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Liver-specific disruption of the murine glucagon receptor produces α-cell hyperplasia: evidence for a circulating α-cell growth factor.
Longuet C, Robledo AM, Dean ED, Dai C, Ali S, McGuinness I, de Chavez V, Vuguin PM, Charron MJ, Powers AC, Drucker DJ
(2013) Diabetes 62: 1196-205
MeSH Terms: Animals, Blood Glucose, Female, Glucagon, Glucagon-Secreting Cells, Glucose, Hepatocytes, Hyperplasia, Insulin Resistance, Intercellular Signaling Peptides and Proteins, Islets of Langerhans, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Glucagon, Signal Transduction
Show Abstract · Added December 5, 2013
Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and α-cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor. Gcgr(Hep)(-/-) mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr(-/-) mice. Despite preservation of islet Gcgr signaling, Gcgr(Hep)(-/-) mice developed hyperglucagonemia and α-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-cell mass, wild-type islets were transplanted into Gcgr(-/-) or Gcgr(Hep)(-/-) mice. Wild-type islets beneath the renal capsule of Gcgr(-/-) or Gcgr(Hep)(-/-) mice exhibited an increased rate of α-cell proliferation and expansion of α-cell area, consistent with changes exhibited by endogenous α-cells in Gcgr(-/-) and Gcgr(Hep)(-/-) pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating α-cell proliferation and mass may facilitate the generation and expansion of α-cells for transdifferentiation into β-cells and the treatment of diabetes.
1 Communities
2 Members
0 Resources
18 MeSH Terms
Regulation of glucose kinetics during exercise by the glucagon-like peptide-1 receptor.
Burmeister MA, Bracy DP, James FD, Holt RM, Ayala J, King EM, Wasserman DH, Drucker DJ, Ayala JE
(2012) J Physiol 590: 5245-55
MeSH Terms: Animals, Corticosterone, Glucagon, Glucagon-Like Peptide-1 Receptor, Glucose, Hyperglycemia, Insulin, Kinetics, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Physical Conditioning, Animal, Receptors, Glucagon
Show Abstract · Added March 5, 2013
In response to oral glucose, glucagon-like peptide-1 receptor (Glp1r) knockout (Glp1r−/−) mice become hyperglycaemic due to impaired insulin secretion. Exercise also induces hyperglycaemia in Glp1r−/− mice. In contrast to oral glucose, exercise decreases insulin secretion. This implies that exercise-induced hyperglycaemia in Glp1r−/− mice results from the loss of a non-insulinotropic effect mediated by the Glp1r. Muscle glucose uptake (MGU) is normal in exercising Glp1r−/− mice. Thus, we hypothesize that exercise-induced hyperglycaemia in Glp1r−/− mice is due to excessive hepatic glucose production (HGP). Wild-type (Glp1r+/+) and Glp1r−/− mice implanted with venous and arterial catheters underwent treadmill exercise or remained sedentary for 30 min. [3-3H]glucose was used to estimate rates of glucose appearance (Ra), an index of HGP, and disappearance (Rd). 2[14C]deoxyglucose was used to assess MGU. Glp1r−/− mice displayed exercise-induced hyperglycaemia due to an excessive increase in Ra but normal Rd and MGU. Exercise-induced glucagon levels were ∼2-fold higher in Glp1r−/− mice, resulting in a ∼2-fold higher glucagon:insulin ratio. Since inhibition of the central Glp1r stimulates HGP, we tested whether intracerebroventricular (ICV) infusion of the Glp1r antagonist exendin(9–39) (Ex9) in Glp1r+/+ mice would result in exercise-induced hyperglycaemia. ICV Ex9 did not enhance glucose levels or HGP during exercise, suggesting that glucoregulatory effects of Glp1 during exercise are mediated via the pancreatic Glp1r. In conclusion, functional disruption of the Glp1r results in exercise-induced hyperglycaemia associated with an excessive increase in glucagon secretion and HGP. These results suggest an essential role for basal Glp1r signalling in the suppression of alpha cell secretion during exercise.
1 Communities
2 Members
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14 MeSH Terms
Exendin-4 decreases amphetamine-induced locomotor activity.
Erreger K, Davis AR, Poe AM, Greig NH, Stanwood GD, Galli A
(2012) Physiol Behav 106: 574-8
MeSH Terms: Amphetamine, Animals, Antimanic Agents, Anxiety, Central Nervous System Stimulants, Conditioning, Operant, Exenatide, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Lithium Chloride, Male, Motor Activity, Peptides, Rats, Rats, Sprague-Dawley, Receptors, Glucagon, Venoms
Show Abstract · Added September 17, 2013
Glucagon-like peptide-1 (GLP-1) is released in response to nutrient ingestion and is a regulator of energy metabolism and consummatory behaviors through both peripheral and central mechanisms. The GLP-1 receptor (GLP-1R) is widely distributed in the central nervous system, however little is known about how GLP-1Rs regulate ambulatory behavior. The abused psychostimulant amphetamine (AMPH) promotes behavioral locomotor activity primarily by inducing the release of the neurotransmitter dopamine. Here, we identify the GLP-1R agonist exendin-4 (Ex-4) as a modulator of behavioral activation by AMPH. We report that in rats a single acute administration of Ex-4 decreases both basal locomotor activity as well as AMPH-induced locomotor activity. Ex-4 did not induce behavioral responses reflecting anxiety or aversion. Our findings implicate GLP-1R signaling as a novel modulator of psychostimulant-induced behavior and therefore a potential therapeutic target for psychostimulant abuse.
Copyright © 2012 Elsevier Inc. All rights reserved.
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3 Members
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17 MeSH Terms
Gene transcripts associated with BMI in the motor cortex and caudate nucleus of calorie restricted rhesus monkeys.
Mitchell AC, Leak RK, Zigmond MJ, Cameron JL, Mirnics K
(2012) Genomics 99: 144-51
MeSH Terms: Animals, Apoptosis, Body Mass Index, Brain, Caloric Restriction, Caudate Nucleus, Gene Expression Regulation, Glucagon-Like Peptide-2 Receptor, Macaca mulatta, Metabolic Networks and Pathways, Mitogen-Activated Protein Kinase 1, Motor Cortex, Neurons, Obesity, Receptor, Insulin, Receptors, Glucagon
Show Abstract · Added August 16, 2012
Obesity affects over 500 million people worldwide, and has far reaching negative health effects. Given that high body mass index (BMI) and insulin resistance are associated with alterations in many regions of brain and that physical activity can decrease obesity, we hypothesized that in Rhesus monkeys (Macaca mulatta) fed a high fat diet and who subsequently received reduced calories BMI would be associated with a unique gene expression signature in motor regions of the brain implicated in neurodegenerative disorders. In the motor cortex with increased BMI we saw the upregulation of genes involved in apoptosis, altered gene expression in metabolic pathways, and the downregulation of pERK1/2 (MAPK1), a protein involved in cellular survival. In the caudate nucleus with increased BMI we saw the upregulation of known obesity related genes (the insulin receptor (INSR) and the glucagon-like peptide-2 receptor (GLP2R)), apoptosis related genes, and altered expression of genes involved in various metabolic processes. These studies suggest that the effects of high BMI on the brain transcriptome persist regardless of two months of calorie restriction. We hypothesize that active lifestyles with low BMIs together create a brain homeostasis more conducive to brain resiliency and neuronal survival.
Copyright © 2011 Elsevier Inc. All rights reserved.
1 Communities
1 Members
0 Resources
16 MeSH Terms
Hepatic glucagon action is essential for exercise-induced reversal of mouse fatty liver.
Berglund ED, Lustig DG, Baheza RA, Hasenour CM, Lee-Young RS, Donahue EP, Lynes SE, Swift LL, Charron MJ, Damon BM, Wasserman DH
(2011) Diabetes 60: 2720-9
MeSH Terms: Animals, Body Weight, Dietary Fats, Disease Progression, Fatty Liver, Glucagon, Lipid Metabolism, Liver, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Receptors, Glucagon, Signal Transduction
Show Abstract · Added December 10, 2013
OBJECTIVE - Exercise is an effective intervention to treat fatty liver. However, the mechanism(s) that underlie exercise-induced reductions in fatty liver are unclear. Here we tested the hypothesis that exercise requires hepatic glucagon action to reduce fatty liver.
RESEARCH DESIGN AND METHODS - C57BL/6 mice were fed high-fat diet (HFD) and assessed using magnetic resonance, biochemical, and histological techniques to establish a timeline for fatty liver development over 20 weeks. Glucagon receptor null (gcgr(-/-)) and wild-type (gcgr(+/+)) littermate mice were subsequently fed HFD to provoke moderate fatty liver and then performed either 10 or 6 weeks of running wheel or treadmill exercise, respectively.
RESULTS - Exercise reverses progression of HFD-induced fatty liver in gcgr(+/+) mice. Remarkably, such changes are absent in gcgr(-/-) mice, thus confirming the hypothesis that exercise-stimulated hepatic glucagon receptor activation is critical to reduce HFD-induced fatty liver.
CONCLUSIONS - These findings suggest that therapies that use antagonism of hepatic glucagon action to reduce blood glucose may interfere with the ability of exercise and perhaps other interventions to positively affect fatty liver.
2 Communities
2 Members
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16 MeSH Terms
Endogenously released GLP-1 is not sufficient to alter postprandial glucose regulation in the dog.
Johnson KM, Farmer T, Schurr K, Patrick Donahue E, Farmer B, Neal D, Cherrington AD
(2011) Endocrine 39: 229-34
MeSH Terms: Acetaminophen, Animals, Blood Glucose, Dogs, Enteroendocrine Cells, Female, Food, Gastric Emptying, Glucagon, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Homeostasis, Insulin, Kinetics, Male, Peptide Fragments, Receptors, Glucagon
Show Abstract · Added February 13, 2015
Glucagon-like peptide-1 (GLP-1) is secreted from the L cell of the gut in response to oral nutrient delivery. To determine if endogenously released GLP-1 contributes to the incretin effect and postprandial glucose regulation, conscious dogs (n = 8) underwent an acclimation period (t = -60 to -20 min), followed by a basal sampling period (t = -20 to 0 min) and an experimental period (t = 0-320 min). At the beginning of the experimental period, t = 0 min, a peripheral infusion of either saline or GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) (Ex-9, 500 pmol/kg/min), was started. At t = 30 min, animals consumed a liquid mixed meal, spiked with acetaminophen. All animals were studied twice (± Ex-9) in random fashion, and the experiments were separated by a 1-2-week washout period. Antagonism of the GLP-1R did not have an effect, as indicated by repeated-measures MANOVA analysis of the Δ AUC from t = 45-320 min of arterial plasma glucose, GLP-1, insulin, glucagon, and acetaminophen levels. Therefore, endogenous GLP-1 is not sufficient to alter postprandial glucose regulation in the dog.
0 Communities
2 Members
0 Resources
17 MeSH Terms
Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients.
Bhatnagar P, Purvis S, Barron-Casella E, DeBaun MR, Casella JF, Arking DE, Keefer JR
(2011) J Hum Genet 56: 316-23
MeSH Terms: African Continental Ancestry Group, Anemia, Sickle Cell, Bayes Theorem, Carrier Proteins, Chromosomes, Human, Pair 17, Cohort Studies, Erythrocyte Count, Erythrocytes, Fetal Hemoglobin, Genome-Wide Association Study, Genotype, Glucagon-Like Peptide-1 Receptor, Haplotypes, Humans, Male, Nuclear Proteins, Polymorphism, Single Nucleotide, Receptors, Glucagon, Repressor Proteins
Show Abstract · Added November 27, 2013
Fetal hemoglobin (HbF) level has emerged as an important prognostic factor in sickle-cell disease (SCD) and can be measured by the proportion of HbF-containing erythrocytes (F-cells). Recently, BCL11A (zinc-finger protein) was identified as a regulator of HbF, and the strongest association signals were observed either directly for rs766432 or for correlated single-nucleotide polymorphisms (SNPs). To identify additional independently associated genetic variants, we performed a genome-wide association study (GWAS) on the proportion of F-cells in individuals of African ancestry with SCD from the Silent Infarct Transfusion (SIT) Trial cohort. Our study not only confirms the association of rs766432 (P-value <3.32 × 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value <1.81 × 10(-15)). The F-cell variances explained independently by these two SNPs are ∼13% (rs7606173) and ∼11% (rs766432), whereas, together they explain ∼16%. Additionally, in men, we identify a novel locus on chromosome 17, glucagon-like peptide-2 receptor (GLP2R), associated with F-cell regulation (rs12103880; P-value <3.41 × 10(-8)). GLP2R encodes a G protein-coupled receptor and involved in proliferative and anti-apoptotic cellular responses. These findings highlight the importance of denser genetic screens and suggest further exploration of the BCL11A and GLP2R loci to gain additional insight into HbF/F-cell regulation.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Glucagon as a critical factor in the pathology of diabetes.
Edgerton DS, Cherrington AD
(2011) Diabetes 60: 377-80
MeSH Terms: Animals, Diabetes Mellitus, Type 1, Glucagon, Mice, Mice, Knockout, Receptors, Glucagon
Added February 13, 2015
0 Communities
2 Members
0 Resources
6 MeSH Terms
Glucagon-like peptide-1 receptor knockout mice are protected from high-fat diet-induced insulin resistance.
Ayala JE, Bracy DP, James FD, Burmeister MA, Wasserman DH, Drucker DJ
(2010) Endocrinology 151: 4678-87
MeSH Terms: Adiposity, Animals, Diet, Atherogenic, Dietary Fats, Female, Glucagon-Like Peptide-1 Receptor, Glucose, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Receptors, Glucagon, Sex Characteristics
Show Abstract · Added March 5, 2013
Glucagon-like peptide-1 augments nutrient-stimulated insulin secretion. Chow-fed mice lacking the glucagon-like peptide-1 receptor (Glp1r) exhibit enhanced insulin-stimulated muscle glucose uptake but impaired suppression of endogenous glucose appearance (endoRa). This proposes a novel role for the Glp1r to regulate the balance of glucose disposal in muscle and liver by modulating insulin action. Whether this is maintained in an insulin-resistant state is unknown. The present studies tested the hypothesis that disruption of Glp1r expression overcomes high-fat (HF) diet-induced muscle insulin resistance and exacerbates HF diet-induced hepatic insulin resistance. Mice with a functional disruption of the Glp1r (Glp1r-/-) were compared with wild-type littermates (Glp1r+/+) after 12 wk on a regular chow diet or a HF diet. Arterial and venous catheters were implanted for sampling and infusions. Hyperinsulinemic-euglycemic clamps were performed on weight-matched male mice. [3-(3)H]glucose was used to determine glucose turnover, and 2[14C]deoxyglucose was used to measure the glucose metabolic index, an indicator of glucose uptake. Glp1r-/- mice exhibited increased glucose disappearance and muscle glucose metabolic index on either diet. This was associated with enhanced activation of muscle Akt and AMP-activated protein kinase and reduced muscle triglycerides in HF-fed Glp1r-/- mice. Chow-fed Glp1r-/- mice exhibited impaired suppression of endoRa and hepatic insulin signaling. In contrast, HF-fed Glp1r-/- mice exhibited improved suppression of endoRa and hepatic Akt activation. This was associated with decreased hepatic triglycerides and impaired activation of sterol regulatory element-binding protein-1. These results show that mice lacking the Glp1r are protected from HF diet-induced muscle and hepatic insulin resistance independent of effects on total fat mass.
0 Communities
2 Members
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17 MeSH Terms
Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts in vivo.
Berglund ED, Kang L, Lee-Young RS, Hasenour CM, Lustig DG, Lynes SE, Donahue EP, Swift LL, Charron MJ, Wasserman DH
(2010) Am J Physiol Endocrinol Metab 299: E607-14
MeSH Terms: Adenylate Kinase, Animals, Area Under Curve, Blood Glucose, Catecholamines, Fat Emulsions, Intravenous, Fatty Acids, Nonesterified, Female, Fibroblast Growth Factors, Glucagon, Glucose Clamp Technique, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, PPAR alpha, Physical Conditioning, Animal, RNA, Messenger, Receptors, Glucagon, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction
Show Abstract · Added December 10, 2013
Hepatic glucagon action increases in response to accelerated metabolic demands and is associated with increased whole body substrate availability, including circulating lipids. The hypothesis that increases in hepatic glucagon action stimulate AMP-activated protein kinase (AMPK) signaling and peroxisome proliferator-activated receptor-α (PPARα) and fibroblast growth factor 21 (FGF21) expression in a manner modulated by fatty acids was tested in vivo. Wild-type (gcgr(+/+)) and glucagon receptor-null (gcgr(-/-)) littermate mice were studied using an 18-h fast, exercise, and hyperglucagonemic-euglycemic clamps plus or minus increased circulating lipids. Fasting and exercise in gcgr(+/+), but not gcgr(-/-) mice, increased hepatic phosphorylated AMPKα at threonine 172 (p-AMPK(Thr(172))) and PPARα and FGF21 mRNA. Clamp results in gcgr(+/+) mice demonstrate that hyperlipidemia does not independently impact or modify glucagon-stimulated increases in hepatic AMP/ATP, p-AMPK(Thr(172)), or PPARα and FGF21 mRNA. It blunted glucagon-stimulated acetyl-CoA carboxylase phosphorylation, a downstream target of AMPK, and accentuated PPARα and FGF21 expression. All effects were absent in gcgr(-/-) mice. These findings demonstrate that glucagon exerts a critical regulatory role in liver to stimulate pathways linked to lipid metabolism in vivo and shows for the first time that effects of glucagon on PPARα and FGF21 expression are amplified by a physiological increase in circulating lipids.
1 Communities
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23 MeSH Terms