bluuebunny/crossref_metadata_2025_split huggingface dataset:
1797-P: ß-arrestin-1 in AgRP Neurons Plays Crucial Role in Maintaining Whole Body Glucose Homeostasis
Authors: PYDI SAI PRASAD , CUI ZHENZHONG , BARELLA LUIZ F. , CUI YINGHONG , CHEN WEI , GAVRILOVA OKSANA , WESS JÜRGEN 
Published: June 2019

Hunger and satiety are regulated, to a major extent, by the agouti-related protein (AgRP)/neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons residing in the arcuate nucleus of the hypothalamus. During starvation, AgRP neurons are strongly activated to promote hunger. Peripheral hormones and nutrients regulate the function of AgRP neurons, thus ensuring proper glucose and energy homeostasis. Recent studies from various labs, including our group, have shown the importance of G-protein coupled receptors (GPCRs) in regulating the activity of AgRP neurons. GPCR function is modulated by a pair of proteins known as beta-arrestin-1 and -2 (barr1 and barr2, respectively), which can terminate GPCR signaling and/or mediate GPCR-independent signaling. It is well established that barr1 and barr2 are involved in many important physiological functions. However, the potential roles of barr1 and barr2 in regulating the activity of AgRP neurons remain unexplored. To address this issue, we generated mice that lacked barr1 or barr2 selectively in AgRP neurons using Cre/loxP-flex-switch technology. Interestingly, AgRP-barr1-KO mice consuming a high fat diet showed significantly impaired glucose tolerance, decreased insulin sensitivity, and elevated plasma glucose and insulin levels. AgRP-barr1-KO mice did not differ from their control littermates in body weight and food intake. More detailed studies into the mechanisms through which barr1 regulates the activity of AgRP neurons may lead to new strategies to alter the activity of AgRP neurons for therapeutic purposes.

Disclosure
S. Pydi: None. Z. Cui: None. L.F. Barella: None. Y. Cui: None. W. Chen: None. O. Gavrilova: None. J. Wess: None.
180-OR: Tissue-Specific Functions of PPARα Overexpression in Liver, Adipose, and Pancreatic ß Cells
Authors: YE RISHENG , SCHERER PHILIPP E. 
Published: June 2019

Peroxisome proliferator-activated receptor (PPAR) α is one of the master regulators of lipid metabolism and the major target of fibrates, a class of drugs improving dyslipidemia in metabolic syndromes. To understand the tissue-specific roles of PPARα and the coordination among multiple organs, we employed newly generated mouse models enabling doxycycline-inducible overexpression of PPARα specifically in liver, adipose or the insulin-producing pancreatic β-cells. Titrated by doxycycline dose, a moderate elevation of PPARα proteins in liver activated the transcription of its target genes. In mice with diet-induced obesity, hepatic overexpression of PPARα significantly reduced steatosis and improved systemic insulin sensitivity. Surprisingly, systemic triglyceride clearance was dramatically impaired, associated with a trend towards faster VLDL secretion. PPARα overexpression in adipose tissues had a marginal effect on systemic insulin sensitivity. However, inflammation was markedly ameliorated in white but not brown fat pads. Pancreatic β-cell-specific overexpression of PPARα resulted in a significant decrease in glucose-stimulated insulin secretion, suggesting a negative impact of PPARα induction on β-cell function. Taken together, our findings reveal the differential actions of enhanced PPARα on local tissues and whole-body metabolism and call for caution to the potential adverse effects from fibrate treatment. Further dissection of PPARα signaling with our mouse models may facilitate the discovery of novel therapeutic targets with high efficacy and specificity.

Disclosure
R. Ye: None. P.E. Scherer: None.

Funding
National Institutes of Health (R01DK55758, R01DK099110, P01-DK088761-01); JDRF (17-2012-36); Novo Nordisk Foundation (to P.E.S.)
1809-P: Comparing Male and Female Metabolic Phenotypes in Mouse Strains Deficient in Leptin Signaling
Authors: FRENCH RICHARD D. , LEIGHTON KRYSTAL , SERRANO JASON , SCHILE ANDY 
Published: June 2019

National Institutes of Health policy states that animal studies should account for sex as a biological variable by including males and females when possible. Male mice are mainly used in diabetes research involving mutations that inactivate the leptin hormone (Lepob) or its receptor (Leprdb). We found that many metabolic phenotypes were similar in males and females from two C57BL/6J mutant strains with transient hyperglycemia (B6-ob and B6-db) and a C57BLKS/J strain with sustained hyperglycemia (BKS-db). In all strains, homozygous ob or db genotypes led to similar male and female weight gain despite sexual dimorphism in weights of control genotypes. In homozygous mutant mice at 8 and 16 weeks of age, the only significant weight differences between males and females were at 8 weeks in B6-db (males weighed 1.7 g more; P = 0.0037) and 16 weeks in B6-ob (females weighed 2.5 g more; P = 0.0017). BKS-db/db males had higher nonfasted blood glucose than females (415 mg/dL vs. 357 mg/dL; P &lt; 0.0001) at 8 weeks, but no other differences were significant at 8 and 16 weeks. Male and female B6-ob/ob and B6-db/db mice reverted to normal blood glucose at similar rates. HbA1c levels were higher in males for all strains at 16 weeks (P &lt; 0.05 for all 3 pairwise comparisons). Male and female mutants had similar body fat percentages, with the exception of higher adiposity in B6-ob/ob females at 16 weeks (6% greater; P = 0.0163). We assessed serum insulin and leptin in BKS-db mice. Insulin was significantly higher in male and female db/db mice relative to db/+ or +/+ controls at 8 weeks, but db/db levels did not differ by sex. Leptin was significantly higher in db/db mice relative to controls (P &lt; 0.0001 for all pairwise comparisons). Leptin did not differ by sex in db/db mice at 8 weeks; leptin levels were significantly higher in females at 16 weeks of age (P = 0.0039). All data will be made publicly available from the Mouse Phenome Database to serve as reference values when considering the use of female ob and db mutant mice in diabetes research.

Disclosure
R.D. French: None. K. Leighton: None. J. Serrano: None. A. Schile: None.
1811-P: Short Term Dopamine D1D2 Receptor Agonist Therapy Induces Long-Term Amelioration of Hyperglycemia in ob/ob Mice
Authors: LUO SHUQIN , EZROKHI MICHAEL , COMINOS NICHOLAS , RAICHE BENJAMIN , CINCOTTA ANTHONY H. 
Published: June 2019

Short term, circadian-timed dopamine precursor (L-DOPA) therapy can produce long term advances or delays in the annual cycle of metabolism in several seasonal vertebrate species as function of the time of day of its administration. It has also been demonstrated that dopamine D1 plus D2 receptor agonist (DA) therapy improves dysmetabolism in leptin inactive animal models of metabolic syndrome to a level that cannot be achieved with either agonist alone. This study therefore investigated the potential for short term DA therapy to induce long term reduction in hyperglycemia in ob/ob mice. In two separate studies, animals were treated either with the dopamine D1 plus D2 agonists (SKF38393 and bromocriptine, respectively) (each 10 mg/kg BW ip) or vehicle prior to the onset of waking for 14 days. After 7 and 11 days of treatment, DA markedly reduced plasma hyperglycemia, triglyceride and FFA levels, and elevated corticosterone levels (Study 1). Remarkably, these DA effects remained 28 days after cessation of the therapy. In Study 2, conducted to assess DA effects on impaired glucose intolerance (IGT), DA therapy again produced long-lasting improvements in hyperglycemia and IGT (Table). This study demonstrates a long-lasting amelioration of dysglycemia in ob/ob mice with a systemic therapy. These studies provide a basis for contemplating development of a clinical DA therapy for metabolic disease.

Disclosure
S. Luo: Employee; Self; VeroScience LLC. M. Ezrokhi: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. B. Raiche: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.
1813-P: An Experimental Model to Combat the Increased Prevalence of Diabetes in Alzheimer’s Disease
Authors: BABICI DENIS , ZHANG JIE , OYDANICH MARKO , NISHIMURA KOICHI , VATNER DOROTHY E. , MOURADIAN M. MARAL , VATNER STEPHEN F. 
Published: June 2019

Alzheimer’s disease is associated with many other disorders of healthful aging; one of the most prominent is the increased prevalence of diabetes in patients with Alzheimer’s, resulting in almost twice the number of hospitalizations compared with that of non-Alzheimer’s patients. The goal of this investigation was to discover an animal model that was protected both from Alzheimer’s Disease and diabetes. The adenylyl cyclase type 5 (AC5) knockout (KO) was selected since it not only lives a third longer than its wild type (WT), but is also a model of healthful aging, with improved metabolism, enhanced exercise capacity and protection against obesity and diabetes. Accordingly, we compared the AC5 KO with that of the J20 mouse, a model for Alzheimer’s disease. Comparisons were made among AC5 KO, J20 and WT mice for behavioral tests indicative of Alzheimer’s and diabetes protection as reflected by the glucose tolerance test. All 3 behavioral tests studied demonstrated that AC5 KO were protected compared to WT, whereas the J20 mice demonstrated behavioral alterations consistent with Alzheimer’s Disease. For example, the water maze test, used to assess spatial learning and memory, demonstrated the expected 134± 7.6% deficit, p&lt;0.05, in the J20 mice, in contrast to the 38± 3.0% improvement, in performance, p&lt;0.05, in AC5 KO. The glucose tolerance test (GTT) also demonstrated protection in AC5 KO and impaired GTT in the J20 mice, i.e., the area under the curve following 1g/kg IP glucose, was 47± 5.2% less, p&lt;0.05, in AC5 KO compared to WT, whereas it was 137± 10.2% higher, p&lt;.05, than WT in the J20 mice. Thus, the AC5 KO mice were protected both against impaired GTT and behavioral changes associated with Alzheimer’s disease, suggesting that inhibition of AC5 would be a novel therapeutic modality, not only for diabetes, but also for the diabetes associated with Alzheimer’s Disease.

Disclosure
D. Babici: None. J. Zhang: None. M. Oydanich: None. K. Nishimura: None. D.E. Vatner: None. M. Mouradian: None. S.F. Vatner: None.

Funding
National Institutes of Health (R01HL102472, R01HL106511, R01HL119464, R01HL124282, R01HL130848, R01HL137368, R01HL137405, R21AG053514)
182-OR: Maternal Glucose and Insulin Are Associated with Lipid Metabolism and Adipogenesis Pathways in Human Umbilical Cord-Derived Mesenchymal Stem Cells: The Healthy Start Echo Cohort
Authors: KELEHER MADELINE , DABELEA DANA , FRIEDMAN JACOB E. , BOYLE KRISTEN E. 
Published: June 2019

We have reported that umbilical cord mesenchymal stem cells (MSCs) from infants born to mothers with obesity have less AMP-activated protein kinase [AMPK] and less inhibitory phosphorylation of glycogen synthase kinase 3 [GSK3]β, a regulator of MSC differentiation. This is accompanied by a greater capacity for in vitro adipogenesis, which positively correlates with infant adiposity. Here we hypothesized that, independent of maternal pre-pregnancy (pp)BMI, maternal glucose and insulin would be associated with GSK3β and AMPK in undifferentiated infant MSCs. We studied 67 women (ppBMI 18-42 kg/m2) at mid (15-23 weeks) and late (24-32 weeks) gestation without preeclampsia or gestational diabetes, as well as their infants’ MSCs. We ran linear models to test the effect of fasting maternal glucose and insulin on each phosphorylated MSC protein, with infant sex and gestational age as covariates, ± ppBMI as a covariate to account for collinearity with metabolic measures. Linear model p-values and Pearson correlations are reported. Maternal glucose at mid (p = 0.03, r = 0.26) and late (p = 0.009, r = 0.35) gestation had a significant effect on AMPKThr172, with no effect of ppBMI, indicating greater AMPK activity with higher maternal glucose. Mid gestation insulin (p = 0.04, r = -0.21) was associated with GSK3βSer9, with the same trend for HOMA-IR—but not when ppBMI was included as a covariate, as it was also negatively associated with GSK3βSer9 (p = 0.02, r = -0.24), showing collinearity of ppBMI and insulin (r = 0.40). This signifies higher ppBMI and insulin with less GSK3β inhibition, which we have previously linked to greater adipogenesis. These results demonstrate the novel finding that maternal glucose during pregnancy is associated with perturbations to lipid metabolism pathways in infant MSCs across a wide range of ppBMI, giving important clues as to how maternal metabolism may impact infant metabolic disease risk.

Disclosure
M. Keleher: None. D. Dabelea: None. J.E. Friedman: Consultant; Self; Janssen Research & Development. K.E. Boyle: None.

Funding
National Institutes of Health (4UH3OD023248-03)
1824-P: Leptin Receptor Neurons in the Hypothalamic Ventromedial Nucleus Play a Physiological Role in Regulating Glucose Tolerance
Authors: FABER CHELSEA L. , HARVEY TRISTA J. , VELASCO KEVIN R. , DAMIAN VINCENT , SCHWARTZ MICHAEL W. , MORTON GREGORY J. 
Published: June 2019

A role for leptin receptor (LepR)-expressing neurons in the hypothalamic ventromedial nucleus (VMN) in glucose homeostasis is suggested by studies in which leptin is administered into, or leptin receptors are deleted from, this brain area. However, whether LepR neurons in the VMN play a physiological role in glycemic control remains unknown. To test this hypothesis, we utilized an optogenetics approach to acutely silence VMNLepR neurons in awake, freely moving mice. We found that while photoinhibition of VMNLepR neurons had no effect on blood glucose levels under basal conditions (Control AUC: 681.6 ± 422.4 vs. Inhib AUC: 565.8 ± 350.7; p=ns, n=10), it impaired glucose tolerance significantly (Control AUC: 9251.7 ± 2032.6 vs. Inhib AUC: 13957.4 ± 4837; p&lt;0.01, n=10). Further, this effect occurred despite no change in glucose-stimulated insulin secretion (GSIS), suggesting that the effect is not secondary to reduced insulin secretion. Consistent with this conclusion, we report that insulin sensitivity was reduced by inhibition of VMNLepR neurons based on insulin tolerance testing (Control AUC: 8341 ± 531 vs. Inhib AUC: 9138 ± 658; p&lt;0.01, n=9). Together, these data suggest that VMNLepR neurons play a physiological role in the control of glucose tolerance and that activity of these neurons is required for normal insulin sensitivity. Future studies will examine both the peripheral mechanism(s) that mediate these effects and to identify the underlying neurocircuitry.

Disclosure
C.L. Faber: None. T.J. Harvey: None. K.R. Velasco: None. V. Damian: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None.

Funding
National Institutes of Health
1836-P: Derivation of Glucagon Kinetics to Reconstruct Glucagon Secretion in Nondiabetic Humans
Authors: LAURENTI MARCELLO C. , MAN CHIARA DALLA , ADAMS J.D. , EGAN AOIFE M. , COBELLI CLAUDIO , VELLA ADRIAN 
Published: June 2019

Impaired glucose tolerance arises out delayed and decreased postprandial insulin secretion together with impaired postprandial suppression of glucagon. Recent studies have demonstrated that β-cell and α-cell dysfunction can occur independently in prediabetes. The effect of diabetes-associated variation in TCF7L2 on α-cell function also suggests a direct role in the pathogenesis of type 2 diabetes (T2DM). Quantification of the relative contribution of α-cell and β-cell function to glucose tolerance has been lacking because of a dearth of information regarding glucagon kinetics in humans. This information is necessary to deconvolute glucagon secretion from peripheral glucose concentrations. Therefore, as part of a series of experiments examining the interaction between a lack of glucagon suppression with intact, mildly or moderately impaired insulin secretion we studied 22 nondiabetic subjects (age = 46 ± 3 years, BMI = 29 ± 1 Kg/M2). An intravenous glucose infusion mimicking the systemic appearance of 50g oral glucose was administered in the presence of a pancreatic clamp over 300 minutes. Glucagon was infused at a rate of 0.65ng/kg/min, starting 120 minutes after initiation of the experiment (and suppression of endogenous glucagon secretion by somatostatin). The observed glucagon appearance rates were used to calculate the kinetic parameters of glucagon. Volume of distribution (Vd) was estimated at 14 ± 2 Litres or 0.16 ± 0.02 L/Kg body weight. Half-life was estimated at 6.1 ± 0.5 minutes with a clearance rate (CL) of 1.6 ± 0.1 L/min. Body surface area and height predicted Vd and CL. The individual parameters were then used to calculate glucagon secretion rates from peripheral glucagon concentrations for each participant. Fasting glucagon secretion rates (101 ± 11 ng/min) decreased (p &lt; 0.01) in the presence of somatostatin (57 ± 5 ng/min). These data demonstrate the application of deconvolution to the quantification of glucagon secretion and its contribution to glucose tolerance.

Disclosure
M.C. Laurenti: Employee; Self; GlySens Incorporated. C. Dalla Man: None. J. Adams: None. A.M. Egan: None. C. Cobelli: None. A. Vella: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Novo Nordisk Inc.

Funding
National Institutes of Health
1843-P: Reduced Sampling for the Estimation of Hepatic and Extrahepatic Insulin Clearance in Children of Different Ethnicities
Authors: PICCININI FRANCESCA , GOWER BARBARA , FERNANDEZ JOSE R. , BERGMAN RICHARD N. 
Published: June 2019

African American (AA) children have lower hepatic insulin clearance than European Americans (EA), as obtained with a 25-sample intravenous glucose tolerance test (FSIGT), over 240 minutes (t=0, 2, 3, 4 5, 6, 8, 10, 12, 15, 19, 20, 21, 22, 24, 26, 28, 30, 35, 40, 50, 60, 70, 180, 240 minutes). C-peptide and insulin concentrations were analyzed with a recent model of hepatic (FEL) and extra-hepatic (CLP) insulin clearance. This model has not been tested in a reduced sampling protocol, easier to be performed in larger cohorts. With data from 203 children of both sexes and 3 ethnic groups [55 AA, 88 EA, 60 HA (Hispanic Americans), age 7-13 years, mean BMI = 19 kg/m2, basal plasma glucose = 99 mg/dL, insulin = 78 pmol/L, C-peptide = 511 pmol/L], a reduced 12-sample schedule was examined (t=0, 2, 4, 8, 19, 22, 26, 30, 40, 50, 70, 180 minutes). FEL and CLP from the reduced protocol were strongly correlated with the full one: FEL: r=0.91, p&lt;0.001; CLP: r=0.96, p&lt;0.001. The mean precision of estimates (coefficient of variation, CV) was similar: CVfull=40%, CVreduced=41%. The lower hepatic but not extra-hepatic insulin clearance in AA vs. EA children was still detectable with the reduced sampling (see Figure 1), that provides virtually identical and precise estimates of insulin clearance. This reduced protocol can be used in larger population-based studies.

Disclosure
F. Piccinini: None. B. Gower: None. J.R. Fernandez: None. R.N. Bergman: Consultant; Self; Zafgen, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK067426); Nutrition Obesity Research Center (DK56336); National Institutes of Health (M01RR00032)
1844-P: Long-Term Remission of Type 2 Diabetes after Weight Loss Requires Effective Clearance of Hepatic VLDL-TG and Maintenance of Low Intrapancreatic Fat
Authors: AL-MRABEH AHMAD , ZHYZHNEUSKAYA SVIATLANA V. , BARNES ALISON C. , HOLLINGSWORTH KIEREN G. , SATTAR NAVEED , LEAN MICHAEL E. , TAYLOR ROY 
Published: June 2019

The Diabetes Remission Clinical Trial (DiRECT) demonstrated initial remission of type 2 diabetes in about half of a large primary care population, and this was associated with decrease in intrapancreatic fat content and return of beta cell function. We have carried out detailed metabolic studies on a subgroup at 2 years, comparing those who remained in remission (HbA1c &lt;6.5%; n=20, 7F/13M, 54.6±7.3 years, BMI 34.5±4.9kg/m2), and those who failed to maintain the initial remission (n=13, 6F/7M, 52.6±8.3 years, BMI 34.9±3.7kg/m2). Pancreas and liver fat were quantified by 3-point Dixon MRI. Hepatic VLDL-triglyceride (VLDL1-TG) production was measured in vivo using a non-isotopic competitive blocking method. Remission of diabetes was associated with major decreases in liver fat, pancreas fat, and hepatic VLDL-TG production during the weight loss phase between baseline to 5 months in both groups. However, those who failed to maintain remission were characterized by more weight regain (11. 3±1.9 vs. 6.6±1.0 kg, p=0.036), and greater increases in both liver (6.2±1.1 vs. 3.6±0.9%, p=0.05), and pancreas fat (+1.0±0.39 vs. -0.48±0.25%, p=0.005) between 5 months and 24 months. Hepatic VLDL-TG pool level remained stable under remission conditions (1046.4± 204.6 to 1638.6± 372.11 mg, p=0.35), whereas there was a significant increase when remission was lost (1328.0± 271.8 to 2865.6±692.4mg, p=0.04). In those who failed to maintain remission, fasting VLDL-TG increased (0.46±0.10 to 0.84±0.17 mmol/l, p&lt;0.05), and there was a positive correlation between the rise in liver fat and intrapancreatic fat (r=0.64, p=0.018). These data emphasize the link between hepatic VLDL-TG-metabolism and accumulation of fat within the liver and pancreas in the pathogenesis of type 2 diabetes, provide further evidence for the role of fat in its pathophysiology, and show that longer term remission of type 2 diabetes is dependent upon avoidance of weight regain.

Disclosure
A. Al-Mrabeh: None. S.V. Zhyzhneuskaya: None. A.C. Barnes: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Consultant; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Roche Diagnostics France, Sanofi. M.E. Lean: Consultant; Self; Counterweight Ltd., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. R. Taylor: Advisory Panel; Self; Wilmington Healthcare. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG.

Funding
Diabetes UK