PMID- 20421298
OWN - NLM
STAT- MEDLINE
DCOM- 20100824
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 26
DP  - 2010 Jun 25
TI  - Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a 
      novel cholinergic relay mechanism.
PG  - 19842-53
LID - 10.1074/jbc.M110.129304 [doi]
AB  - The intestinal peptides GLP-1 and GIP potentiate glucose-mediated insulin 
      release. Agents that increase GLP-1 action are effective therapies in type 2 
      diabetes mellitus (T2DM). However, GIP action is blunted in T2DM, and GIP-based 
      therapies have not been developed. Thus, it is important to increase our 
      understanding of the mechanisms of GIP action. We developed mice lacking 
      GIP-producing K cells. Like humans with T2DM, "GIP/DT" animals exhibited a normal 
      insulin secretory response to exogenous GLP-1 but a blunted response to GIP. 
      Pharmacologic doses of xenin-25, another peptide produced by K cells, restored 
      the GIP-mediated insulin secretory response and reduced hyperglycemia in GIP/DT 
      mice. Xenin-25 alone had no effect. Studies with islets, insulin-producing cell 
      lines, and perfused pancreata indicated xenin-25 does not enhance GIP-mediated 
      insulin release by acting directly on the beta-cell. The in vivo effects of 
      xenin-25 to potentiate insulin release were inhibited by atropine sulfate and 
      atropine methyl bromide but not by hexamethonium. Consistent with this, carbachol 
      potentiated GIP-mediated insulin release from in situ perfused pancreata of 
      GIP/DT mice. In vivo, xenin-25 did not activate c-fos expression in the hind 
      brain or paraventricular nucleus of the hypothalamus indicating that central 
      nervous system activation is not required. These data suggest that xenin-25 
      potentiates GIP-mediated insulin release by activating non-ganglionic cholinergic 
      neurons that innervate the islets, presumably part of an 
      enteric-neuronal-pancreatic pathway. Xenin-25, or molecules that increase 
      acetylcholine receptor signaling in beta-cells, may represent a novel approach to 
      overcome GIP resistance and therefore treat humans with T2DM.
FAU - Wice, Burton M
AU  - Wice BM
AD  - Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid 
      Research, Washington University School of Medicine, St. Louis, Missouri 63110, 
      USA. bwice@dom.wustl.edu
FAU - Wang, Songyan
AU  - Wang S
FAU - Crimmins, Dan L
AU  - Crimmins DL
FAU - Diggs-Andrews, Kelly A
AU  - Diggs-Andrews KA
FAU - Althage, Matthew C
AU  - Althage MC
FAU - Ford, Eric L
AU  - Ford EL
FAU - Tran, Hung
AU  - Tran H
FAU - Ohlendorf, Matthew
AU  - Ohlendorf M
FAU - Griest, Terry A
AU  - Griest TA
FAU - Wang, Qiuling
AU  - Wang Q
FAU - Fisher, Simon J
AU  - Fisher SJ
FAU - Ladenson, Jack H
AU  - Ladenson JH
FAU - Polonsky, Kenneth S
AU  - Polonsky KS
LA  - eng
GR  - R37 DK031842/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341/DK/NIDDK NIH HHS/United States
GR  - UL1 RR024992/RR/NCRR NIH HHS/United States
GR  - RC1DK086163/DK/NIDDK NIH HHS/United States
GR  - P60 DK020579/DK/NIDDK NIH HHS/United States
GR  - 5P30 DK052574/DK/NIDDK NIH HHS/United States
GR  - DK31842/DK/NIDDK NIH HHS/United States
GR  - UL1 TR000448/TR/NCATS NIH HHS/United States
GR  - R01 DK088126/DK/NIDDK NIH HHS/United States
GR  - R01 DK031842/DK/NIDDK NIH HHS/United States
GR  - P30 DK052574/DK/NIDDK NIH HHS/United States
GR  - RC1 DK086163/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 - 20100426
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Blood Glucose)
RN  - 0 (Cholinergic Agonists)
RN  - 0 (Insulin)
RN  - 144092-28-4 (xenin 25)
RN  - 39379-15-2 (Neurotensin)
RN  - 59392-49-3 (Gastric Inhibitory Polypeptide)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 8Y164V895Y (Carbachol)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Blood Glucose/metabolism
MH  - Blotting, Western
MH  - Carbachol/pharmacology
MH  - Cell Line, Tumor
MH  - Cholinergic Agonists/pharmacology
MH  - Drug Synergism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fasting/blood
MH  - Female
MH  - Gastric Inhibitory Polypeptide/genetics/*metabolism/pharmacology
MH  - Glucagon-Like Peptide 1/*pharmacology
MH  - Glucose/*pharmacology
MH  - Humans
MH  - Insulin/blood/metabolism
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/cytology/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurotensin/blood/*pharmacology
MH  - Pancreas/drug effects/metabolism
PMC - PMC2888395
EDAT- 2010/04/28 06:00
MHDA- 2010/08/25 06:00
PMCR- 2011/06/25
CRDT- 2010/04/28 06:00
PHST- 2010/04/28 06:00 [entrez]
PHST- 2010/04/28 06:00 [pubmed]
PHST- 2010/08/25 06:00 [medline]
PHST- 2011/06/25 00:00 [pmc-release]
AID - S0021-9258(18)49659-7 [pii]
AID - M110.129304 [pii]
AID - 10.1074/jbc.M110.129304 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Jun 25;285(26):19842-53. doi: 10.1074/jbc.M110.129304. Epub 
      2010 Apr 26.