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Results: 21 to 27 of 27

Publication Record


Hepatic energy state is regulated by glucagon receptor signaling in mice.
Berglund ED, Lee-Young RS, Lustig DG, Lynes SE, Donahue EP, Camacho RC, Meredith ME, Magnuson MA, Charron MJ, Wasserman DH
(2009) J Clin Invest 119: 2412-22
MeSH Terms: Adenosine Diphosphate, Adenosine Monophosphate, Adenosine Triphosphate, Animals, Energy Metabolism, Glucagon, Liver, Male, Mice, Mice, Inbred C57BL, Phosphoenolpyruvate Carboxykinase (GTP), Receptors, Glucagon, Signal Transduction
Show Abstract · Added March 18, 2013
The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor- null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism.
3 Communities
1 Members
0 Resources
13 MeSH Terms
The glucagon-like peptide-1 receptor regulates endogenous glucose production and muscle glucose uptake independent of its incretin action.
Ayala JE, Bracy DP, James FD, Julien BM, Wasserman DH, Drucker DJ
(2009) Endocrinology 150: 1155-64
MeSH Terms: Adenylate Kinase, Animals, Female, Glucagon-Like Peptide-1 Receptor, Glucose, Incretins, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Phosphorylation, Physical Conditioning, Animal, Receptors, Glucagon, Signal Transduction
Show Abstract · Added March 5, 2013
Glucagon-like peptide-1 (GLP-1) diminishes postmeal glucose excursions by enhancing insulin secretion via activation of the beta-cell GLP-1 receptor (Glp1r). GLP-1 may also control glucose levels through mechanisms that are independent of this incretin effect. The hyperinsulinemic-euglycemic clamp (insulin clamp) and exercise were used to examine the incretin-independent glucoregulatory properties of the Glp1r because both perturbations stimulate glucose flux independent of insulin secretion. Chow-fed mice with a functional disruption of the Glp1r (Glp1r(-/-)) were compared with wild-type littermates (Glp1r(+/+)). Studies were performed on 5-h-fasted mice implanted with arterial and venous catheters for sampling and infusions, respectively. During insulin clamps, [3-(3)H]glucose and 2[(14)C]deoxyglucose were used to determine whole-body glucose turnover and glucose metabolic index (R(g)), an indicator of glucose uptake. R(g) in sedentary and treadmill exercised mice was determined using 2[(3)H]deoxyglucose. Glp1r(-/-) mice exhibited increased glucose disappearance, muscle R(g), and muscle glycogen levels during insulin clamps. This was not associated with enhanced muscle insulin signaling. Glp1r(-/-) mice exhibited impaired suppression of endogenous glucose production and hepatic glycogen accumulation during insulin clamps. This was associated with impaired liver insulin signaling. Glp1r(-/-) mice became significantly hyperglycemic during exercise. Muscle R(g) was normal in exercised Glp1r(-/-) mice, suggesting that hyperglycemia resulted from an added drive to stimulate glucose production. Muscle AMP-activated protein kinase phosphorylation was higher in exercised Glp1r(-/-) mice. This was associated with increased relative exercise intensity and decreased exercise endurance. In conclusion, these results show that the endogenous Glp1r regulates hepatic and muscle glucose flux independent of its ability to enhance insulin secretion.
0 Communities
2 Members
0 Resources
17 MeSH Terms
Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic beta-cells and inhibiting insulin secretion.
De León DD, Li C, Delson MI, Matschinsky FM, Stanley CA, Stoffers DA
(2008) J Biol Chem 283: 25786-93
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Cyclic AMP, Gene Expression Regulation, Glucagon-Like Peptide-1 Receptor, Glucose, Hypoglycemia, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Peptide Fragments, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Receptors, Glucagon, Sulfonylurea Receptors
Show Abstract · Added December 21, 2016
Congenital hyperinsulinism is a disorder of pancreatic beta-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in brain damage or death if untreated. Loss-of-function mutations in the K(ATP) channel (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of congenital hyperinsulinism. Most patients are unresponsive to available medical therapy and require palliative pancreatectomy. Similar to the human condition, the SUR-1(-/-) mouse is hypoglycemic when fasted and hyperglycemic when glucose-loaded. We have previously reported that the glucagon-like peptide-1 receptor antagonist exendin-(9-39) raises fasting blood glucose in normal mice. Here we examine the effect of exendin-(9-39) on fasting blood glucose in SUR-1(-/-) mice. Mice were randomized to receive exendin-(9-39) or vehicle. Fasting blood glucose levels in SUR-1(-/-) mice treated with exendin-(9-39) were significantly higher than in vehicle-treated mice and not different from wild-type littermates. Exendin-(9-39) did not further worsen glucose tolerance and had no effect on body weight and insulin sensitivity. Isolated islet perifusion studies demonstrated that exendin-(9-39) blocked amino acid-stimulated insulin secretion, which is abnormally increased in SUR-1(-/-) islets. Furthermore, cAMP content in SUR-1(-/-) islets was reduced by exendin-(9-39) both basally and when stimulated by amino acids, whereas cytosolic calcium levels were not affected. These findings suggest that cAMP plays a key role in K(ATP)-independent insulin secretion and that the GLP-1 receptor is constitutively active in SUR-1(-/-) beta-cells. Our findings indicate that exendin-(9-39) normalizes fasting hypoglycemia in SUR-1(-/-) mice via a direct effect on insulin secretion, thereby raising exendin-(9-39) as a potential therapeutic agent for K(ATP) hyperinsulinism.
0 Communities
0 Members
1 Resources
20 MeSH Terms
Insulin action in the double incretin receptor knockout mouse.
Ayala JE, Bracy DP, Hansotia T, Flock G, Seino Y, Wasserman DH, Drucker DJ
(2008) Diabetes 57: 288-97
MeSH Terms: Adipose Tissue, Animals, Crosses, Genetic, Dietary Fats, Energy Metabolism, Female, Glucagon-Like Peptide-1 Receptor, Glucose Clamp Technique, Hyperinsulinism, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Receptors, Cell Surface, Receptors, Gastrointestinal Hormone, Receptors, Glucagon
Show Abstract · Added August 19, 2014
OBJECTIVE - The incretins glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide have been postulated to play a role in regulating insulin action, although the mechanisms behind this relationship remain obscure. We used the hyperinsulinemic-euglycemic clamp to determine sites where insulin action may be modulated in double incretin receptor knockout (DIRKO) mice, which lack endogenous incretin action.
RESEARCH DESIGN AND METHODS - DIRKO and wild-type mice were fed regular chow or high-fat diet for 4 months. Clamps were performed on 5-h-fasted, conscious, unrestrained mice using an arterial catheter for sampling.
RESULTS - Compared with wild-type mice, chow and high fat-fed DIRKO mice exhibited decreased fat and muscle mass associated with increased energy expenditure and ambulatory activity. Clamp rates of glucose infusion (GIR), endogenous glucose production (endoR(a)), and disappearance (R(d)) were not different in chow-fed wild-type and DIRKO mice, although insulin levels were lower in DIRKO mice. Liver Akt expression was decreased but Akt activation was increased in chow-fed DIRKO compared with wild-type mice. High-fat feeding resulted in fasting hyperinsulinemia and hyperglycemia in wild-type but not in DIRKO mice. GIR, suppression of endoR(a), and stimulation of R(d) were inhibited in high fat-fed wild-type mice but not in DIRKO mice. High-fat feeding resulted in impaired tissue glucose uptake (R(g)) in skeletal muscle of wild-type mice but not of DIRKO mice. Liver and muscle Akt activation was enhanced in high fat-fed DIRKO compared with wild-type mice.
CONCLUSIONS - In summary, DIRKO mice exhibit enhanced insulin action compared with wild-type mice when fed a regular chow diet and are protected from high-fat diet-induced obesity and insulin resistance.
0 Communities
1 Members
0 Resources
18 MeSH Terms
A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog.
Rivera N, Everett-Grueter CA, Edgerton DS, Rodewald T, Neal DW, Nishimura E, Larsen MO, Jacobsen LO, Kristensen K, Brand CL, Cherrington AD
(2007) J Pharmacol Exp Ther 321: 743-52
MeSH Terms: Aniline Compounds, Animals, C-Peptide, Dogs, Dose-Response Relationship, Drug, Female, Gluconeogenesis, Glucose, Glycogenolysis, Liver, Male, Receptors, Glucagon, beta-Alanine
Show Abstract · Added December 10, 2013
Elevated glucagon is associated with fasting hyperglycemia in type 2 diabetes. We assessed the effects of the glucagon receptor antagonist (2R)-N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2-hydroxy-b-alanine (NNC 25-0926) on hepatic glucose production (HPG) in vivo, using arteriovenous difference and tracer techniques in conscious dogs. The experiments consisted of equilibration (-140 to -40 min), control (40-0 min), and experimental [0-180 min, divided into P1 (0-60 min) and P2 (60-180 min)] periods. In P1, NNC 25-0926 was given intragastrically at 0 (veh), 10, 20, 40, or 100 mg/kg, and euglycemia was maintained. In P2, somatostatin, basal intraportal insulin, and 5-fold basal intraportal glucagon (2.5 ng/kg/min) were infused. Arterial plasma insulin levels remained basal throughout the study in all groups. Arterial plasma glucagon levels remained basal during the control period and P1 and then increased to approximately 70 pg/ml in P2 in all groups. Arterial plasma glucose levels were basal in the control period and P1 in all groups. In P2, the arterial glucose level increased to 245+/-22 and 172+/-15 mg/dl in the veh and 10 mg/kg groups, respectively, whereas in the 20, 40, and 100 mg/kg groups, there was no rise in glucose. Net hepatic glucose output was approximately 2 mg/kg/min in all groups during the control period. In P2, it increased by 9.4+/-2 mg/kg/min in the veh group. In the 10, 20, 40, and 100 mg/kg groups, the rise was only 4.1+/-0.9, 1.6+/-0.6, 2.4+/-0.7, and 1.5+/-0.3 mg/kg/min, respectively, due to inhibition of glycogenolysis. In conclusion, NNC 25-0926 effectively blocked the ability of glucagon to increase HGP in the dog.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors.
Dardevet D, Moore MC, DiCostanzo CA, Farmer B, Neal DW, Snead W, Lautz M, Cherrington AD
(2005) Am J Physiol Gastrointest Liver Physiol 289: G806-14
MeSH Terms: Animals, Dogs, Female, Glucagon-Like Peptide-1 Receptor, Glucose, Insulin, Insulin Secretion, Liver, Male, Portal Vein, Receptors, Glucagon
Show Abstract · Added December 10, 2013
Whether glucagon-like peptide (GLP)-1 requires the hepatic portal vein to elicit its insulin secretion-independent effects on glucose disposal in vivo was assessed in conscious dogs using tracer and arteriovenous difference techniques. In study 1, six conscious overnight-fasted dogs underwent oral glucose tolerance testing (OGTT) to determine target GLP-1 concentrations during clamp studies. Peak arterial and portal values during OGTT ranged from 23 to 65 pM and from 46 to 113 pM, respectively. In study 2, we conducted hyperinsulinemic-hyperglycemic clamp experiments consisting of three periods (P1, P2, and P3) during which somatostatin, glucagon, insulin and glucose were infused. The control group received saline, the PePe group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally, the PePo group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then intraportally (P3), and the PeHa group received GLP-1 (1 pmol.kg(-1).min(-1)) peripherally (P2) and then through the hepatic artery (P3) to increase the hepatic GLP-1 load to the same extent as in P3 in the PePo group (n = 8 dogs/group). Arterial GLP-1 levels increased similarly in all groups during P2 ( approximately 50 pM), whereas portal GLP-1 levels were significantly increased (2-fold) in the PePo vs. PePe and PeHa groups during P3. During P2, net hepatic glucose uptake (NHGU) increased slightly but not significantly (vs. P1) in all groups. During P3, GLP-1 increased NHGU in the PePo and PeHa groups more than in the control and PePe groups (change of 10.8 +/- 1.3 and 10.6 +/- 1.0 vs. 5.7 +/- 1.0 and 5.4 +/- 0.8 micromol.kg(-1).min(-1), respectively, P < 0.05). In conclusion, physiological GLP-1 levels increase glucose disposal in the liver, and this effect does not involve GLP-1 receptors located in the portal vein.
0 Communities
2 Members
0 Resources
11 MeSH Terms
Engineering physiologically regulated insulin secretion in non-beta cells by expressing glucagon-like peptide 1 receptor.
Wu L, Nicholson W, Wu CY, Xu M, McGaha A, Shiota M, Powers AC
(2003) Gene Ther 10: 1712-20
MeSH Terms: Adenoviridae, Animals, Cells, Cultured, Diabetes Mellitus, Type 1, Gene Expression, Genetic Therapy, Genetic Vectors, Glucagon-Like Peptide-1 Receptor, Glucose, Humans, Insulin, Insulin Secretion, Male, Mice, Mice, Inbred NOD, Mice, SCID, Pituitary Gland, Pituitary Hormones, Rats, Rats, Sprague-Dawley, Receptors, Glucagon, Stimulation, Chemical, Transduction, Genetic
Show Abstract · Added December 10, 2013
Glucagon-like peptide 1 (GLP-1) is released from neuroendocrine cells in the intestine in the postprandial state and augments glucose-stimulated insulin secretion from pancreatic beta cells. To develop non-beta cells that exhibit physiologically regulated insulin secretion, we coexpressed the GLP-1 receptor and human insulin in primary rat pituitary cells using adenovirus-mediated gene transfer. The transduced cells were analyzed in a perifusion system and after transplantation into mice. Normal pituitary cells do not express the GLP-1 receptor as shown by the absence of GLP-1 receptor mRNA and the inability of GLP-1 to stimulate pituitary hormone secretion. Following transduction with an adenovirus carrying the GLP-1 receptor cDNA, the pituitary cells expressed functional GLP-1 receptors as reflected by the ability of GLP-1 to stimulate secretion of pituitary hormones. When both the GLP-1 receptor and human insulin were introduced, GLP-1 stimulated cosecretion of human insulin and endogenous pituitary hormones. GLP-1 was similar in potency to the hypothalamic-releasing hormones and stimulated hormone secretion in a dose-dependent fashion. In contrast to pancreatic beta cells, the hormone-releasing effect of GLP-1 on transduced pituitary cells was not dependent on the concentration of extracellular glucose. After transplantation of pituitary cells coexpressing human insulin and GLP-1 receptor into mice, enteral glucose stimulated insulin secretion. These results demonstrate a new approach to engineer physiologically regulated insulin secretion by non-beta cells.
0 Communities
2 Members
0 Resources
23 MeSH Terms