PMID- 20197503
OWN - NLM
STAT- MEDLINE
DCOM- 20100503
LR  - 20220331
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 298
IP  - 5
DP  - 2010 May
TI  - Exendin-4 increases blood glucose levels acutely in rats by activation of the 
      sympathetic nervous system.
PG  - E1088-96
LID - 10.1152/ajpendo.00464.2009 [doi]
AB  - Exendin-4 (Ex-4), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), 
      shares many of the actions of GLP-1 on pancreatic islets, the central nervous 
      system (CNS), and the gastrointestinal tract that mediates glucose homeostasis 
      and food intake. Because Ex-4 has a much longer plasma half-life than GLP-1, it 
      is an effective drug for reducing blood glucose levels in patients with type 2 
      diabetes mellitus (T2DM). Here, we report that acute administration of Ex-4, in 
      relatively high doses, into either the peripheral circulation or the CNS, 
      paradoxically increased blood glucose levels in rats. This effect was independent 
      of the insulinotropic and hypothalamic-pituitary-adrenal activating actions of 
      Ex-4 and could be blocked by a GLP-1R antagonist. Comparable doses of GLP-1 did 
      not induce hyperglycemia, even when protected from rapid metabolism by a 
      dipeptidyl peptidase IV inhibitor. Acute hyperglycemia induced by Ex-4 was 
      blocked by hexamethonium, guanethidine, and adrenal medullectomy, indicating that 
      this effect was mediated by sympathetic nervous system (SNS) activation. The 
      potency of Ex-4 to elevate blood glucose waned with chronic administration such 
      that after 6 days the familiar actions of Ex-4 to improve glucose tolerance were 
      evident. These findings indicate that, in rats, high doses of Ex-4 activate a SNS 
      response that can overcome the expected benefits of this peptide on glucose 
      metabolism and actually raise blood glucose. These results have important 
      implications for the design and interpretation of studies using Ex-4 in rats. 
      Moreover, since there are many similarities in the response of the GLP-1R system 
      across mammalian species, it is important to consider whether there is acute 
      activation of the SNS by Ex-4 in humans.
FAU - Perez-Tilve, Diego
AU  - Perez-Tilve D
AD  - Department of Functional Biology and Health Sciences, Faculty of Biology, 
      Laboratory of Endocrinology, Campus of Vigo, As Lagoas-Marcosende, University of 
      Vigo, E-36310 Vigo, Spain.
FAU - Gonzalez-Matias, Lucas
AU  - Gonzalez-Matias L
FAU - Aulinger, Benedikt A
AU  - Aulinger BA
FAU - Alvarez-Crespo, Mayte
AU  - Alvarez-Crespo M
FAU - Gil-Lozano, Manuel
AU  - Gil-Lozano M
FAU - Alvarez, Elias
AU  - Alvarez E
FAU - Andrade-Olivie, Amalia M
AU  - Andrade-Olivie AM
FAU - Tschop, Matthias H
AU  - Tschop MH
FAU - D'Alessio, David A
AU  - D'Alessio DA
FAU - Mallo, Federico
AU  - Mallo F
LA  - eng
GR  - R01 DK057900/DK/NIDDK NIH HHS/United States
GR  - DK-56863/DK/NIDDK NIH HHS/United States
GR  - DK-57900-05/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100302
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Blood Glucose)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Peptides)
RN  - 0 (Venoms)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9P1872D4OL (Exenatide)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Blood Glucose/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Eating/drug effects
MH  - Exenatide
MH  - Glucagon-Like Peptide 1/metabolism
MH  - Hypoglycemic Agents/administration & dosage
MH  - Male
MH  - Peptides/*administration & dosage
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sympathetic Nervous System/*drug effects/metabolism
MH  - Time Factors
MH  - Venoms/*administration & dosage
PMC - PMC2867369
EDAT- 2010/03/04 06:00
MHDA- 2010/05/04 06:00
PMCR- 2011/05/01
CRDT- 2010/03/04 06:00
PHST- 2010/03/04 06:00 [entrez]
PHST- 2010/03/04 06:00 [pubmed]
PHST- 2010/05/04 06:00 [medline]
PHST- 2011/05/01 00:00 [pmc-release]
AID - ajpendo.00464.2009 [pii]
AID - E-00464-2009 [pii]
AID - 10.1152/ajpendo.00464.2009 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2010 May;298(5):E1088-96. doi: 
      10.1152/ajpendo.00464.2009. Epub 2010 Mar 2.