A Human Glucagon-Like Peptide-1-albumin Recombinant Protein with Prolonged Hypoglycemic Effect Provides Efficient and Beneficial Control of Glucose Metabolism in Diabetic Mice

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.

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Hypoglycemic effect of deoxynojirimycin–polysaccharide on high fat diet and streptozotocin-induced diabetic mice via regulation of hepatic glucose metabolism

Chemico-Biological Interactions ◽

10.1016/j.cbi.2014.11.003 ◽

2015 ◽

Vol 225 ◽

pp. 70-79 ◽

Cited By ~ 30

Author(s):

You-gui Li ◽

Dong-feng Ji ◽

Shi Zhong ◽

Tian-bao Lin ◽

Zhi-qiang Lv

Keyword(s):

Glucose Metabolism ◽

High Fat Diet ◽

Hypoglycemic Effect ◽

Diabetic Mice ◽

High Fat ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose

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Differential effects of glucagon-like peptide-1 on microvascular recruitment and glucose metabolism in short- and long-term insulin resistance

The Journal of Physiology ◽

10.1113/jp270129 ◽

2015 ◽

Vol 593 (9) ◽

pp. 2185-2198 ◽

Cited By ~ 16

Author(s):

Kim A. Sjøberg ◽

Stephen Rattigan ◽

Jacob F. Jeppesen ◽

Anne-Marie Lundsgaard ◽

Jens J. Holst ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Metabolism ◽

Differential Effects ◽

Short And Long Term ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Microvascular Recruitment

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Effect of glucagon-like peptide-1 and ghrelin on liver metabolites in steers

Animal Production Science ◽

10.1071/an14363 ◽

2014 ◽

Vol 54 (10) ◽

pp. 1732 ◽

Cited By ~ 2

Author(s):

M. El-Sabagh ◽

D. Taniguchi ◽

T. Sugino ◽

T. Obitsu ◽

K. Taniguchi

Keyword(s):

Growth Hormone ◽

Glucose Metabolism ◽

Plasma Concentrations ◽

Latin Square ◽

Multivariate Statistical ◽

Flight Mass Spectrometry ◽

Nutrient Partitioning ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Regulatory Effects

Glucagon-like peptide 1 (GLP-1) and ghrelin have opposite regulatory effects on glucose metabolism in non-ruminants. However, mechanisms by which GLP-1 and ghrelin regulate nutrient partitioning, particularly in the liver, have been much less demonstrated in ruminants. A novel metabolomic method based on capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) combined with multivariate statistical analysis was applied to address the GLP-1 and ghrelin-induced metabolic changes in the liver of steers. Three Holstein steers (400 ± 5.0 kg LW) fed a maintenance diet according to Japanese feeding standards were randomly assigned to three treatments (GLP-1, ghrelin and saline) in a 3 × 3 Latin square design with one week apart. Liver biopsies were taken 30 min after a single injection (1.0 μg/kg LW) of GLP-1 or ghrelin, and analysed for metabolites by Agilent CE-TOFMS system. Also, blood samples were collected for plasma hormones analysis. Results indicated that 20 and 10 liver metabolites were altered (P < 0.05) by GLP-1 and ghrelin, respectively. Pathway analysis showed that GLP-1 is involved in biochemical pathways related to glycolysis/gluconeogenesis, lipogenesis and lipid export from the liver, oxidative stress defence and protein turnover. Ghrelin was shown to be involved in pathways related to glycolysis, protein anabolism and phospholipid biosynthesis. However, plasma concentrations of insulin, growth hormone and glucagon did not differ between treatments. These results imply that GLP-1 and ghrelin are involved in multibiochemical pathways that go beyond simply regulating glucose metabolism. In addition, the effects of GLP-1 and ghrelin may potentially be independent of insulin and growth hormone, respectively.

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