bluuebunny/crossref_metadata_2025_split huggingface dataset:
1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction
Authors: TAO RONGYA , COPPS KYLE D. , WHITE MORRIS F. , STOEHR OLIVER 
Published: June 2019

In humans, type 2 diabetes progresses when beta-cells fail to compensate peripheral insulin resistance. Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1, and are important integrators of heterologous regulation. Systemic ablation of the Irs2 gene in mice causes β-cell dysfunction that prevents compensatory insulin secretion while insulin resistance progresses to life threatening hyperglycemia. Upregulation of IRS2 in pancreatic β-cell using rat insulin-2 promoter (Irs2RIP) promotes sufficient hyperinsulinemia to prevent diabetes. Targeted Irs2 deletion using CreRIP also causes beta-cell failure and hyperglycemia, but the mechanism is unclear because CreRIP drives deletion in beta-cells and hypothalamus—especially in the arcuate nucleus (ARC). AGRP neurons in the ARC play an important role in regulating energy homeostasis, but it is unknown whether IRS2 in the AGRP neurons might also affect beta-cell function. Here we show that disruption of Irs2 (but not Irs1) in AGRP neurons (Irs2f/fCreAgrp-mice) reduced islet mass by 45%. To test insulin secretory function, we subjected mice to hyperglycemic clamps. The glucose infusion rate to maintain steady-state hyperglycemia decreased significantly. Moreover, insulin secretion failed to respond to L-arginine treatment in aged Irs2f/fCreAgrp-mice. Moreover, Irs2f/fCreAgrp-mice displayed progressive deterioration of glucose homeostasis and a lack of beta -cell compensation during high fat diet. Overall, our results indicate that dysfunction of Irs2 in AGRP neurons might contribute to the pathophysiology of type 2 diabetes.

Disclosure
R. Tao: None. K.D. Copps: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories. O. Stoehr: None.

Funding
National Institutes of Health (5R01DK098655-06)
1841-P: Fasting Test Distinguished Organic from Functional Hypoglycemia
Authors: SKRHA JAN , PRAZNY MARTIN , KRIZOVA JARMILA , SKRHA JAN 
Published: June 2019

Nondiabetic hypoglycemia may be caused by hepatic or renal failure, drugs, malnutrition, malignancy or functional changes. The fasting test may be used to distinguish organic hypoglycemia by insulinoma from functional (reactive) hypoglycemia. The aim was to compare if clinical and biochemical characteristics could clearly differentiate both diagnoses during fasting test.
In total, 84 patients (mean age 50 ± 16 years; 54 females) with history of unclear hypoglycemia were examined at our department in the last 8 years. Their liver and renal functions were normal. All patients underwent a 72-hour fasting test. The test was stopped earlier when neuroglycopenic symptoms developed. Blood samples were taken for glucose (BG), insulin (Ins) and C peptide measurements at the beginning, in 6-hour intervals and at the end of the test.
Fasting test was positive (F+ group) in 43 persons developing neuroglycopenic symptoms and thus it was stopped earlier (duration 24 ± 17 hours) as compared to F- group (41 persons) without these symptoms during the whole 72-hours of fasting. Both groups were similar in age, BMI or arterial pressure. Significant differences between F+ and F- group were observed at the end of the test (BG: 2.0 ± 0.4 vs. 3.8 ± 0.8 mmol/l, p&lt;0.0001; Ins: 61 (11; 111) vs. 13 (5; 22) mU/L, p&lt;0.0001; C peptide: 1.4 (0.5; 2.1) vs. 0.4 (0.1; 0.6) nmol/L, p&lt;0.0001). All patients in F+ group developed spontaneous hypoglycemia &lt;2.5 mmol/l during fasting but it was not true in F- group. The insulin/BG ratio (normal value &lt;5.0 mU/mmol) could significantly distinguish both groups at the end of fasting (29.7 vs. 3.5 mU/mmol, p&lt;0.0001). Insulinoma was then confirmed in all F+ patients at surgery.
Fasting test represents the most important diagnostic tool in the evaluation of unclear nondiabetic hypoglycemia. Neuroglycopenic symptoms together with spontaneous hypoglycemia by fasting are the most sensitive indicators of insulinoma. In addition, the insulin/BG ratio seems to be of highest benefit in distinguishing organic and functional hypoglycemia.

Disclosure
J. Skrha: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Lilly Diabetes. M. Prazny: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis, Takeda Pharmaceutical Company Limited. Board Member; Self; Bayer AG. Consultant; Self; Medtronic, Roche Diabetes Care. Speaker's Bureau; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi-Aventis, Servier, Teva Pharmaceutical Industries Ltd. J. Krizova: None. J. Skrha: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Sanofi.

Funding
RVO-VFN00064165
1856-P: A High Sugar (Fructose) Diet Increases C-Reactive Protein (CRP) in Rhesus Macaques: Relationships with Changes of Apolipoproteins and Adiponectin
Authors: HAVEL PETER J. , GRAHAM JAMES L. , STANHOPE KIMBER L. , BUTLER ANDREW 
Published: June 2019

CRP is produced by the liver in response to factors released from macrophages and adipocytes. High circulating CRP concentrations are therefore an indicator of inflammation and/or injury. We examined the effects of dietary fructose on plasma CRP concentrations in a nonhuman primate model of diet-induced metabolic syndrome. Adult male rhesus macaques 12±3 years of age, weighing 16.2±1.9 kg (n=29) maintained on chow (LabDiet 5047) ad libitum were provided with flavored fructose beverages containing 75g of fructose (300 kcal/day). Fasting plasma samples were collected at baseline and after 1 and 3 months. Indices of glucose homeostasis (insulin, glucose, HOMA-IR), adiposity/metabolic homeostasis (leptin, adiponectin) and lipid metabolism (TG, cholesterol, LDL-C, HDL-C, VLDL-C, ApoA1, ApoB, ApoC3 and ApoE) were analyzed. Fructose consumption induced weight gain +1.5±0.2 kg, and insulin resistance, accompanied by increases of plasma leptin, decreased adiponectin, hypertriglyceridemia and increases of ApoC3 and ApoE. Plasma CRP increased from 1.9±0.2 mg/l to 2.9±0.3 mg/l (%∆ = 81±13%) and 2.9±0.3 mg/l (%∆ = +91±14%; both p&lt;0.001) at 1 and 3 months respectively. Bivariate correlation analysis of log-transformed data compared fructose-induced changes (Δ) of CRP with Δ’s of body weight and metabolic indices. After 1 month of fructose consumption, strong positive associations were identified between ΔCRP and ΔApoE (r=0.62, p&lt;0.001), ΔApoC3 (r=0.56, p=0.002), and negatively with Δadiponectin (r=-0.49, p=0.007). After 3 months of fructose exposure, the strong associations between ΔCRP and ΔApoE (r=0.49, p=0.007) and significant relationships with ΔApoC3 (r=0.45, p=0.015) and Δadiponectin (r=-0.39, p=0.038) remained. These results support an important link between fructose diet-induced inflammation with changes of the anti-inflammatory adipocyte hormone (adiponectin) and dysregulated hepatic lipoprotein metabolism.

Disclosure
P.J. Havel: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc. J.L. Graham: Research Support; Self; Arrowhead Research, Bristol-Myers Squibb Company, Magnamosis Inc. K.L. Stanhope: None. A. Butler: None.

Funding
National Institutes of Health
1857-P: Modified Mesenchymal Stromal Cells: A Novel and Safe Therapy for Treating Nonalcoholic Fatty Liver Disease (NAFLD) in Obesity and Diabetes
Authors: DOMINGUES CLEYTON C. , KUNDU NABANITA , KROPOTOVA YANA , SEN SABYASACHI 
Published: June 2019

Background: Mesenchymal stromal cells (MSCs) can home-in to inflamed fat depots to deliver antioxidants locally and help reduce oxidative stress, inflammation and improve NAFLD in high-fat diet (HFD) induced obese (DIO) diabetic mice.
Methods: Antioxidants Sod2 (mitochondrial), Catalase (cytosolic) or Null (control) genes were upregulated individually, or in combination in adipose-derived MSCs. Modified MSCs were examined in-vitro in presence of adipogenic media to mimic DIO milieu. Next, modified MSCs were delivered intraperitoneally (IP) in mice that received 45% or 60% HFD for 8 to16 weeks.
Results: In-vitro, we noted reduced MSC lipid droplets with SOD2, Catalase and combination compared to Null. Inflammatory marker IL6 mRNA, was down-regulated in SOD2, Cat and combination MSCs vs. Null-MSCs. In-vivo, n=4, Glucose tolerance test (GTT) improved with SOD2 MSC delivery in (p=0.07) at week-4. Plasma inflammatory marker TNFa, was reduced in both SOD2 and Catalase MSC groups (p&lt;0.05) vs. Null-MSCs group. Analysis of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (∼1000 and 100-fold, respectively) and PGC1A mRNA was upregulated. Increased Ucp1 was confirmed by staining. There was a reduction in liver fat content by histology and liver triglyceride assay (p&lt;0.05). Outcome measures of SOD2+Catalase combination MSC delivery in-vivo is pending.
Conclusion: Upregulation of SOD2 plus Catalase, in-vitro, reduced inflammation in adipogenic media more so than individual gene upregulation. In-vivo, delivery of Sod2 and Catalase upregulated individually in MSCs, reduced inflammation and improved GTT with concomitant increased browning of white fat and reduced liver fat. Our results indicate that antioxidant upregulated modified MSC delivery IP, to target inflamed fat depots helps reduce oxidative stress and inflammation and can be an efficient tool for treating obesity, diabetes and NAFLD.

Disclosure
C.C. Domingues: None. N. Kundu: None. Y. Kropotova: None. S. Sen: None.

Funding
Clinical and Translational Science Institute at Children's National
1862-P: Insulin-Independent Glucose Utilization during Exercise Is Impaired in Type 1 Diabetes: A New Model Based Analysis
Authors: ROMERES DAVIDE , SCHIAVON MICHELE , BASU ANANDA , COBELLI CLAUDIO , BASU RITA , MAN CHIARA DALLA 
Published: June 2019

We have previously shown that low insulin coupled with euglycemia or mild hyperglycemia appear to be the most favorable milieu for type 1 diabetes (T1D) during exercise. However, the contributions of insulin-dependent (IDGU) and insulin independent (IIGU) effects of exercise on glucose utilization are unknown. To do so, we studied 6 T1D (age 29±3 years, BMI 28.3±2.0 kg/m2, VO2 max 28.7±2.9 ml/kg/min, mean±SE) and 6 ND (age=28.2±4.2 year, BMI=23.6 ±1.0 kg/m2, VO2 max 36.6±2.9 ml/kg/min) subjects with a glucose clamp, during, before and after a 60 min exercise session at 65% VO2max, on three visits: euglycemia-low insulin (V1); euglycemia-high insulin (V2) and hyperglycemia-low insulin (V3) in random order. Glucose turnover was measured with the isotope dilution technique using [6,6-2H2]glucose. We modified the minimal model to measure the IDGU and IIGU components of glucose utilization (Figure 1, upper panel). Results demonstrate that while IDGU was similar in both groups (data not shown), IIGU (expressed as percent change from baseline) during exercise was significantly lower in T1D than ND subjects, though the trend across the visits were similar (Figure 1, lower panel). Further studies are necessary to determine the cause for this abnormality in T1D to optimize glucose control.

Disclosure
D. Romeres: None. M. Schiavon: None. A. Basu: Research Support; Spouse/Partner; AstraZeneca. C. Cobelli: None. R. Basu: Other Relationship; Self; AstraZeneca. C. Dalla Man: None.

Funding
National Institutes of Health (R01090541)
1871-P: Mir 103/107 Regulates Lipid Metabolism by Inhibiting Betatrophin/ANGPTL8
Authors: ABU-FARHA MOHAMED , CHERIAN PREETHI THOMAS , KHAIRI IRINA AL , AL-MULLA FAHD , ABUBAKER JEHAD 
Published: June 2019

Angiopoietin-like protein 8 (ANGPTL8)/betatrophin is liver and adipocyte produced hormone that has been associated with insulin resistance and dyslipidaemia. The interaction of ANGPTL8 with ANGPTL3 causes an inhibition of lipoprotein lipase (LPL) activity and ultimately increases serum levels of triglyceride. Identification of ANGPTL8 and ANGPTL3 inhibitors have been pursued as potential drug target to treat dyslipidaemia. In this study we used target prediction algorithms to show that mir103 has a putative binding sites in the 3' untranslated region of ANGPTL8. Overexpression of mir103 in HepG2 cells or its mimic resulted in decreased ANGPTL8 RNA and protein level compared to scrambled microRNA control. Cloning the 3’UTR of ANGPTL8 with Luciferase reporter assay confirmed the direct binding and repression of luciferase activity by mir103 to ANGPTL8 compared to its control. Palmitic acid treatment of HepG2 cells mimicked dyslipidaemia and increased ANGPTL8 level which was reduced after treatment with mir103. Additionally, expression of miR103 and ANGPTL8 in circulation and adipose tissue was evaluated in 144 participants that included 82 non-obese (BMI &lt;30 kg/m2) and 62 obese (BMI &gt;30 kg/m2). Mir103 levels in small RNA extracted from plasma and adipose tissue was measured by RT-PCR. Mir103 was higher in non-obese people in both plasma and adipose tissue. ANGPTL8 level on the other hand was higher in obese individuals (1200.5 ±110.2 pg/ml) compared to non-obese (720.7 ±80.9 pg/ml, p-value =0007). MiR103 was inversely associated with BMI (p-value &lt; 0.001), leptin (p-value = 0.010) and triglyceride (p-value =0.011). Taken together, our data confirms the binding and inhibition of mir103 to ANGPTL8 under normal and high fat conditions. It also sheds light on the potential role of mir103 in regulating lipid metabolism which can be used as a future therapeutic target for dyslipidaemia and other metabolic related diseases.

Disclosure
M. Abu-Farha: None. P.T. Cherian: None. I. Al Khairi: None. F. Al-Mulla: None. J. Abubaker: None.

Funding
Dasman Diabetes Institute; Kuwait Foundation for the Advancement of Sciences (RA2016-025)
188-OR: Partial Depletion of CD206 M2-Like Macrophages Enhances Preadipocyte Differentiation via Reduction of Wnt Signaling
Authors: NAWAZ ALLAH , NAKAGAWA TAKASHI , YAGI KUNIMASA , FUJISAKA SHIHO , TOBE KAZUYUKI , OKABE KEISUKE , KADO TOMONOBU , LIU JIANHUI , BILAL MUHAMMAD 
Published: June 2019

Several pieces of evidence indicate that Wnt/β-catenin pathway may regulate the mesenchymal stem cells fate proliferation in vivo. The Wnt signaling is also known to inhibit preadipocyte differentiation into adipocyte. Adipose tissue macrophages play important roles in the maintenance of tissue homeostasis by regulating insulin sensitivity via their anti-inflammatory actions. However, how CD206 M2-like macrophages linked to Wnt signaling in maintaining the preadipocyte differentiation, remains elusive. In the present study, we aimed to investigate the physiological role of CD206 linked to Wnt signaling in preadipocyte differentiation. We show that C1q, which can mediate Wnt signaling, is abundantly expressed in CD206 M2-like macrophages in epididymal adipose tissue. Then, we examined whether CD206 M2-macrophages depletion activate or inhibit Wnt signaling and preadipocyte differentiation. Here, we show that the expression of M2 marker genes was reduced with a reduced expression of Wnt signaling genes in adipose tissue of CD206-reduced mice. Western blot analysis confirmed reduced protein level of β-catenin in CD206-reduced mice that can contribute to regulate the preadipocyte/progenitor’s activity. We presumed that the reduction of C1q-induced Wnt signaling promoted adipogenesis. We also found that depletion of CD206 M2-like macrophages resulted in the generation of the smaller adipocyte, upregulated expression of metabolically favorable genes and enhanced insulin sensitivity in both chow and high-fat diet-fed CD206-reduced mice. Taken together, we show that partial depletion of CD206 M2-like macrophages inhibits Wnt/β-catenin pathway activity in mice and increases preadipocyte differentiation, thus ameliorating insulin resistance in lean and obese mice.

Disclosure
A. Nawaz: Research Support; Spouse/Partner; Astellas Pharma Inc., Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company. Research Support; Self; Japan Society for the Promotion of Science. Research Support; Spouse/Partner; Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Shionogi & Co., Ltd., Takeda Pharmaceutical Company Limited. T. Nakagawa: None. K. Yagi: None. S. Fujisaka: None. K. Tobe: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Japan Diabetes Society. Research Support; Self; Bristol-Myers Squibb Company. K. Okabe: None. T. Kado: None. J. Liu: None. M. Bilal: None.

Funding
Japan Society for the Promotion of Science
1881-P: The SGLT2 Inhibitor Dapagliflozin Improves Glucose Control and Enhances Liver Fatty Acid Oxidation and Ketone Body Formation in Insulin Resistant Obese Zucker Rats
Authors: KROON TOBIAS , HAGSTEDT THERESE , KJELLSTEDT ANN , LINDBLOM ANNA , LÖFGREN LARS , BOUCHER JEREMIE , SÖRHEDE WINZELL MARIA , LINDEN DANIEL , WALLENIUS KRISTINA 
Published: June 2019

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective treatments for improving glucose control and reducing cardiovascular events in patients with T2D. In the present study we examined the metabolic effects of chronic treatment of the SGLT2i dapagliflozin in obese insulin resistant Zucker rats. Three different studies were performed with the aims to assess: 1) liver CoA intermediates, 2) whole-body FA metabolism using a constant infusion of 3H-palmitate and 3) tissue-specific rates of FA utilization and storage using 3H-labelled bromo-palmitate and 14C-labelled palmitate, respectively. Four weeks treatment with dapagliflozin (1 mg/kg/d p.o.) markedly increased glucosuria, reduced HbA1c and fasting plasma glucose and insulin levels and increased pancreatic insulin content compared to vehicle treated rats. Liver acetyl-CoA levels were increased while the malonyl-CoA/acetyl-CoA ratio was decreased following dapagliflozin treatment, suggestive of an increased liver FA oxidation. Treatment with dapagliflozin also increased liver HMG-CoA levels, an intermediate in ketone body formation, indicating that the acetyl-CoA is diverted to ketone body formation. This was supported by increased fasting plasma levels of the ketone body β-hydroxybutyrate in the dapagliflozin-treated rats compared to vehicle. Dapagliflozin treatment resulted in increased plasma FA levels and rates of whole-body FA oxidation. The increased whole-body FA oxidation was subsequently found to be driven by an increase in liver FA utilization.
In conclusion, dapagliflozin improves glucose homeostasis and enhances FA utilization in insulin resistant obese animals. These results suggest that dapagliflozin-induced glucose loss in urine signals a fasting state to the liver, which leads to an increased FA oxidation and ketone body production.

Disclosure
T. Kroon: Employee; Self; AstraZeneca. T. Hagstedt: None. A. Kjellstedt: None. A. Lindblom: Employee; Self; AstraZeneca. L. Löfgren: Employee; Self; AstraZeneca. J. Boucher: Employee; Self; AstraZeneca. M. Sörhede Winzell: Employee; Self; AstraZeneca. D. Linden: Employee; Self; AstraZeneca. K. Wallenius: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.
1898-P: The Role of the Diabetes Gene and Wnt Pathway Effector TCF7L2 in Hepatic Metabolic Zonation
Authors: AYALA IRISCILLA I. , DEFRONZO RALPH A. , NORTON LUKE 
Published: June 2019

The Transcription Factor 7-like 2 (TCF7L2) gene is associated with type 2 diabetes (T2D), but the function of the protein in metabolic tissues is controversial. The liver regulates whole body lipid and carbohydrate metabolism, and the development of T2D and nonalcoholic fatty liver disease (NAFLD) is linked to hepatic insulin resistance and dyslipidemia. The liver is metabolically zonated and hepatocytes are specialized to execute the diverse metabolic functions of the liver. We previously demonstrated that TCF7L2 transcriptionally regulates multiple metabolic pathways in hepatocytes, and hypothesized that TCF7L2 controls metabolic zonation in vivo. We generated mice expressing inactive TCF7L2 in liver (Hep-ΔE11-TCF7L2) and examined zonation, lipid metabolism and the development of NAFLD. We observed complete disruption of hepatic zonation in Hep-ΔE11-TCF7L2, as determined by the absence of glutamine synthetase expression in pericentral (PC) hepatocytes. Interestingly, using laser capture microdissection and TCF/LEF reporter mice, we observed that TCF7L2 and Wnt/β-catenin signaling genes were expressed throughout the liver, but that the activity of TCF7L2 was restricted to PC hepatocytes. Consistent with TCF7L2 activity in glycolytic PC hepatocytes only, Hep-ΔE11-TCF7L2 mice had normal glucose tolerance and insulin sensitivity. However, HFD-fed Hep-ΔE11-TCF7L2 mice were protected from adipose tissue expansion and weight gain, but had elevated circulating FFA. In a subset of Hep-ΔE11-TCF7 mice, we detected a severe NASH phenotype histologically, and RNA-Seq analysis revealed significant alterations in the expression of genes involved in cholesterol and lipid metabolism, and inflammatory and fibrotic pathways. These data show that TCF7L2 activity is highly restricted in mature liver, but that TCF7L2 is required for hepatic metabolic zonation. Our data also suggest that disrupted metabolic zonation may contribute to the development of NAFLD.

Disclosure
I.I. Ayala: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. L. Norton: None.

Funding
National Institutes of Health