CHIARA DALLA , COBELLI CLAUDIO , MCCORMICK DANIEL J. , WILKINS LUKE R. , BASU RITA , BASU ANANDA 
Published: June 2020

We have recently developed a novel isotope dilution method using nonradioactive, stable human Glucagon (Phe 6 13C9, 15N; Phe 22 13C9, 15N) tracer to measure glucagon turnover. In this study we combined this method with organ catheterization technique to estimate the effects of increasing circulating glucagon concentrations, spanning the physiological range, on splanchnic and leg glucagon extraction. We present data from the first 6 healthy subjects (age 25±3.6 yrs; BMI 26.7±4.5 kg/m2; fasting glucose 4.6±0.5 mM; HbA1c 5.1±0.3%) completed thus far. After IRB approval and informed consent, subjects were admitted in the morning after an overnight fast to Interventional Radiology, where catheters were placed in the right femoral artery and vein under local anesthesia with aseptic precautions. Under fluoroscopic guidance, a hepatic venous catheter was positioned through the femoral vein. Glucagon tracer was infused intravenously and Indocyanine Green infused via the femoral artery sheath to measure splanchnic and femoral plasma flows. After a 90 min period for basal sampling, exogenous glucagon was infused at 0.65 ng/kg/min for 60 minutes (low) followed by 1.5 ng/kg/min (high) for another 60 minutes. Plasma samples were collected periodically from femoral artery, femoral vein and hepatic vein for concentrations of Glucagon tracer (Tandem Mass Spectrometry), glucagon, glucose and Indocyanine Green (Spectrophotometry) concentrations. Arterial glucagon concentrations were 45.2±9.6 pg/ml (basal), 56.3±13.3 pg/ml (low) and 81.4±15.5 pg/ml (high). While fractional splanchnic glucagon extraction remained relatively unchanged (24.0±12.5% vs. 27.7±15.6% vs. 23.5±10.1%: basal vs. low vs. high), fractional leg glucagon extraction tended to increase (13.5±3.8% vs. 16.0±7.2% vs. 18.5±9.4%: basal vs. low vs. high) with increasing glucagon concentrations. These initial data suggest differing mechanisms of glucagon clearance across the splanchnic and leg tissues in humans.

Disclosure
F. Ruchi: None. Y.R. Yadav: None. D. Romeres: None. S. Sawleh: None. L.M. Benson: None. K.L. Johnson: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. C. Cobelli: None. D.J. McCormick: None. L.R. Wilkins: None. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca.

Funding
National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)
1913-P: Rate of Preceding Glucose Fall Does Not Affect the Glucose Response to Low-Dose Glucagon in People with Type 1 Diabetes
Authors: LAUGESEN CHRISTIAN , SCHMIDT SIGNE , NØRGAARD KIRSTEN , RANJAN AJENTHEN 
Published: June 2020

Aim: To investigate whether the preceding rate of glucose fall affects the glucose response to subcutaneous (s.c.) low-dose glucagon administration.
Methods: Ten adults with insulin pump-treated type 1 diabetes completed a randomized, single-blinded, 2-way cross-over study. Using hyperinsulinemic clamp technique, plasma glucose (PG) levels were initially stabilized at 8.0 mmol/l for ≥ 2 hrs. Thereafter, the glucose infusion rate was reduced to obtain either a rapid or a slow PG fall, while the insulin infusion was maintained at a fixed rate. When PG reached 3.9 mmol/l, insulin and glucose infusions were discontinued and a s.c. bolus of 150 µg glucagon was administered. PG levels were measured frequently for the following 120 min.
Results: The positive incremental area under the glucose curve (AUC) after administration of low-dose glucagon did not differ between the visits with a preceding rapid or slow glucose fall rate (mean ± s.e.m: 110 ± 25 vs. 73 ± 24 mmol/l x min, p = 0.21). Similarly, no significant difference in total AUC, peak PG, incremental peak PG, time-to-peak PG or PG at 120 min was observed.
Conclusions: Preceding glucose fall rate under fixed insulin level conditions did not affect the glucose response to low-dose s.c. glucagon administration.

Disclosure
C. Laugesen: None. S. Schmidt: Advisory Panel; Self; Medtronic. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. A. Ranjan: None.
1914-P: Prolonged (12-Hour) Glucagon Infusion Stimulates Adipocyte Lipolysis and Inflammation In Vivo in Humans
Authors: TRIPATHY DEVJIT , FOURCAUDOT MARCEL , NORTON LUKE , DEFRONZO RALPH A. , CHEN XI 
Published: June 2020

Hyperglucagonemia is a characteristic feature of T2DM and contributes to the metabolic disturbances. Although some rodent studies have suggested that glucagon stimulates lipolysis in adipocytes, the long-term effect of hyperglucagonemia on adipose tissue metabolism and glucose homeostasis in vivo in humans is unclear. The aim of the present study was to examine the effect of 12-hour glucagon infusion on hepatic glucose production (HGP) and adipocyte metabolism in healthy individuals. 8 NGT subjects (5M/3F, age=35±5, BMI = 24±1) received a 12-hour (6PM to 6AM) glucagon infusion (6ng/kg/min) with 3-3H-glucose infusion followed by subcutaneous adipose tissue biopsy at 6AM. On a different day the subjects returned for a repeat study with infusion (6PM to 6AM) of normal saline. Plasma glucagon increased from 57±3 to 219±21 pg/ml. Plasma glucose increased transiently after the start of glucagon and declined to baseline levels at 6AM. Plasma insulin levels increased significantly following glucagon compared to saline (20±7 vs. 8±3 mU/L, p&lt;0.05) and remained elevated at 6AM. Basal HGP (3.2±0.1 vs. 2.9±0.1 mg/kg/min, p&lt;0.01) and fasting plasma FFA concentrations (0.70±0.1 vs. 0.39±0.1 mM, p&lt;0.01) were increased after 12-hour glucagon infusion despite increased plasma insulin levels, indicating severe hepatic and adipocyte insulin resistance. Lipolysis-related gene expression in adipose tissue biopsy were upregulated following 12-hour glucagon infusion (ATGL, 1.14±0.07 vs. 0.77±0.03; HSL, 1.17±0.03 vs. 0.9±0.13; MGL, 1.2±0.04 vs. 0.82±0.2, all p&lt;0.05). Plasma concentration of inflammatory markers were also increased after 12-hour glucagon infusion (IL-1β, 0.65±0.05 vs. 0.49±0.05 pg/mL; TNF-α, 2.03±0.23 vs. 1.75±0.17 pg/mL, both p&lt;0.05). Overall, these results demonstrate that prolonged physiologic hyperglucagonemia causes marked hepatic and adipocyte insulin resistances, stimulates lipolysis and increases plasma FFA, and induces adipocyte and systemic inflammation.

Disclosure
D. Tripathy: None. M. Fourcaudot: None. L. Norton: None. R.A. DeFronzo: None. X. Chen: None.
1919-P: Dysfunction of BCAA Catabolism in Pancreatic Alpha Cells Is Associated with Higher Glucagon Secretion in Diabetic Mice
Authors: WADA ERI , KOBAYASHI MASAKI , KIKUCHI OSAMU , KOHNO DAISUKE , KITAMURA TADAHIRO 
Published: June 2020

Background: Circulating plasma glucagon level is known to increase in diabetic state. We found that postprandial plasma glucagon level significantly increased in diabetic mice more than that in the control group. However, it’s still unknown which nutrient stimulates glucagon secretion as well as the underlying mechanism of glucagon secretion enhancement in diabetic state. Therefore, we aimed to answer these questions by using diabetic mouse models and isolated islets.
Methods: Plasma glucagon levels were measured by sandwich ELISA in several diabetic model mice after oral administration of various nutrients. The effects of nutrients on glucagon secretion were assessed using isolated islets from diabetic mice. The expression levels of nutrient catabolism-related factors were analyzed in diabetic mice compared with control mice.
Results and Discussions: Rather than carbohydrate or lipid, protein increased plasma glucagon levels in all diabetic models including high-fat diet mice, STZ mice, and db/db mice. Among amino acids, branched-chain amino acids (BCAA), but not the other essential or nonessential amino acids, increased plasma glucagon. BCAA directly stimulated glucagon secretion in isolated islets from diabetic mice, which was suppressed by amino acid transporter inhibitor (BCH) or branched-chain alpha-ketoacid dehydrogenase (BCKDK) inhibitor (BT2). This suggests that BCAA’s stimulation of glucagon secretion is mediated by BCAA catabolism in alpha cells. We also found that the expression level of BCKDK was higher, while branched-chain amino acid transaminase 2 (BCAT2) was lower, in diabetic islets than control islets. Considering that dysfunction of BCAA catabolism has been reported in both adipocytes and hepatocytes of diabetic mice, the dysfunction of BCAA catabolism might be a common pathogenesis for metabolic disorders observed in diabetes.

Disclosure
E. Wada: None. M. Kobayashi: None. O. Kikuchi: None. D. Kohno: None. T. Kitamura: None.
1929-P: Serum Creatinine Levels Positively Correlates with the Development of Type 2 Diabetes Mellitus in Male Rhesus Monkeys
Authors: BRACERO DOMINIC , HANSEN BARBARA C. 
Published: June 2020

Sarcopenic obesity (SO) is the condition in which an individual has both sarcopenia, the progressive age related loss of muscle mass and function, as well as obesity. This is significant as both are regarded as potential risk factors for cardiometabolic diseases and having them concomitantly may potentiate their adverse health effects. This increases the importance of earlier detection of sarcopenic obese patients, which has proven difficult as the exact definition of sarcopenia is not agreed upon. We sought to establish a serum biomarker that would serve as a proxy for sarcopenia. Serum creatinine was hypothesized to be a suitable proxy as it is has been shown to correlate with lean body mass. We performed a prospective longitudinal cohort study on 76 obese male rhesus monkeys (Macaca mulatta) with an age range of 8-20 years old. Sarcopenic obesity was defined at a body fat % greater than 27 and a serum creatinine level less than 0.8mg/dl. Body weight, blood pressure, blood chemistry, hemoglobin A1c, fasting glucose and fasting insulin were all measured at least bi-annually. A subgroup of 34 monkeys underwent DEXA scans in order to determine lean body mass, body fat %, and fat mass to correlate to serum creatinine. Statistical analysis was performed using SPSS statistical software. Of the 76 obese male monkeys studied 58 were categorized as obese only while 18 meet criteria for sarcopenic obesity. In the obese only category 14% (8/58) went on to develop T2DM versus 39% (7/18) in the SO group. In the subgroup of 34 monkeys that underwent DEXA scanning serum creatinine was positively correlated with lean body mass p&lt;0.001 and negatively correlated with age p&lt;0.001. Neither fat mass not body fat % was found to significantly correlate with serum creatinine.
In conclusion lower serum creatine levels were associated with increased risk of developing T2DM in prospectively longitudinally studied obese male rhesus monkeys and may serve as a proxy for sarcopenia.

Disclosure
D. Bracero: None. B.C. Hansen: None.
1948-P: STING in Hematopoietic Cells Promotes Obesity-Associated Adipose Tissue Inflammation and Systemic Insulin Resistance in Mice
Authors: ZHU BILIAN , LI HONGGUI , WU CHAODONG 
Published: June 2020

Stimulator of interferon genes (STING) is a mediator of innate immunity. Previous research has validated that STING promotes macrophage-stimulated nonalcoholic fatty liver disease. However, it remains to be elucidated how STING regulates the pathogenesis of white adipose tissue (WAT) inflammation, which is a causal factor of obesity-associated systemic insulin resistance and metabolic dysregulation. We examined the expression of STING in adipose tissue of mice with high fat diet (HFD)-induced obesity. We also determined the effect of STING disruption or presence only in hematopoietic cells on diet-induced WAT inflammation and systemic insulin resistance in chimeric mice. Upon HFD feeding for 12 weeks, C57BL/6J mice revealed overt WAT inflammation and systemic insulin resistance compared with mice fed a low-fat diet. These changes were accompanied with increased STING expression in WAT whereas STING-positive cells were located predominantly within the crown structures. In mice whose STING was disrupted in all cells, the severity of HFD-induced WAT inflammation and systemic insulin resistance was significantly smaller than that in wild type mice. When the role of STING in hematopoietic cells was examined, the severity of HFD-induced WAT inflammation and systemic insulin resistance in chimeric mice whose STING was disrupted only in hematopoietic cells was also smaller than that in control chimeric mice whose STING was intact in all cells. In contrast, the severity of HFD-induced phenotype in mice whose STING was intact only in hematopoietic cells was greater than that in mice whose STING was disrupted in all cells. In cultured cells, STING-driven macrophage factors increased adipocyte proinflammatory responses and decreased adipocyte insulin signaling. Together, these results suggest that increased STING in hematopoietic cells plays a critical role in promoting WAT inflammation and systemic insulin resistance.

Disclosure
B. Zhu: None. H. Li: None. C. Wu: None.

Funding
American Diabetes Association (1-17-IBS-145 to C.W.)
1955-P: Interleukin-1ß Orchestrates Non–Glucose Dependent Cephalic Phase Insulin Release in Health and Obesity
Authors: WIEDEMANN SOPHIA J. , DROR EREZ , MEIER DANIEL T. , TRIMIGLIOZZI KELLY , MOLINA-TIJERAS JOSE ALBERTO , SCHULZE FRIEDERIKE , RACHID LEILA , HÄUSELMANN STÉPHANIE P. , ROHM THERESA V. , MEREAU HELENE , MAGNAN CHRISTOPHE , BOENI-SCHNETZLER MARIANNE , DONATH MARC Y. 
Published: June 2020

The non-glucose dependent spike in insulin levels immediately following the beginning of a meal is called the cephalic or pre-absorptive phase of insulin secretion. Even though this early insulin response is of marked consequence for overall postprandial insulin release, its basic mechanisms remain largely unexplored. Here, we show that both genetic and pharmacologic blockade of interleukin-1β (IL-1β) leads to a pronounced reduction in cephalic phase insulin secretion (-0.65 [95%CI= -1.137 to -0.172]). Assessing mice fed a high-fat diet, we found that the cephalic phase insulin response was abolished in obesity. In a systematic review and meta-analysis of trials studying cephalic phase insulin release in healthy human volunteers, we found that this was equally the case in humans. In contrast, high-fat diet-fed mice pre-treated with a specific anti-IL-1β antibody once a week developed no such impairment. We therefore conclude, that dysregulation of physiologic IL-1β signaling, specifically during cephalic phase, may contribute to the overall pathology of metabolic disease. Thus, we identify cephalic phase inflammatory signaling as a novel and potentially modifiable target in the regulation of glucose metabolism.

Disclosure
S.J. Wiedemann: None. E. Dror: None. D.T. Meier: None. K. Trimigliozzi: None. J. Molina-Tijeras: None. F. Schulze: None. L. Rachid: None. S.P. Häuselmann: None. T.V. Rohm: None. H. Mereau: None. C. Magnan: None. M. Boeni-Schnetzler: None. M.Y. Donath: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Roche Pharma, Sanofi-Aventis.
1956-P: Inhibition of Tissue Macrophage Proliferation Improves Insulin Resistance in Liver and Adipose Tissue
Authors: WADA TOSHIAKI , SENOKUCHI TAKAFUMI , YAMADA SARIE , MORITA YUTARO , MOTOSHIMA HIROYUKI , MATSUMURA TAKESHI , ARAKI EIICHI 
Published: June 2020

Objective: Insulin resistance (IR) is based on chronic inflammation in part through the activation of adipose tissue macrophages (Mϕ). Nonalcoholic fatty liver disease (NAFLD) is accepted to be strongly associated with IR. Mϕ in adipose tissue and liver have been reported to proliferate, but the pathophysiological significance of tissue Mϕ proliferation remains unclear. We examined the effects of Mϕ proliferation on IR and tissue inflammation using high-fat fed mice whose Mϕ proliferation was specifically inhibited.
Methods and Results: Mϕ specific inhibition of proliferation in mice was achieved by transgenic expression of cyclin-dependent kinase inhibitor 1B (p27kip) under the regulation of scavenger receptor promoter/enhancer. After 10-week high-fat diet load in control and Tg mice, glucose tolerance and IR were assessed, and liver and epididymal white adipose tissue (eWAT) were collected. Significant improvement of IR was showed in Tg mice in ipGTT, ipITT, ipPTT, and tissue Akt phosphorylation after insulin injection. Increased peripheral insulin sensitivity and reduced hepatic glucose production in Tg mice were confirmed by glucose clump. In Immunohistochemistry, proliferation of Mϕ was suppressed in liver and eWAT from Tg mice. Liver triglyceride content decreased in Tg mice. The mRNA expression of M1 Mϕ markers were decreased, and that of M2 Mϕ markers were increased in liver and eWAT of Tg mice. Crown-like structure formation was less observed in Tg eWAT. The mRNA expression of inflammatory cytokines/chemokines was suppressed, and that of M2 Mϕ marker was increased in Tg eWAT. Flow cytometry analysis confirmed decreased M1/​​M2 ratio in liver and eWAT Mϕ from Tg mice.
Conclusions: Proliferation of Mϕ is involved in the development of IR in liver and adipose tissue, and the progression of hepatic steatosis. Inhibition of Mϕ proliferation ameliorates tissue inflammation, therefore could potentially be the therapeutic target for IR and type 2 diabetes.

Disclosure
T. Wada: None. T. Senokuchi: None. S. Yamada: None. Y. Morita: None. H. Motoshima: None. T. Matsumura: None. E. Araki: Advisory Panel; Self; Abbott. Speaker’s Bureau; Self; ARKRAY, Astellas Pharma Inc., AstraZeneca, Eli Lilly Japan K.K., Merck & Co., Inc., Novo Nordisk Inc., WebMD LLC. Other Relationship; Self; Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
196-LB: Synergetic and Distinct Roles in the Control of Food Intake and Energy Balance for Subpopulations of NTS Neurons
Authors: CHENG WENWEN C. , NDOKA ERMELINDA , MAERZ BASMA , ROELOFS KAREN J. , RHODES CHRISTOPHER J. , SEELEY RANDY J. , SANDOVAL DARLEEN A. , OLSON DAVID , MYERS MARTIN G. 
Published: June 2020

To understand hindbrain pathways involved in the control of food intake, we initially defined markers for distinct subsets of nucleus tractus solitarius (NTS) neurons that respond to food intake, including those that express calcitonin receptor (Calcr), leptin receptor (LepRb), or cholecystokinin (CCK). While the chemogenetic activation of each of these NTS populations decreased short- and long-term food intake and body weight, only CCKNTS cells activated aversive CGRP-containing neurons of the parabrachial nucleus (CGRPPBN cells) and promoted a conditioned taste aversion. Indeed, the combined activation of CalcrNTS+LepRbNTS (LCNTS) cells provoked a stronger and more durable suppression of food intake and body weight than any single population but failed to promote aversive responses. Thus, while CCKNTS cells provoke aversive anorexia, CalcrNTS and LepRbNTS cells cooperatively suppress food intake without engaging aversive systems. To understand the roles for these NTS neurons in the physiologic control of food intake and energy balance, we chronically silenced them and examined food intake and energy balance. We found that silencing any single NTS population not only interfered with the response to gut peptide-mimetics, but also increased food intake and body weight, and that high-calorie food accentuated this effect. Additionally, simultaneously silencing multiple populations further increased food intake and body weight, promoting greater adiposity. These findings not only reveal the importance of both aversive and non-aversive brainstem circuits for the control of long-term energy balance, but also identify multiple synergistic hindbrain circuits that non-aversively suppress feeding. These non-aversive systems represent ideal targets for the potential treatment of obesity and associated metabolic diseases.

Disclosure
W.C. Cheng: None. E. Ndoka: None. B. Maerz: None. K.J. Roelofs: None. C.J. Rhodes: Employee; Self; AstraZeneca. R.J. Seeley: Consultant; Self; Ionis Pharmaceuticals, Inc., Kintai, Kintai, Novo Nordisk A/S, Sanofi, Scohia Pharma Inc. Research Support; Self; AstraZeneca, Novo Nordisk A/S, Pfizer Inc. Stock/Shareholder; Self; Redesign Health. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S. D. Olson: Research Support; Self; MedImmune, Inc, Novo Nordisk A/S. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc.

Funding
American Diabetes Association (1-16-PDF-021 to W.C.C.)