bluuebunny/crossref_metadata_2025 huggingface dataset:
1851-P: Renal Denervation Attenuates Endogenous Glucose Production Increase with SGLT2 Inhibition in Patients with Renal Transplant Recipients and Impaired Fasting Glucose
Authors: DANIELE GIUSEPPE , SOLIS-HERRERA CAROLINA , DARDANO ANGELA , MARI ANDREA , TURA ANDREA , GIUSTI LAURA , KURUMTHODATHU JANCY J. , BROCCHI ALEX A.G. , CAMPI BEATRICE , SABA ALESSANDRO , BIANCHI ANNA MARIA , TREGNAGHI CARLA , EGIDI MARIA FRANCESCA , ABDUL-GHANI MUHAMMAD , DEFRONZO RALPH A. , DELPRATO STEFANO
Published: June 2020

Background: The glucosuria induced by sodium-glucose cotransporter-2 inhibitors (SGLT2i) stimulates endogenous (hepatic) glucose production (EGP) blunting the decline in HbA1c. We hypothesized that, in response to glucosuria, a renal signal is generated and stimulated EGP.

Aim: To examine the effect of acute administration of dapagliflozin (DAPA) in nondiabetic, renal transplant subjects on SGLT2i-induced stimulation of EGP.

Methods: 20 subjects [10 with intact native kidneys (IK) and 10 with bilateral nephrectomy (NK)] underwent measurement of EGP ([6,6-2H2]-glucose) before and for 6 hours after administration of DAPA or placebo (PLC) on 2 separate days.

Results: DAPA induced greater glucosuria in subjects with IK versus NK (8.6±1.1 vs. 5.5±0.5 grams/6-hrs; p=0.02). During 6-hour, plasma glucose decreased slightly and similarly in both groups, with no difference compared to PLC. Following PLC, there was a progressive time-related decline in EGP that was similar in both groups. Following DAPA, EGP declined in both groups but the decrement in EGP was 56% greater in the NK. During DAPA, urinary glucose excretion was correlated with EGP (r = 0.34, p<0.05). Plasma insulin, C-peptide, glucagon, pre-hepatic insulin/glucagon ratio, lactate, alanine and pyruvate concentrations were similar in PLC and DAPA. β-hydroxybutyrate increased with DAPA in the IK, while a small increase was observed only at 360 min in the NK. Plasma epinephrine did not change after DAPA and PLC in both groups. Following DAPA, plasma norepinephrine increased slightly in the IK and decreased in the NK.

Conclusions: In NK subjects the hepatic compensatory response to acute SGLT2i-induced glucosuria was attenuated compared to diabetic subjects with IK, suggesting a SGLT2i-mediated stimulation of hepatic glucose production via efferent renal nerves in an attempt to compensate for the urinary glucose loss, i.e., a renal-hepatic axis.

Disclosure

G. Daniele: None. C. Solis-Herrera: Consultant; Self; Lexicon Pharmaceuticals, Inc. A. Dardano: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. A. Tura: None. L. Giusti: None. J.J. Kurumthodathu: None. A.A.G. Brocchi: None. B. Campi: None. A. Saba: None. A. Bianchi: None. C. Tregnaghi: None. M. Egidi: None. M. Abdul-Ghani: None. R.A. DeFronzo: None. S. DelPrato: None.
1854-P: Kcnh6 Improves Glucose Metabolism by Inhibiting Oxidative Stress
Authors: LU JING , ZHANG LIN , SHI TING-TING
Published: June 2020

Mitochondria plays an important role in maintaining intracellular Ca2+homeostasis, and its defects may be responsible for disorders in glucose metabolism and type 2 diabetes (T2D). Mitochondrial Ca2+overload causes superoxide production and functional impairment, culminating in apoptosis. In previous studies, we first demonstrated that Kcnh6 knockout mice exhibited impaired glucose tolerance or diabetes. However, the precise role of Kcnh6 on glucose metabolism remains unknown. Here, we show that Kcnh6 can improve glucose metabolism in the liver. Kcnh6 increases glucose uptake and decreases glycogen synthesis in the liver accompanied by increased expression of glucose transporters, insulin receptor substrates and decreased expression of enzymes for glycogen synthesis. Kcnh6knockout mice display elevated levels of oxidative stress accompanied by increased mitochondrial and intracellular ROS and calcium. As a result of anti-oxidative stress, Kcnh6 improves hepatic glucose metabolism disorder through the JNK and p38MAPKsignaling pathways.

In summary, Kcnh6 can improve hepatic glucose metabolism by regulating mitochondrial Ca2+and Inhibiting oxidative stress. As in glucose metabolism in the liver is considered to be the primary cause of the development of T2D, Kcnh6 may serve as a new diabetes target.

Disclosure

J. Lu: None. L. Zhang: None. T. Shi: None.

Funding

National Key Research and Development Program of China (2017YFC0909600); National Natural Science Foundation of China (81800688); Beijing Municipal Administration of Hospitals Incubating Program (PX2019006)
1867-P: White and Brown Rice Supplementation Changes High-Fat Diet–Induced Dysbiosis of Gut Microbiome and Improves Energy and Glucose Metabolism
Authors: YOKOMIZO HISASHI , ISHIKADO ATSUSHI , SHINJO TAKANORI , PARK KYOUNGMIN , MAEDA YASUTAKA , LI QIAN , WU I-HSIEN , MATSUMOTO MOTONOBU , DEVKOTA SUZANNE , KOSTIC ALEKSANDAR , KING GEORGE L.
Published: June 2020

Increased white rice (WR) with parallel decreased brown rice (BR) consumption has been associated with increased prevalence of type 2 diabetes (T2DM). To test whether WR and BR have differential effects on energy and glucose metabolism, C57BL/6 mice were fed 6 different diets: control diet (CD, 10% Fat), high-fat diet (HFD, 46% Fat) with either no rice, WR or BR. BR and, surprisingly, WR activated PGC1α and UCP-1 expressions in brown adipose tissue (BAT) and increased energy expenditure as measured by oxygen consumption, CO2 release and heat production, resulting in reduced body weight (36%, 23%) and improvements of glucose tolerance and insulin sensitivity while on HFD after 18 weeks. To investigate the underlying mechanism, gut microbial analysis was performed. Gut microbiota composition showed clear differences between HFD vs. CD or vs. the addition of BR or WR. Ratio of Firmicutes to Bacteroidetes was 3.7-fold increased in HFD vs.CD, but decreased by the WR (46%) or BR (59%). Increased alpha diversity was observed by WR and BR on HFD. Heat map binary showed that several genera are different in HFD+BR vs. HFD or HFD+WR vs. HFD. Analysis of family abundance revealed that Lachnospiraceae, Ruminococcaceae and Streptococcaceae are 2.5, 1.2 and 2.6-fold increased in HFD, which were reduced by WR or BR. Analysis of genus abundance showed that Lactococcus, Dorea, Peptococcus, Clostridium XIVb, Johnsonella, Anaerovorax are 2.6, 3.7, 2.9, 2.7, 4.7 and 1.7-fold respectively, increased in HFD, which were reduced by WR or BR on HFD. In addition, mice on BR+HFD showed greater reductions than mice on WR+HFD in family and genus levels.

Our results demonstrated that supplementation with BR or WR, to a lesser degree, changed HFD-induced gut microbial composition at family and genus levels, in parallel with improved systemic energy and glucose metabolism via activation of BAT and increased energy expenditure, resulting in reduced body weight and improved insulin sensitivity.

Disclosure

H. Yokomizo: None. A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. T. Shinjo: None. K. Park: None. Y. Maeda: None. Q. Li: None. I. Wu: None. M. Matsumoto: Employee; Self; Sunstar Group. S. Devkota: None. A. Kostic: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.
1868-P: Implementation of Dietary Methionine Restriction Using Casein after Selective, Oxidative Deletion of Methionine
Authors: FANG HAN , STONE KIRSTEN P. , FORNEY LAURA , SIMS LANDON C. , GETTYS THOMAS W.
Published: June 2020

Restriction of methionine in rodent diets increases energy expenditure, limits weight gain, improves insulin sensitivity, and reduces hepatic and circulating lipids. Dietary methionine restriction (MR) is implemented using diets formulated from elemental amino acids (AA) that reduce methionine content to restricted levels of ∼0.17%. However, translational implementation of dietary MR with elemental AA-based diets is confounded by poor palatability. To solve this problem and restrict methionine using intact proteins, casein was subjected to mild oxidation to selectively reduce methionine. Diets were then formulated using oxidized casein, adding back methionine to produce a final concentration of 0.17%. The biological efficacy of dietary MR using the oxidized casein diet was compared to the standard elemental MR diet. Thirty-two, 5-week old male C57BL/6J mice were divided into two groups of 16, with one group receiving the Elemental Control (El Con) diet and the other receiving the Casein Control (Cas Con) diet for 10 days. Thereafter, 8 mice continued on the El Con diet and 8 mice were switched to the Elemental MR (El MR) diet. In similar fashion, 8 mice continued on the Cas Con diet and 8 mice were switched to the Oxidized Casein (Ox Cas) MR diet. Over the subsequent 8 weeks, the behavioral, metabolic, and endocrine responses to the 4 diets were assessed to evaluate the relative efficacy of the 2 approaches to restricting dietary methionine. The El MR diet produced the expected reductions in body weight, fat mass accumulation, fasting insulin, and hepatic and circulating triglycerides, while increasing energy expenditure, serum FGF-21 levels, and weight-specific food consumption. The Ox Cas MR diet produced increases and decreases in each of these variables that paralleled the effects of the El MR diet. Collectively, these findings demonstrate that dietary MR can be effectively implemented using casein after selective oxidative reduction of methionine.

Disclosure

H. Fang: None. K.P. Stone: None. L. Forney: None. L.C. Sims: None. T.W. Gettys: None.

Funding

Pennington Foundation
187-OR: Randomized Clinical Trial of the IADPSG vs. Carpenter Coustan Criteria for Diagnosis of Gestational Diabetes Mellitus
Authors: SCIFRES CHRISTINA M. , ABEBE KALEAB , SIMHAN HYAGRIV , CATALANO PATRICK , COSTACOU TINA , COMER DIANE M. , ORRIS STEVEN R. , LY KATHLEEN , DECKER ALISON , MENDEZ DARA , DAVIS ESA
Published: June 2020

No clinical consensus regarding the optimal diagnostic approach for gestational diabetes mellitus (GDM) exists. Participants were randomized to two GDM testing criteria following a blinded non-fasting 50g glucose challenge test (GCT): Carpenter Coustan (CC) or IADPSG. GDM was diagnosed in the CC arm if the 50g GCT was > 135 mg/dL and the fasting 100g OGTT had 2 or more abnormal values. GDM was diagnosed in the IADPSG arm if the fasting 75g OGTT had one or more abnormal values; the 50g GCT was ignored for diagnosis. Participants and providers were informed whether GDM was present but blinded to all test results and which criteria were used for diagnosis. Treatment for GDM occurred per routine clinical care. We hypothesized lower rates of LGA favoring the IADPSG arm, both overall and after restricting to women without GDM. From 2015-2019, 921 women were enrolled and randomized (CC=460; IADPSG-461); however, delivery records were available for only 878 women. Baseline characteristics were similar between groups. While GDM diagnosis (14.4% vs. 4.5%, p<0.001) and diabetes medication use (9.3 v 2.4%; p<0.001) were more common in the IADPSG arm, there were no differences in LGA, either overall (OR=0.90, 95% CI 0.51-1.58) or restricting to women without GDM (OR=0.86, 95% CI 0.47-1.57).

Disclosure

C.M. Scifres: None. K. Abebe: None. H. Simhan: None. P. Catalano: None. T. Costacou: None. D.M. Comer: None. S.R. Orris: None. K. Ly: None. A. Decker: None. D. Mendez: None. E. Davis: None.

Funding

National Institutes of Health (1R01HD079647)
1878-P: The Role and Potential Mechanism of LncRNA Gm15441 in Skeletal Muscle Glucose and Lipid Metabolism
Authors: YOU LIANGHUI , ZENG YU , GU NAN , JI CHENBO
Published: June 2020

It has been established that Long noncoding RNAs (lncRNAs) play a pivotal role in regulating systemic glucose and lipid homeostasis. Previously, we identified a insulin-resistance (IR) related lncRNA named Gm15441, which was upregualted in skeletal muscle from db/db mice by RNA-sequencing. Here, we explored the relationship between Gm15441 and skeletal muscle function in vitro and in vivo and the possible mechanism involved in that process. Real-time PCR analyses revealed Gm15441 was abundant in skeletal muscle compared to other metabolic tissues. Additionally, Gm15441 expression was observed upregualted in IR cells (pamitate-treated C2C12 myotubes) and mice (db/db, ob/ob and aged mice). Overexpression of Gm15441 by plasmid transfection in C2C12 myotubes decreased Glut4, p-Akt/Akt and p-Irs1/Irs1 protein levels and attenuated glucose uptake capacity by the 2-NBDG method. Gm15441 overexpression also impaired mitochondrial oxygen consumption and Pgc1α expression. Moreover, adeno-associated viral (AAV) vectors to induce Gm15441 expression in skeletal muscles. Six-week-old male mice were administered with AAV-GFP or AAV-Gm15441 vectors followed with or without high-fat diet (HFD) for 14 weeks. Body weight gain and food intake were not different among the groups, but AAV-Gm15441 mice under HFD showed decreased glucose tolerance and insulin sensitivity. These mice exhibited ectopic lipid accumulation in skeletal muscle by HE staining, although no difference was observed in skeletal muscle weights and serum TG. A global mRNA analysis further indicated a possible regulatory role of Pparα-Pgc1α pathway in Gm15441-mediated dysregulation of glucose-lipid metabolism. Collectively, these findings improve our understanding of lncRNAs involved in skeletal muscle glucose-lipid metabolism and represent potential therapeutic targets to IR and associated metabolic diseases. Key words: lncRNA, Gm15441, skeletal muscle, insulin resistance, Pgc1α.

Disclosure

L. You: None. Y. Zeng: None. N. Gu: None. C. Ji: None.
188-OR: Assessing the Validity of Diagnosis Codes for Gestational Diabetes Ascertainment
Authors: HSU SARAH , MATHIEU KENYA , KAIMAL ANJALI , THADHANI RAVI , JAMES KAITLYN , POWE CAMILLE E.
Published: June 2020

Background: Researchers often rely on diagnosis codes from billing/administrative data to ascertain diagnoses, including gestational diabetes (GDM). We assessed the validity of relying on these diagnosis codes for GDM ascertainment, using laboratory criteria for GDM as the reference.

Methods: We studied women seen at our hospital for prenatal care between 1998-2016. Women underwent GDM screening using a 50-gram glucose loading test (GLT) followed by a diagnostic 100-gram 3-hour oral glucose tolerance test (GTT) if the GLT result was ≥140 mg/dl. We defined GDM using National Diabetes Data Group (NDDG) criteria, which was in clinical use during the study period. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for ICD code-based ascertainment of GDM using codes for GDM (ICD-9: 648.8; ICD-10: O24.4) recorded in administrative data from inpatient and outpatient encounters. In a sensitivity analysis we included additional codes that broadly represent diabetes and abnormal glucose diagnoses (ICD-9: 249, 250, 648.0, 790.2; ICD-10: O24.0-3, O24.8-9, E08-E13, R73.0, R73.9). In a secondary analysis, we defined GDM using Carpenter-Coustan (CC) criteria.

Results: Out of 49195 pregnancies, 1258 (2.6%) met NDDG criteria and 2039 (4.1%) met CC criteria based on GLT and GTT values. In the same cohort, 589 (1.2%) had GDM ICD-9/10 codes. Using NDDG criteria as the reference, we observed sensitivity of 35.2% and specificity of 99.7% for these codes. This resulted in a PPV of 75.2% and an NPV of 98.3%. In our sensitivity analysis, 700 (1.4%) pregnancies had at least one of the codes on the expanded list. The sensitivity (37.4%) and specificity (99.5%) of this set of codes was similar to the more restricted set. Results were similar for GDM defined by CC criteria.

Conclusion: Using diagnosis codes from administrative data to ascertain GDM resulted in underestimation of cases. One in 4 cases identified by these codes could not be confirmed with laboratory data.

Disclosure

S. Hsu: None. K. Mathieu: None. A. Kaimal: None. R. Thadhani: None. K. James: None. C.E. Powe: None.

Funding

Massachusetts General Hospital
1886-P: Serum Dihydroceramides Predict Insulin Sensitivity in Humans and Cause Insulin Resistance In Vitro
Authors: ZARINI SIMONA , BROZINICK JOSEPH T. , PERREAULT LEIGH , NEWSOM SEAN A. , KAHN DARCY E. , KEREGE ANNA , HARRISON KATHLEEN A. , BERGMAN BRYAN C.
Published: June 2020

Serum ceramides are related to insulin resistance, decrease after insulin sensitizing lifestyle interventions, and are linked to CVD risk in humans. To what extent other serum sphingolipids may serve to regulate insulin sensitivity remains unknown. We performed this study to quantify a broad range of serum sphingolipids in individuals spanning the physiologic range of insulin sensitivity, and to determine if specific sphingolipid species promote insulin resistance in vitro. We evaluated serum sphingolipid content in lean (n=15), endurance trained athletes (n=16), obese (n=15), and people with type 2 diabetes (T2D; n=12). Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps and serum sphingolipids measured using targeted lipidomics. Quantitative sphingolipid analysis revealed no differences between sphinganine, sphingosine, glucosyl- and lactosyl-ceramides, gangliosides, sphingomyelins, and sulfatides. Total serum ceramides were significantly increased in obese compared to lean individuals (p=0.01), with significant inverse relationships between C18:0 (p=0.002), C20:0 (p=0.02), and C22:0 (p-0.009) species and insulin sensitivity. Total serum dihydroceramides (p=0.0007) and most individual species were significantly greater in obese and T2D compared to lean and athletes, with C18:0 dihydroceramide showing the strongest inverse relationship to insulin sensitivity (p=0.002). We administered C18:0 dihydroceramide in liposomes to primary cultured myocytes and found that it significantly decreased insulin sensitivity in vitro by 36 +/- 6% (p=0.002), measured by insulin-stimulated glycogen synthesis. These data extend what is known regarding ceramides and insulin resistance and show a novel potential role for serum dihydroceramides, especially C18:0 species, in predicting and promoting insulin resistance in humans.

Disclosure

S. Zarini: None. J.T. Brozinick: Employee; Self; Eli Lilly and Company. L. Perreault: Advisory Panel; Self; Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. S.A. Newsom: None. D.E. Kahn: None. A. Kerege: None. K.A. Harrison: None. B.C. Bergman: Consultant; Spouse/Partner; Novo Nordisk Inc., Sanofi US. Research Support; Self; Eli Lilly and Company. Speaker’s Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc.

Funding

National Institutes of Health (R01DK089170, T32DK07658, P30DK048520, RR-00036)
1895-P: Knocking Out Intestinal GPR17 Improves Glucose Homeostasis and Increases Satiety during Fasting-Refeeding Challenge
Authors: YAN SHIJUN , REILLY AUSTIN , CONLEY JASON M. , REN HONGXIA
Published: June 2020

Aims: G protein-coupled receptors (GPCRs) in the intestinal enteroendocrine cells (EECs) regulate gut hormone secretion by responding to nutritional, microbial, and inflammatory factors, which contributes to the maintenance of glucose and energy homeostasis. We investigated the expression of GPR17, an orphan GPCR, in human and murine gastrointestinal tract and determined its metabolic roles using intestinal specific Gpr17 knockout mice.

Methods: Gpr17 expression was profiled by quantitative RT-PCR, immunohistochemistry and flow cytometry. To elucidate the metabolic function of intestinal Gpr17, we generated constitutive (Vil1Cre,Gpr17-/-) and inducible (Vil1Cre-ERT2,Gpr17-/-) intestine-specific Gpr17 knockout mice and analyzed their metabolic features, including glucose tolerance, indirection calorimetry, feeding and microbiome composition. We measured nutrient-stimulated incretin secretion in Gpr17 knockout mice and cultured intestinal organoids.

Results: We found that Gpr17 was enriched in Glucagon-like peptide 1 (GLP-1) expressing EECs in human and rodent intestine. Both constitutive and inducible Gpr17 intestinal knockout mice displayed improved glucose tolerance without alterations in pancreatic function and microbiota. In addition, Gpr17 intestinal knockout mice exhibited reduced foraging activity and less rebound hyperphagia in a fasting-refeeding paradigm. Notably, Gpr17 deficient mice and intestinal organoids responded to nutritional cues with enhanced GLP-1, but not GIP, secretion. Forskolin induced cAMP production was significantly inhibited by a synthetic Gpr17 agonist in GLUTag cells overexpressing Gpr17.

Conclusions: Our work suggests GPR17 signaling in the enteroendocrine cells fine-tunes GLP-1 secretion. Targeting intestinal GPR17 for appetite and glucose metabolism represents a potential therapeutic strategy for type 2 diabetes and obesity.

Disclosure

S. Yan: None. A. Reilly: None. J.M. Conley: None. H. Ren: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120772, R00DK098294); Indiana Diabetes Center (P30DK097512); Indiana Clinical and Translational Sciences Institute (UL1TR002529)
1898-P: Colonic Short-Chain Fatty Acids Lower Endogenous Glucose Production
Authors: LANE ADELINA I.L. , WENINGER SAVANNA N. , DUCA FRANK
Published: June 2020

Hyperglycemia is a hallmark characteristic of diabetes, resulting in elevated blood glucose levels, due in part to a chronic elevation in endogenous hepatic glucose production (GP). Recent work has highlighted the gut microbiota as a salient contributor to energy and glucose homeostasis. One potential mechanism may be through increased short-chain fatty acid (SCFA) signaling mechanisms. SCFAs are bacterial breakdown products of nondigestible dietary fibers, occurring mainly in the colon, and have been shown to improve glucose homeostasis. Interestingly, recent work has highlighted that ingested nutrients can activate small intestinal nutrient-sensing mechanisms to lower hepatic glucose production via a neuronal gut-brain-liver axis mediated via gut peptide signaling. However, no one has directly tested whether colonic SCFAs can regulate GP via a similar colonic neuronal mechanism. To test this, we directly infused SCFAs (acetate, propionate, butyrate; 10mM or 100mM) into the colon during a pancreatic euglycemic clamp, the gold standard for measuring endogenous glucose production and uptake, in high-fat diet (HFD) fed rats that we previously found to have diminished levels of SCFAs in the large intestine. Administration of either acetate, propionate or butyrate (10mM or 100mM) directly into the colon of HFD-fed rats resulted in an increased glucose infusion rate needed to maintain euglycemia, which was due to a significant decrease in endogenous GP compared to saline infusion. Furthermore, we found that this was mediated via GLP-1 receptor signaling, as co-administration of exendin-9 with either SCFA (10mM) abolished the GP-lowering effect. Additionally, portal levels of GLP-1 were significantly increased at the end of the pancreatic clamp in rats receiving infusion of acetate, butyrate, or propionate compared to saline. Taken together, this work demonstrates that colonic SCFAs can activate a GLP-1 receptor mediated pathway in the colon to lower endogenous GP.

Disclosure

A.I.L. Lane: None. S.N. Weninger: None. F. Duca: None.

Funding

National Institutes of Health (R01DK121804)
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<0.05) and remained elevated at 6AM. Basal HGP (3.2±0.1 vs. 2.9±0.1 mg/kg/min, p<0.01) and fasting plasma FFA concentrations (0.70±0.1 vs. 0.39±0.1 mM, p<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<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<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<0.001 and negatively correlated with age p<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.)