bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enterohepatic Circulation of Bile Acids Is Activated by Bariatric Surgery before Weight Loss Becomes Apparent
Authors: KITAHARA YOSHIRO , KAWANABE HARUKA , HASUMURA MAI , IWAI YUSUKE , OKAMATSU YORIKO 
Published: June 2018

Bariatric surgery induces metabolic improvement before weight loss occurs. Plasma levels of bile acids (BA) are increased after bariatric surgery and this change is reported to contribute significantly to metabolic improvement. In this study, we investigated rats with duodeno-jejunal bypass (DJB) surgery to assess the mechanism underlying the increase in plasma BA after bariatric surgery, especially before weight loss was detectable. Sprague-Dawley rats were fed a high-fat diet for 10 weeks and then were subjected to DJB surgery. Significant weight loss was noted in the DJB rats from 4 weeks after surgery. However, plasma triglycerides (TG) and the hepatic TG content were reduced at 2 weeks after surgery, although food intake was comparable between DJB rats and sham-operated rats. Plasma levels of total BA were elevated from 2 weeks after DJB surgery. In week 2, plasma levels of cholate and chenodeoxycholate were about 5-fold higher in DJB rats than in sham-operated rats, while cecal levels of both BA were lower in DJB rats compared with sham-operated rats. The increase in plasma BA was suppressed by administration of one of bile acid sequestrants, colestimide. Intestinal expression of BA transporters (ASBT, ABCC3, and OSTα) was up-regulated in DJB rats, and hepatic expression of Cyp7A1 was also up-regulated in DJB rats at 2 weeks after surgery. These findings suggest that activation of de novo biosynthesis and increased enterohepatic circulation of BA contribute to elevation of plasma BA levels after DJB surgery before weight loss becomes apparent. These changes led to alteration of gut microbiota in DJB rats, and the resting core body temperature of DJB rats was increased over that of sham-operated rats from 2 weeks after surgery. Therefore, elevation of plasma BA levels early after bariatric surgery by activation of de novo BA synthesis and enterohepatic circulation may play an important role in postoperative metabolic improvement and weight loss.

Disclosure
Y. Kitahara: Employee; Self; Ajinomoto Co., Inc. H. Kawanabe: Employee; Self; Ajinomoto Co., Inc. M. Hasumura: Employee; Self; Ajinomoto Co., Inc. Y. Iwai: Employee; Self; Ajinomoto Co., Inc. Y. Okamatsu: Employee; Self; Ajinomoto Co., Inc..
Impairment of M2a-Subtype Macrophage Activation by Il-4-Irs2 Pathway in Obesity
Authors: KUBOTA TETSUYA , INOUE MARIKO , KUBOTA NAOTO , TAKAMOTO ISEKI , UEKI KOHJIRO , YAMAUCHI TOSHIMASA , KADOWAKI TAKASHI 
Published: June 2018

Introduction: M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood.
Methods: We found that the phosphorylation levels of Irs2 by IL-4 were significantly reduced along with decreased Irs2 expression in macrophages of high-fat (HF) diet-fed mice. To investigate the role of Irs2 in the macrophages, we then generated myeloid cell-specific Irs2-deficient (MIrs2KO) mice.
Results: HF diet-fed MIrs2KO mice showed impairment of IL-4-induced M2a-subtype macrophage activation, resulting in insulin resistance. Expressions of the maker genes for M2a-subtype macrophages were downregulated by stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex via impairment of the IL-4/Irs2 pathway. Furthermore, Irs2 expression was significantly suppressed by insulin treatment in macrophages, suggesting that chronic hyperinsulinemia downregulates macrophage Irs2 expression via insulin receptor (IR). Indeed, in myeloid cell-specific IR-deficient mice, the IL-4-Irs2 pathway was preserved in the macrophages due to the lack of IR-mediated downregulation of Irs2, resulting in a reduced degree of inflammation and insulin resistance.
Conclusion: These data suggest that in obesity, downregulation of macrophage Irs2 is induced by hyperinsulinemia, resulting in impaired IL-4-induced M2a-subtype macrophage activation, and insulin resistance.

Disclosure
T. Kubota: None. M. Inoue: None. N. Kubota: None. I. Takamoto: None. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc. T. Yamauchi: Research Support; Self; Novo Nordisk Inc., Daiichi Sankyo Company, Limited, Sanofi, Takeda, Tanabe-Mitsubishi. T. Kadowaki: Consultant; Self; Novo Nordisk A/S, AstraZeneca, Merck Sharp & Dohme Corp.. Research Support; Self; Kissei Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Sanofi, Kyowa Hakko Kirin Co., Ltd., Novo Nordisk A/S, Astellas Pharma, Daiichi Sankyo Company, Limited, Takeda, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Astellas Pharma, AstraZeneca, Merck Sharp & Dohme Corp., Ono Pharmaceutical Co., Ltd., Takeda, Eli Lilly and Company, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk A/S.
Adipocyte-Selective Deletion of ß-Arrestin-1 in Mice Causes Adiposity, Impaired Glucose Tolerance, and Reduced Insulin Sensitivity
Authors: PYDI SAI PRASAD , WESS JÜRGEN 
Published: June 2018

In obese individuals, excess fat accumulates in adipose tissue (AT), leading to altered AT metabolism and increased insulin resistance, a key feature of type 2 diabetes (T2D). Therefore, it is of great importance to understand the signaling pathways that regulate AT function. Activation of certain G protein-coupled receptors (GPCRs) in AT has been reported to have beneficial effects on whole body glucose homeostasis. GPCR signaling is modulated by β-arrestin-1 and -2 (barr1 and barr2, respectively), two intracellular proteins which can terminate GPCR signaling and/or mediate G protein-independent signaling. The two β-arrestins are known to regulate many important physiological functions, primarily based on work with whole body knockout (KO) mice. The potential roles of barr1 and barr2 in regulating adipocyte function in vivo remain unexplored. To address this issue, we used Cre-lox technology to generate mutant mice that lacked barr1 selectively in adipocytes (adipo-barr1 KO mice). Interestingly, adipo-barr1 KO mice maintained on a high-fat diet showed significantly increased body weight and adiposity, impaired glucose tolerance, and reduced insulin sensitivity. Moreover, blood glucose and plasma insulin levels were elevated in adipo-barr1 KO mice, indicative of peripheral insulin resistance. RNA-seq analysis revealed the down regulation of key genes involved in glycolysis, glycogen synthesis and insulin signaling. More detailed studies into the mechanisms through which barr1 regulates adipocyte function may identify novel signaling pathways that can be targeted for therapeutic purposes.

Disclosure
S. Pydi: None. J. Wess: None.
Impact of Obesity on Outcomes of Diabetic Ketoacidosis—Results from the National Inpatient Sample
Authors: ELSHEIKH ARWA , ABDULLAH ABDULLAH , WAHAB ABDUL , EIGBIRE GEORGE E. , SALAMA AMR , RAJAMANI KRISHNAKUMAR 
Published: June 2018

Introduction: Obesity is associated with better outcomes in patients with myocardial infarction and sepsis among other conditions a phenomena being described as obesity paradox. The impact of obesity and morbid obesity in DKA is not well studied.
Objective: To estimate the impact of obesity and morbid obesity on in-hospital mortality in patients hospitalized for diabetic ketoacidosis (DKA).
Methods: Data from the National Inpatient Sample (NIS) for the years 2012 to 2014, Health Care Utilization Project were reviewed. Patients with a diagnosis of DKA were included using the relevant ICD 9 codes. The primary outcome measured was in-hospital mortality. The Odds Ratio (OR) adjusted for age, gender, Charlson index and sepsis was calculated for obesity and morbid obesity respectively.
Results: A total of 4,468,339 individuals with a diagnosis of DM were reviewed in this retrospective study. 132,362 patients (2.96%), who had a diagnosis of DKA were included. In patients with DKA, obesity (BMI 30-40) was present in 7,635 (5.77%). Morbid obesity was present in 5,290 (4%). Mortality was 1.8% vs. 1.9%, p=0.65 in patients with obesity and (3.5% vs. 1.9%, p&lt;0.001) in patients with morbid obesity. In multiple logistic regression and after adjustment to age, gender, Charlson index and sepsis, morbid obesity was associated with increased OR for mortality: 1.37 (95% CI, 1.18-1.61).
Conclusion: In patients with DKA, morbid obesity was associated with increased mortality. A BMI of (30-40) was not associated with increased mortality. No protective effect of obesity or morbid obesity (obesity paradox) was observed in our study.

Disclosure
A. Elsheikh: None. A. Abdullah: None. A. Wahab: None. G.E. Eigbire: None. A. Salama: None. K. Rajamani: None.
Racial Differences in Insulin Resistance, Secretion, and Clearance
Authors: KIM SUN H. 
Published: June 2018

Hispanics and Asians have a higher risk for type 2 diabetes than non-Hispanic whites (NHW); however, the mechanisms remain unclear. We evaluated differences in insulin physiology and the relationship between obesity and insulin action between NHWs (n=68) compared with Hispanics (n=33) and Asians (n=36). All participants were part of our ongoing registry. All were nondiabetic and had the following measurements: 1) insulin resistance (steady-state plasma glucose, SSPG, using the insulin suppression test, IST); 2) insulin secretion rate (using the graded-glucose infusion test, GGIT); and 3) insulin clearance rate (GGIT). Relationships were compared between measures of obesity (BMI, waist circumference) and SSPG, and between SSPG and insulin secretion rate and clearance rate using multivariate regression. Compared with NHWs, both Hispanics and Asians had higher degrees of insulin resistance than predicted by BMI or WC (Figure, p&lt;0.01). Thus, to achieve the same SSPG concentration, the BMI equivalent of 30 kg/m2 in NHWs was 26 in Hispanics and Asians. Insulin secretion and clearance rates were similar for degree of insulin resistance.
In conclusion, higher risk for diabetes in Hispanics and Asians may relate to greater risk for obesity-associated insulin resistance.

Disclosure
S.H. Kim: None.
Ctgf Promotes Differentiation, Regeneration, and Proliferation of ß Cells
Authors: TOWNSEND SHANNON E. , PASEK RAYMOND , COTTAM MATTHEW A. , GANNON MAUREEN A. 
Published: June 2018

One potential model of type 2 diabetes etiology is that those with the disease were born with less β-cell mass making them susceptible to stressors such as obesity. Thus, it would be of therapeutic potential to find mechanisms that increase functional β-cell mass. One candidate that has been studied in our lab is Connective tissue growth factor (Ctgf). Ctgf is a secreted protein known to be involved in cell adhesion, migration and, in some cell types, proliferation. Previous studies in our lab have shown that Ctgf is crucial for β-cell development, with loss of Ctgf resulting in fewer β-cells and decreased β-cell proliferation, thus decreased β-cell mass at birth. Ctgf is also important in situations of metabolic stress, such as pregnancy or β-cell loss. Haploinsufficiency during pregnancy results in decreased maternal β-cell proliferation while in contrast, over-expression of Ctgf results in increased β-cell proliferation and regeneration in a model of partial β-cell ablation. Treatment of human and mouse islets ex vivo with recombinant human Ctgf (rhCTGF) has resulted in increased β-cell proliferation. To determine whether smaller fragments of the 40 kD Ctgf protein can promote proliferation, mouse and human islets were treated with either an N-or C-terminal fragment independently.
Results show that N-terminal Ctgf is responsible for promoting β-cell proliferation in both mouse and human islets. Further studies will elucidate the mechanisms by which Ctgf promotes β-cell proliferation as well as through what receptor it acts on β-cells.

Disclosure
S.E. Townsend: None. R. Pasek: None. M.A. Cottam: None. M.A. Gannon: None.
Adverse Impact of Hashimoto's Thyroiditis on Pancreatic Beta-Cell Function in Type 2 Diabetic Patients
Authors: ZHANG YUANYUAN , SUN RONGXIN , ZHANG LIJIE , FANG YUAN , YU CAIGUO , YUAN SHASHA , FENG YINGMEI , ZHAO DONG 
Published: June 2018

Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease and often complicated with other metabolic disorders. It has been shown that HT patients have higher levels of antibodies against proinsulin than controls. The incidence of HT in T2DM patients is unclear and has never been studied whether beta cell function differ between T2DM patients alone and complexed with HT.
Methods: 8T2DM patients who were recruited between November 2015 till June 2016 to Endocrinology Center in Lu He hospital were analyzed. HT was diagnosed if either serum TPO antibody or TG antibody exceeded the normal range. After a 12-hour overnight fast, venous blood samples were obtained to measure total cholesterol, triglyceride, HDL-c, FBG, insulin and Scr. Oral glucose tolerance test (OGTT) was examined in the patients and serum c-peptide levels were quantified at 0, 1, 2, and 3 hours after glucose administration.
Results: 8T2DM patients were included in the study. 249 patients were diagnosed HT.Compared with non-HT subjects, T2DM with HT were more males (44.7% vs. 35.2%, p=0.02) and had higher values of systolic blood pressure (133.8 mm Hg vs. 131.1 mmHg, p=0.03). Although age, body mass index, HbA1c, serum cholesterol and serum triglyceride did not differ between two groups (p≥0.17 for all), fasting C-peptide levels were lower in T2DM complicated with HT than T2DM alone (1.09 ±0.90 nmol/L vs. 1.28±0.98 nmol/L, p=0.004). To further compare beta cell function, patients were performed OGTT test. Serum C-peptide levels remained lower at 1 and 2 hours after oral administration of 75-g glucose in T2DM with HT than T2DM alone (1 hour: 2.10±1.77 nMol/L vs. 2.33 ±1.84 nMol/L, p=0.03; 2 hours: 3.04±2.56 vs. 3.47±2.77 nmol/L, p=0.02). Serum C-peptide levels were comparable three hours after 75-g glucose intake (3.16±2.45 nmol/L vs. 3.50±2.78 nMol/L, p=0.49).
Conclusion: The prevalence of HT is relatively high in T2DM patients, which was associated with reduced beta cell function.

Disclosure
Y. Zhang: None. R. Sun: None. L. Zhang: None. Y. Fang: None. C. Yu: None. S. Yuan: None. Y. Feng: None. D. Zhao: None.
Canagliflozin Improves Glycemic Control and Beta-Cell Mass in the TallyHo Polygenic Model of Type 2 Diabetes
Authors: POPESCU IULIANA , MUSSMAN GEORGE M. , HUGHES COREY B. , JANES TERRANCE J. , RAY PHIL , CLAY BUNN R. , FOWLKES JOHN , THRAILKILL KATHRYN M. 
Published: June 2018

SGLT2 inhibitors reduce insulin resistance and may improve beta-cell function in humans with T2D. We studied the effects of Canagliflozin (Cana) on glucose homeostasis, islet architecture and endocrine cell fate in male TallyHO/JngJ (TH) mice, a new model of T2D, which mimics many aspects of polygenic T2D in humans. By 8 weeks of age, all TH mice developed moderate obesity and hyperglycemia compared to control SWR/J mice; ∼60% of TH mice converted quickly to overt diabetes, characterized by elevated BG values (&gt;400mg/dL) (HG mice), while the remaining cohort maintained lower BG values (250-400mg/dL) until the end of the study (LG mice). Mice from both groups (HG, LG) were then randomized to receive Chow or Chow-containing Cana (100ppm) diet for 10 weeks, prior to sacrifice. Cana treatment significantly decreased the fasting BG levels only in the HG mice (HG/Cana) compared with untreated HG/Chow mice (207.7±34.6 vs. 452.2±163.4mg/dL, p&lt;0.0001), improved glucose and insulin excursion curves during an ipGTT (p&lt;0.0001 for AUC values) and decreased HbA1c values (4.3±0.7 vs. 6.2±0.93%, p&lt;0.0001). Non-fasting plasma insulin and C-peptide levels, pancreatic insulin content and HOMA-B index were all significantly higher in HG/Cana than in HG/Chow mice, suggesting improved beta-cell function by Cana. Immunofluorescence staining for islet hormones showed that, compared to untreated animals, Cana reestablished the islet area and the beta-cell number/islet in HG mice (possibly due to reduced apoptosis of beta-cells), in addition to decreased number of alpha- and delta-cells/islet. In HG/Cana mice, the majority of Ins+ cells expressed the glucose transporter Glut2, while its expression was undetectable in Ins+ cells of the HG/Chow mice, further suggesting an improvement in glucose sensing capability of beta-cells with Cana treatment. Our study shows that Cana has beneficial effects on preserving beta-cell mass, identity and function in a model of early onset T2D.

Disclosure
I. Popescu: None. G.M. Mussman: None. C.B. Hughes: None. T.J. Janes: None. P. Ray: None. R. Bunn: None. J. Fowlkes: None. K.M. Thrailkill: None.
Diabetes-Specific Risk Taking—Psychometric Properties of a Measure for Adolescents with Type 1 Diabetes (T1D)
Authors: WASSERMAN RACHEL M. , PATTON SUSANA R. , CLEMENTS MARK A. , FINCH JONATHAN H. , BOSCHERT KELSEY , SCHWARTZ DAVID D. , ANDERSON BARBARA 
Published: June 2018

Among people with T1D, adolescents have the poorest adherence and worst glycemic control of any other age group, despite recent advances in treatment and technology. Clinically, adolescents are known to take risks with their diabetes care (e.g., driving without first checking blood glucose), but these risky diabetes behaviors have not been empirically studied. We report psychometric properties of the new 31-item Diabetes-Specific Risk-Taking Inventory (DSRI) for youth 15-18 years old. On the DSRI, youth report the frequency they engaged in 31 diabetes-specific risk-taking behaviors over the past year. We surveyed a national sample of 224 adolescents (participants in the T1Dx registry) (M age=16.4±1.1, 47% female, M A1c=8.3±1.3, 76.8% on insulin pumps) in a cross-sectional design. Participants completed the DSRI as well as measures of adherence, general risk-taking, executive functioning, depressive symptoms, and incidence of severe hypoglycemia and DKA over the past year, using a secure web portal, RedCap. The DSRI demonstrated excellent internal reliability (internal consistency: α=.90; item-total correlations: r range=.21-.64). Construct validity was demonstrated through significant associations (all p&lt;.01) with validated measures: more frequent diabetes-specific risk-taking was related to poorer adherence (r=-.75), greater general risk-taking (r=.57), greater executive dysfunction (r=.34), more depressive symptoms (r=-26), and report of severe hypoglycemia over the past year (r=.22). The DSRI was not associated with DKA. Overall, initial psychometrics suggest the DSRI reliably and validly captures risks that adolescents take with their diabetes care. This self-report measure has the potential to be an innovative and actionable clinical tool that can be used to screen for high risk behaviors that are not routinely assessed in clinical care and inform transition readiness from pediatric to adult care.

Disclosure
R.M. Wasserman: None. S.R. Patton: None. M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc.. J.H. Finch: None. K. Boschert: None. D.D. Schwartz: None. B. Anderson: Advisory Panel; Self; Sanofi-Aventis.
Endocannabinoid Receptors Activity Modifies Insulin Secretion in Response to Glucose Exposition
Authors: VILCHES-FLORES ALONSO , GARCIA-LUNA GUADALUPE M. 
Published: June 2018

Background: Recent studies suggest the participation of the endocannabinoid system in the development of type 2 diabetes mellitus, involved with the regulation of physiological and metabolic processes. The endocannabinoid system is expressed in pancreatic islets and presents a key role in gene expression and regulation of pancreatic hormones secretion. In type 2 diabetes patients and in obesity the blood levels of endocannabinoids are increased, however, little is known about the mechanism of actions in islets and its relation with glucose in media.
Methods: Isolated pancreatics islets of mouse were incubated for 24 hours at 5.5mM and 15mM glucose concentration, in the presence of anandamide or THC as cannabinoid receptors agonists, or with antagonist AM251. Glucose-stimulated insulin secretion and intracellular cAMP were analyzed by ELISA and cytosolic calcium changes were measured by spectrofluorometry with FURA-2.
Results: Activation of endocannabioid receptors significantly increases cAMP levels at low glucose concentration, meanwhile no further changes were observed at high-glucose concentration, correlated with a similar effect in insulin secretion. Shor-time exposure to the antagonist decreases insulin secretion under both glucose conditions. Anandamide does not induce changes in intracellular calcium but THC decreases it at high glucose concentration. Antagonist AM251 enhances calcium fluctuations, suggestion an indirect modulation of insulin secretion.
Conclusions: Endocannabinoid receptors modulation regulates intracellular mechanisms involved in insulin secretion, according to glucose exposure, in isolated pancreatic mouse islets.

Disclosure
A. Vilches-Flores: None. G.M. Garcia-Luna: None.
PRMT1-Orchestrated Fibroblast Activation in Renal Fibrosis Induced by TGFß/Smad3 Signaling Pathway
Authors: ZHU YU ,   SHANGHAI EAST HOSPITAL
Published: June 2018

TGFβ/Smad3 signaling pathway contributes predominantly to fibroblast activation and epithelial trans-differentiation in diabetic nephrology (DN). Our previous study has demonstrated that protein arginine methyltransferase 1 (PRMT1) mediated glomerular fibrosis in DN via phosphorylation of ERK. However, it is far from clear whether PRMT1 plays an important role in renal fibrosis induced by TGFβ1 signaling pathway. To investigate PRMT1 function, we used AMI-1, a novel inhibitor for PRMT1, in fibroblast both in vitro and in murine unilateral ureteral obstruction (UUO). Immunoblot analysis showed that AMI-1 reduced rat fibroblast cells (NRK-49F) and mouse tubular epithelial cells (mTEC) activation and accumulation of extra cellular matrix(ECM) and phosphorylation of Smad3 induced by serum or TGFβ1 (5ng/ml). The TGFβ1 induced deposited ECM and phosphorous Smad3 synthesis were repressed in NRK-49F transfected with small interfering RNA for PRMT1. Through immunoblot, immunohistochemistry and Masson analysis, UUO induced renal architecture and fibrosis were effectively attenuated by AMI-1 (10mg/kg, intraperitoneal injection once a day). α-SMA and PRMT1 were co-expressed in activated fibroblast in renal glomerular and tubular interstitial induced by UUO in mice and IgA nephrology and diabetic nephrology in human kidneys via dual-immunofluorescence staining. Taken together, our data reveals that AMI-1 presents a restrainable protection on TGFβ1 induced signaling, suggesting that its in-vivo application might extend to the treatment of fibrotic diseases.

Disclosure
Y. Zhu: None.