bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Hepatic Glucose Production by Transforming Growth Factor Beta 1 via Protein Kinase A
Authors: PAN QUAN , CHEN YUNMEI , YAN HUI , YANG WANBAO , SHEN ZHENG , DAHANAYAKA SUDATH A. , GUO SHAODONG 
Published: June 2018

Hepatic glucose production (HGP) is crucial for blood glucose homeostasis, while an impaired regulation of HGP contributes to hyperglycemia in patients with type 2 diabetes mellitus. Hepatokines are proteins secreted by hepatocytes, and some of them can directly affect glucose metabolism. Here we examined the role of transforming growth factor beta 1 (TGF-β1) in regulating glucose homeostasis. We generated the liver-specific TGF-beta1 knockout mice and found that hepatic TGF-β1 deficient mice exhibited a lower blood glucose levels. Hepatic TGF-β1 deficiency increased insulin sensitivity and protected mice from diet-induced obesity and hyperglycemia. In vitro studies using mouse primary hepatocytes, TGF-β1 augmented glycogenolysis and gluconeogenesis, activated protein kinase A (PKA) signaling, promoted the stability of the O-class of the forkhead transcription factor 1 (Foxo1), and increased the level of key gluconeogenic genes, glucose-6-phosphatase (G6Pase) and phosphorenolpyruvate carboxykinase (PEPCK). These findings underscore an important role of hepatic TGF-β1 in contribution to blood glucose homeostasis, and hepatic TGF-β1 may serve as an important hepatokine and therapeutic target for glycemic control in insulin resistance and type 2 diabetes mellitus.

Disclosure
Q. Pan: None. Y. Chen: None. H. Yan: None. W. Yang: None. Z. Shen: None. S.A. Dahanayaka: None. S. Guo: None.
Neudesin, a Novel Regulator of Energy Metabolism in Obesity and Type 2 Diabetes Mellitus—The Effect of Acute Fasting and Endoscopic Duodenal-Jejunal Bypass Liner Implantation
Authors: KRATOCHVILOVA HELENA , LACINOVÁ ZDENA , KLOUCKOVA JANA , KAVÁLKOVÁ PETRA , CINKAJZLOVA ANNA , TRACHTA PAVEL , KRIZOVA JARMILA , BENES MAREK , VLASAKOVA ZUZANA , PELIKANOVA TEREZIE , MRAZ MILOS , HALUZIK MARTIN 
Published: June 2018

Neudesin has recently been identified as a negative regulator of energy expenditure in experimental animals; however, its role in humans remains unexplored. The aim of our study was to assess the effects of obesity and type 2 diabetes mellitus along with selected interventions including acute fasting and endoscopic duodenal-jejunal by-pass liner implantation (DJBL) on its serum levels and adipose tissue mRNA expression. Fifteen obese T2DM subjects undergoing DJBL implantation, 15 subjects with functional hypoglycemia subjected to 72-hour fasting (Fast) and 12 healthy controls (C) were included in the study. Samples were taken at baseline and 6 and 10 months after DJBL and after 78 hours of fasting and 2 hours after realimentation, respectively. Serum neudesin was measured using ELISA kit (Neudesin Human ELISA, Biovendor, CR). qRT PCR was used to detect mRNA expression of neudesin in white adipose tissue (WAT). Baseline serum neudesin levels were comparable between all groups (1.77 ± 0.86 vs. 1.74 ± 0.54 vs. 1.88 ± 0.70 ng/ml, n.s. for DJBL vs. Fast vs. C). Along with reduction in body weight (BMI 42.8 ± 6.53 vs. 36.6 ± 4.91 kg/m2, p=0.038) and improvement of HbA1c (73.5 ± 17.2 vs. 50.0 ± 12.6 mmol/mol, p=0.001) DJBL increased serum neudesin at 6 and 10 months after procedure (1.77 ± 0.86 vs. 2.28 ± 1.27 vs. 2.13 ± 1.02 ng/ml, p=0.001 for baseline vs. 6 vs. 10 months), while having no effect on neudesin mRNA expression in WAT. In contrast, acute fasting decreased serum neudesin during the whole period (1.74 ± 0.54 vs. 1.46 ± 0.48 ng/ml, p=0.001 for baseline vs. 72 hours) with no impact of subsequent realimentation (1.37 ± 0.44 ng/ml, n.s. 2 h postprandially).To conclude, serum neudesin levels are regulated differently during acute fasting and chronic weight reduction induced by DJBL. Further studies are needed to assess its potential in the treatment of obesity and T2DM.

Disclosure
H. Kratochvilova: None. Z. Lacinová: None. J. Klouckova: None. P. Kaválková: None. A. Cinkajzlova: None. P. Trachta: None. J. Krizova: None. M. Benes: None. Z. Vlasakova: None. T. Pelikanova: None. M. Mraz: None. M. Haluzik: None.
Comparative Effects of Medical vs. Surgical Weight Loss on Body Composition in a Randomized Trial
Authors: VARMA SANSKRITI , BROWN TODD , CLARK JEANNE , MARUTHUR NISA , SCHWEITZER MICHAEL , MAGNUSON THOMAS , LEE CLARE 
Published: June 2018

Bariatric surgery leads to more rapid and greater weight loss (WL) compared to medical weight loss (MWL), but differences in body composition changes for these methods of WL remain unclear. Due to the known health risks associated with central adiposity, we sought to understand if changes in regional distribution of fat mass (FM) and lean mass (LM) differ by surgical vs. medical WL. This 1:1:1 randomized trial among 15 persons with type 2 diabetes and BMI 30-39.9 kg/m2 compared changes in body composition (measured by dual energy x-ray absorptiometry) at the time of 10% WL (or nine months after intervention) for patients receiving MWL, adjustable gastric banding (AGB), or Roux-en-Y gastric bypass (RYGB). We used non-parametric tests to evaluate differences across all arms and to compare AGB to RYGB. We present results for the 12 participants who received the study intervention and completed follow-up. All participants were women, and 75% were African American. Time to 10% weight loss was shorter for AGB and RYGB. Total FM losses were similar across arms. While differences across arms were not statistically significant, the AGB arm tended to have greater total LM and peripheral FM losses.
In conclusion, at similar overall WL, AGB may lead to preferential loss of peripheral FM and total LM. The change in total FM and truncal FM were similar across all three groups. Larger studies are needed to confirm these findings.
MWLAGBRYGBPALLPAGB vs. RYGBN444Age (Years, Mean)4654.351.5Mean BMI, Kg/m2Baseline37.135.535Final353231.6Weight, KgBaseline104.796.394.4Final98.286.985.4% Change-6.1-9.8-10.00.0381.0Time to 10% Weight Loss, months7.472.772.510.0380.77Body Composition OutcomesTotal Fat Mass, KgBaseline50.043.044.5Final45.537.738.9% Change-8.5-12.0-12.90.671.0Truncal Fat Mass, KgBaseline24.424.724.2Final21.722.020.4% Change-11.0-10.9-16.30.670. 77Peripheral Fat Mass, KgBaseline24.217.019.2Final22.614.417.3% Change-5.0-15.0-8.70.670.56Lean Mass, KgBaseline53.251.546.9Final50.444.943.3% Change-5.2-12.4-7.30.070.15Abbreviations: MWL: medical weight loss, AGB: adjustable gastric band, RYGB: Roux-en-Y gastric bypass, BMI: body mass indexPALL for comparison across groups using Kruskal-Wallis testPAGB vs RYGB represents comparison of AGB to RYGB group using Wilcoxon-Mann-Whitney test

Disclosure
S. Varma: None. T. Brown: Advisory Panel; Self; Merck & Co., Inc.. J. Clark: None. N. Maruthur: None. M. Schweitzer: Consultant; Self; Ethicon US, LLC.. T. Magnuson: None. C. Lee: None.
Therapeutic Potential of EP3 Receptor Antagonists for Treatment of Noninsulin Dependent Diabetes Mellitus across Multiple Preclinical Models
Authors: RANKIN MATTHEW M. , GUO LILI , BAKAJ IVONA , HO GEORGE , RADY BRIAN , ZHAO SHUYUAN , STAHLE PAUL L. , GHOSH AVIJIT , SHI YIFAN , PATEL SHEFALI , TRYPUTSEN VOLHA , LUBOMIRSKI MARIUSZ , ZHANG XUQING , ZHU BIN , WINTERS MICHAEL P. , MACIELAG MARK J. , NORQUAY LISA D. 
Published: June 2018

The EP3 receptor (EP3r) is a member of the EP receptor subfamily, which facilitate a broad range of physiological and pathological prostaglandin E2 (PGE2) actions. Multiple reports have demonstrated that infusion of PGE2 blunts glucose-stimulated insulin secretion (GSIS) in healthy subjects and that inhibition of PGE2 production in noninsulin dependent diabetes mellitus (NIDDM) patients can partially restore impaired GSIS. The suppression of GSIS by PGE2 has been attributed to EP3r, resulting in the suggestion that EP3r antagonism may be an attractive strategy for treatment of NIDDM. We sought to investigate the therapeutic potential of EP3r antagonists in preclinical models. EP3r-mediated suppression of GSIS was validated in vivo using a dose-range (3-30 µg/kg/minutes) of the EP3r-specific agonist sulprostone in conscious rat ivGTTs. Using this model, we defined the EP3r antagonist plasma exposure required to oppose maximal EP3r-mediated GSIS suppression. Efficacy of an EP3r-specific antagonist was then evaluated in the GK, ZDF, and DIO/streptozotocin diabetic rat models. Despite achieving plasma concentrations at least 2-fold higher than the efficacious exposure predicted by the ivGTT model, an EP3r antagonist did not impact GSIS nor glucose homeostasis in these models. We further interrogated the ability of EP3r to suppress GSIS in conscious non-human primates (NHPs) using infusions of both sulprostone and an EP3r-specific antagonist during ivGTT. In NHPs sulprostone resulted in a significant reduction in both the fasting insulin and acute insulin response compared to vehicle. Surprisingly, EP3r agonism also significantly suppressed fasting plasma glucagon. Given the combined effect on islet hormone secretion in NHPs, and the lack of EP3r antagonist efficacy across multiple diabetic rodent models, these results call into question the therapeutic potential of EP3r antagonists for NIDDM patients.

Disclosure
M.M. Rankin: Employee; Self; Janssen Research & Development. L. Guo: None. I. Bakaj: None. G. Ho: None. B. Rady: Employee; Self; Janssen Research & Development. S. Zhao: Employee; Self; Janssen Research & Development. P.L. Stahle: Employee; Self; Janssen Research & Development. A. Ghosh: None. Y. Shi: Employee; Self; Janssen Research & Development. Employee; Spouse/Partner; Bristol-Myers Squibb Company. S. Patel: None. V. Tryputsen: None. M. Lubomirski: None. X. Zhang: None. B. Zhu: Employee; Self; Janssen Research & Development. M.P. Winters: None. M.J. Macielag: Employee; Self; Janssen Research & Development. L.D. Norquay: Employee; Self; Janssen Research & Development.
Impacts of a Two-Part Multidisciplinary Diabetes Education Program on Glycemic Control and Hospital Use
Authors: WHITLEY HEATHER P.Q. , STALLWORTH ANGELA , DESAI DEEPTHI , HANSON COURTNEY 
Published: June 2018

Background: Emergency room and hospital use remain high among those with diabetes. Interventions need to be developed to reduce the utilization of this high-cost care while still improving diabetes management.
Purpose: To analyze changes in outcomes for patient with diabetes who attend a two-part multidisciplinary diabetes education program, which includes a 1-day DSME class and a ½ day “Speed Dating” session in terms of ER and hospital use, A1C, and LDL-cholesterol from January 2016-2018.
Method: Adult patients with diabetes at a family medicine clinic are enrolled and attend an 8-hour DSME class followed by a 3-hour multidisciplinary clinic 2 weeks later during which patients rotate every 30 min through 5 centers hosted by a 1) family medicine physician, 2) clinical pharmacist (CDE), 3) nurse or dietician (CDE), 4) case manager, and 5) clinical psychologist to address and improve care. Data was systematically extracted from the electronic medical record (EMR) 6 months before, 6 and 12 months after attending the class to determine impact of the program. Paired t-tests determined significance between baseline and post-intervention measures.
Results: Over 24 months, 22 adults attended the program. At baseline patients had an average A1C of 10.2% and LDL of 115 mg/dL. Six months before attending the class they presented to the ER 0.68 times, were admitted to the hospital 0.5 times, and when admitted, had an average length of stay (LOS) of 5.3 days. After attending the program patients’ A1C declined to 9.1% at 6 months (p=0.28) and 8.7% at 12 months (p=0.022). Their LDL-C declined to 110 mg/dl (p = 0.71). Although ER use increased to 0.8, their hospital admission rate and LOS decreased to 0.36 and 3.3 days respectively per patient.
Implications: Incorporation of the DSME plus Speed Dating program improved care by lower A1C by 1.5%, hospital admission rate by 0.14, and LOS by 2 days over a 6-month window. Ultimately these improvements additionally lower healthcare costs.

Disclosure
H.P.Q. Whitley: None.A. Stallworth: None.D. Desai: None.C. Hanson: None.
Diabetes Educator Impact in Value-Based Care Models
Authors: KOSHINSKY JANICE L. , KRALL JODI , RUPPERT KRISTINE , KANTER JUSTIN , SOLANO FRANCIS X. , SIMINERIO LINDA M. 
Published: June 2018

Background: Health systems are implementing value-based care models focused on quality. Organized care teams set the foundation for successful models with processes that address patient outreach and engagement. The purpose of this study was to evaluate the impact of “Glucose to Goal (G2G),” a diabetes educator (DE) driven, population-based intervention on glycemic improvement in reaching quality metrics for diabetes mellitus (DM) care.
Methods: A large primary care (PC) network established pod-style patient-centered medical homes (PCMHs) clustered by grouping multiple PC practices together based on patient panel size, hospital affiliation, and geographic proximity, and incorporating expanded care teams (DE, behavioral health, social worker, wellness guide, nurse care manager). Specific to DM, PCMHs adopted the G2G intervention whereby DEs used population health reports to proactively identify patients with HbA1c levels above target (&gt;7%). G2G was assessed in 5 pods by comparing HbA1c values for only those patients with DM with pre/post results who participated over a three-month period (n=284) to those who did not (n=265).
Results: A total of 80% of patients receiving G2G improved their HbA1c levels with 46.8% reducing HbA1c by 1% and 24% reducing HbA1c by 2%. Comparatively, 31.3% of patients not receiving G2G improved their HbA1c with only 6.4% reducing HbA1c by 1% and only 1.5% reducing HbA1c by 2% or more. This translated into more than 1.5% difference in mean HbA1c change between groups, with patients receiving DE experiencing a mean reduction in HbA1c of 1.35% (8.61 to 7.26%) compared to increase of 0.35% (7.96 to 8.30%) for those not participating in DE (p&lt;0.0001).
Conclusions: Study findings demonstrate the relevance of DE services in value-based PC models. As healthcare systems shift focus from volume to value, effective approaches to manage diabetes and improve patient outcomes take on new meaning.

Disclosure
J.L. Koshinsky: None.J. Krall: None.K. Ruppert: None.J. Kanter: None.F.X. Solano: None.L.M. Siminerio: None.
Mechanism by Which Dapagliflozin Induces Euglycemic Ketoacidosis in Rats
Authors: PERRY RACHEL J. , SONG JOONGYU D. , WANG YONGLIANG , SHULMAN GERALD I. 
Published: June 2018

Sodium-glucose transport protein 2 inhibitors (SGLT2i) are the most recent class of antidiabetic agents; however concerns have been raised about their potential to induce euglycemic ketoacidosis by an unknown mechanism. Here we report that dapagliflozin increases rates of hepatic ketogenesis (35±4 vs. 136±8 μmol/[kg-min], p&lt;0.0001) in normal Sprague-Dawley rats by increasing plasma catecholamine (epinephrine 0.5±0.1 vs. 7.3±0.5 nM, p&lt;0.001, norepinephrine 2.5±0.5 vs. 19.8±5.2 nM, p&lt;0.01) and corticosterone (115±15 vs. 233±28 ng/mL, p&lt;0.01) concentrations secondary to volume depletion (weight change -1.9±0.4% vs. -7.1±0.4%), thereby increasing white adipose tissue lipolysis, hepatic acetyl-CoA content, hepatic glucose production and hepatic ketogenesis. Dapagliflozin-induced reductions in plasma insulin concentrations were shown to be necessary but not sufficient to induce these changes since the effects of dapagliflozin to increase hepatic ketogenesis were abrogated when extracellular volume depletion was prevented with saline infusion or free access to water. Furosemide treatment induced similar volume depletion and increases in plasma catecholamine and corticosterone concentrations without any associated changes in WAT lipolysis, hepatic glucose production or hepatic ketogenesis, likely due to its lack of an effect on plasma insulin levels. Furthermore the effects of dapagliflozin to promote increased rates of hepatic ketogenesis and hepatic glucose production were dissociated from changes in plasma glucagon concentrations, which increased (89.5±3.8 vs. 379.2±11.8 ng/mL, p&lt;0.0001) through a central mechanism following ICV injection of dapagliflozin without any alterations in body weight or ketosis, and hepatic malonyl-CoA. Taken together these data identify SGLT2i-induced dehydration as a potential target to prevent SGLT2i-induced euglycemic ketoacidosis.

Disclosure
R.J. Perry: None.J.D. Song: None.Y. Wang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..
Neuronal FGF-21 Signaling–A Sensor of Dietary Protein Restriction
Authors: HILL CRISTAL M. , DEHNER MADELEINE V. , MCDOUGAL DAVID , BERTHOUD HANS-RUDOLF , MUENZBERG HEIKE , MORRISON CHRISTOPHER 
Published: June 2018

The central nervous system is acknowledged as a major regulator of both energy and glucose homeostasis. Our data demonstrate that dietary protein restriction increases energy expenditure and improves glucose homeostasis, and that the metabolic hormone FGF-21 coordinates these adaptive responses. However, the tissue site mediating these FGF-21-dependent effects is unclear. In this study, mice with dysfunctional FGF-21 signaling in either the central nervous system (CNS) or adipose tissue were fed a control or low protein (LP) diet to assess changes in body weight and associated metabolic endpoints. We first deleted the required FGF co-receptor beta-Klotho (Klb) from neurons to test whether CNS FGF-21 signaling is required for increased energy expenditure or improved glucose homeostasis in mice consuming a low protein diet. Our data show that LP diet increased energy expenditure (p≤0.01) and reduced body weight (p≤0.001) in control littermates, but these effects were lost in mice bearing CNS-specific deletion of Klb (p=0.65). Protein restriction in the context of a high fat diet also improved glucose tolerance (P≤0.001) and insulin sensitivity (p≤0.001) in control littermates, but these effects were also lost in mice lacking Klb in the CNS. We next tested whether FGF-21 signaling within adipose tissue contributed to the metabolic effects of protein restriction. However, in this case LP diet reduced body weight (p=0.90) and increased food intake (p= 0.98) similarly in control littermates and mice bearing adipose-specific deletion of Klb. Collectively, these data highlight CNS FGF-21 signaling as the first known neuroendocrine mechanism to explain the coordinated metabolic changes induced by dietary protein restriction.

Disclosure
C.M. Hill: None. M.V. Dehner: None. D. McDougal: None. H. Berthoud: None. H. Muenzberg: None. C. Morrison: None.
New Prebiotics to Ameliorate High-Fat Diet-Induced Obesity and Diabetes via Modulation of Microbiome-Gut-Brain Axis
Authors: AHMADI SHOKOUH , NAGPAL RAVINDER K. , WANG SHAOHUA , YADAV HARIOM 
Published: June 2018

Role of gut microbiome in obesity and diabetes became apparent from several independent studies, indicating that gut microbiome modulators like prebiotics may improve microbiome perturbations (dysbiosis) to ameliorate metabolic derangements. We isolated water soluble, non-digestible polysaccharides from 5 foods (acorn, quinoa, sunflower, pumpkin and sago seeds) and assessed their impact on amelioration of high fat diet (HFD)-induced obesity and diabetes in mice and human microbiome using fecal slurry culture model. During isolation, purification, biochemical and digestion resistance characterization, and fermentation pattern by human fecal microbiome, we selected acorn and sago derived prebiotics, on the basis of purity, protein contamination and yield. All prebiotics increased short chain fatty acid (SCFA) production along with enhanced microbial diversity. Feeding of acorn and sago derived prebiotics supplemented HFD (5%) for 8 weeks, significantly reduced diet induced glucose intolerance and insulin resistance, without affecting adiposity. Beneficial effects of acorn and sago derived prebiotics were superior than inulin-feeding. Feeding of both prebiotics and inulin increased diversity of gut microbiome and enhanced SCFA production into the mice gut. Metabolic function was positively correlated with increased food conversion ratio indicating enhanced whole body metabolic rate by prebiotic feeding. Gastrointestinal motility was enhanced without changing food intake, after probiotic intervention. Hypothalamic energy signaling in terms of increased pro-opiomelanocortin and decreased agouti-related peptide and neuropeptide Y expression, was modulated by prebiotics administration. These results indicate that newly isolated prebiotics ameliorate HFD-induced defects of glucose metabolism via modulating microbiome-gut-brain axis, and can be used to prevent/treat diet induced obesity and diabetes.

Disclosure
S. Ahmadi: None. R.K. Nagpal: None. S. Wang: None. H. Yadav: None.
Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Exome Sequencing
Authors: PARK SEUNG SHIN , JANG SE SONG , LEE YOUNG AH , CHO YOUNG MIN , JANG HAK CHUL , PARK KYONG SOO , KWAK SOO HEON 
Published: June 2018

Background: Targeted exome sequencing is widely used for genetic diagnosis of rare disease and it is replacing Sanger sequencing. In this study we investigated pathogenic variants of monogenic diabetes genes in Korean early onset diabetes patients using targeted exome sequencing.
Method: The main eligible criteria for this study was: non-type 1 diabetes patients with age of onset &lt; 30 years old and body mass index (BMI) &lt; 30 kg/m2. Among the 2353 patients screened from the diabetes registry of Seoul National University Hospital Diabetes Clinic, a total of 93 participants were eligible. We analyzed 30 monogenic diabetes genes using targeted exome sequencing. Identified genetic variants were evaluated by ACMG-AMP guideline for their pathogenicity.
Result: Among the 93 index patients, a total of 83 rare (minor allele frequency &lt; 0.5%), non-silent variants were found and evaluated for its pathogenicity according to the ACMG-AMP guideline. These variants were classified as likely benign (N=8), uncertain significance (N=59), likely pathogenic (N=13), and pathogenic (N=5). Three causative mutations were identified in HNF4A (p.R136W, p.M1I, p.R89Q), four mutations in five patients were identified in HNF1A (c.G-124C, p.Y166N, p.L26Q, p.R278Q), four mutations were found in GCK (p.G410S, p.N231S, p.L164F, p.H156fs) and one mutation was identified in HNF1B (p.L168P). Other causative mutations were identified in WFS1 (p.R629W), INS (c.C-60G), ABCC8 (p.R933Q) and FOXP3 (p.Q200R). Mitochondria 3243 A&gt;G variant was identified in two patients. Patients with pathogenic variants had higher MODY probability score and lower BMI than those without causative gene variants (p=0.015, p=0.039, respectively).
Conclusions: In this study, a total of 19 (20.4%) participants were identified to have monogenic cause of diabetes among 93 early onset diabetes patients. Further research is required to validate the clinical utility of targeted exome sequencing in early onset diabetes patients.

Disclosure
S. Park: None. S. Jang: None. Y. Lee: None. Y. Cho: None. H. Jang: None. K. Park: None. S. Kwak: None.