bluuebunny/crossref_metadata_2025_split 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&lt;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 &gt; 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&lt;0.001) and diabetes medication use (9.3 v 2.4%; p&lt;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)