TY - JOUR
T1 - Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism
AU - Wice, Burton M.
AU - Wang, Songyan
AU - Crimmins, Dan L.
AU - Diggs-Andrews, Kelly A.
AU - Althage, Matthew C.
AU - Ford, Eric L.
AU - Tran, Hung
AU - Ohlendorf, Matthew
AU - Griest, Terry A.
AU - Wang, Qiuling
AU - Fisher, Simon J.
AU - Ladenson, Jack H.
AU - Polonsky, Kenneth S.
PY - 2010/6/25
Y1 - 2010/6/25
N2 - The intestinal peptides GLP-1 and GIP potentiate glucosemediated 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.Studieswithislets, insulin-producingcelllines,andperfused pancreata indicated xenin-25 does not enhance GIP-mediated insulin release by acting directly on the β-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 β-cells, may represent a novel approach to overcome GIP resistance and therefore treat humans with T2DM.
AB - The intestinal peptides GLP-1 and GIP potentiate glucosemediated 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.Studieswithislets, insulin-producingcelllines,andperfused pancreata indicated xenin-25 does not enhance GIP-mediated insulin release by acting directly on the β-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 β-cells, may represent a novel approach to overcome GIP resistance and therefore treat humans with T2DM.
UR - http://www.scopus.com/inward/record.url?scp=77953733812&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953733812&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.129304
DO - 10.1074/jbc.M110.129304
M3 - Article
C2 - 20421298
AN - SCOPUS:77953733812
SN - 0021-9258
VL - 285
SP - 19842
EP - 19853
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -