Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism.
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.
Wice
Burton M
BM
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
Wang
Songyan
S
Crimmins
Dan L
DL
Diggs-Andrews
Kelly A
KA
Althage
Matthew C
MC
Ford
Eric L
EL
Tran
Hung
H
Ohlendorf
Matthew
M
Griest
Terry A
TA
Wang
Qiuling
Q
Fisher
Simon J
SJ
Ladenson
Jack H
JH
Polonsky
Kenneth S
KS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002217:Carbachol / Q000494:pharmacology; D045744:Cell Line, Tumor; D018679:Cholinergic Agonists / Q000494:pharmacology; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005215:Fasting / Q000097:blood; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009496:Neurotensin / Q000097:blood / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism
D001786:Blood Glucose; D018679:Cholinergic Agonists; D007328:Insulin; C077659:xenin 25; D009496:Neurotensin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D002217:Carbachol; D005947:Glucose