TY - JOUR
T1 - The combination of GIP plus xenin-25 indirectly increases pancreatic polypeptide release in humans with and without type 2 diabetes mellitus
AU - Chowdhury, Sara
AU - Wang, Songyan
AU - Patterson, Bruce W.
AU - Reeds, Dominic N.
AU - Wice, Burton M.
N1 - Funding Information:
Portions of this research were supported by funds from: NIH grant numbers 5RC1 DK086163 and 5RO1 DK008126 ; the American Diabetes Association ; grant number 1-13-CE-46 ; the Washington University Diabetes Research and Training Center Immunoassay Core (Grant number P60 DK020579 ); the Washington University Nutrition Obesity Research Center Grant ( P30 DK056341 ) from the National Institute of Diabetes and Digestive and Kidney Diseases ; the Washington University Clinical and Translational Science Award ( UL1 RR024992 ); the Biologic Therapy Core Facility of the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes–Jewish Hospital in St. Louis, MO ( NCI Cancer Center Support Grant P30 CA91842 ); the NIH National Center for Research Resources ( P41 RR00954 and UL1 RR024992 ); the Washington University Digestive Disease Research Core Center ( P30 DK52574-16 ) and the Blum Kovler Foundation . The funding agencies played no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
PY - 2013/11/10
Y1 - 2013/11/10
N2 - Xenin-25 (Xen) is a 25-amino acid neurotensin-related peptide that activates neurotensin receptor-1 (NTSR1). We previously showed that Xen increases the effect of glucose-dependent insulinotropic polypeptide (GIP) on insulin release 1) in hyperglycemic mice via a cholinergic relay in the periphery independent from the central nervous system and 2) in humans with normal or impaired glucose tolerance, but not type 2 diabetes mellitus (T2DM). Since this blunted response to Xen defines a novel defect in T2DM, it is important to understand how Xen regulates islet physiology. On separate visits, subjects received intravenous graded glucose infusions with vehicle, GIP, Xen, or GIP plus Xen. The pancreatic polypeptide response was used as an indirect measure of cholinergic input to islets. The graded glucose infusion itself had little effect on the pancreatic polypeptide response whereas administration of Xen equally increased the pancreatic polypeptide response in humans with normal glucose tolerance, impaired glucose tolerance, and T2DM. The pancreatic polypeptide response to Xen was similarly amplified by GIP in all 3 groups. Antibody staining of human pancreas showed that NTSR1 is not detectable on islet endocrine cells, sympathetic neurons, blood vessels, or endothelial cells but is expressed at high levels on PGP9.5-positive axons in the exocrine tissue and at low levels on ductal epithelial cells. PGP9.5 positive nerve fibers contacting beta cells in the islet periphery were also observed. Thus, a neural relay, potentially involving muscarinic acetylcholine receptors, indirectly increases the effects of Xen on pancreatic polypeptide release in humans.
AB - Xenin-25 (Xen) is a 25-amino acid neurotensin-related peptide that activates neurotensin receptor-1 (NTSR1). We previously showed that Xen increases the effect of glucose-dependent insulinotropic polypeptide (GIP) on insulin release 1) in hyperglycemic mice via a cholinergic relay in the periphery independent from the central nervous system and 2) in humans with normal or impaired glucose tolerance, but not type 2 diabetes mellitus (T2DM). Since this blunted response to Xen defines a novel defect in T2DM, it is important to understand how Xen regulates islet physiology. On separate visits, subjects received intravenous graded glucose infusions with vehicle, GIP, Xen, or GIP plus Xen. The pancreatic polypeptide response was used as an indirect measure of cholinergic input to islets. The graded glucose infusion itself had little effect on the pancreatic polypeptide response whereas administration of Xen equally increased the pancreatic polypeptide response in humans with normal glucose tolerance, impaired glucose tolerance, and T2DM. The pancreatic polypeptide response to Xen was similarly amplified by GIP in all 3 groups. Antibody staining of human pancreas showed that NTSR1 is not detectable on islet endocrine cells, sympathetic neurons, blood vessels, or endothelial cells but is expressed at high levels on PGP9.5-positive axons in the exocrine tissue and at low levels on ductal epithelial cells. PGP9.5 positive nerve fibers contacting beta cells in the islet periphery were also observed. Thus, a neural relay, potentially involving muscarinic acetylcholine receptors, indirectly increases the effects of Xen on pancreatic polypeptide release in humans.
KW - Cholinergic
KW - GIP
KW - Neuronal relay
KW - Neurotensin receptor
KW - Pancreatic polypeptide
KW - Xenin
UR - http://www.scopus.com/inward/record.url?scp=84888131978&partnerID=8YFLogxK
U2 - 10.1016/j.regpep.2013.10.003
DO - 10.1016/j.regpep.2013.10.003
M3 - Article
C2 - 24183983
AN - SCOPUS:84888131978
SN - 0167-0115
VL - 187
SP - 42
EP - 50
JO - Regulatory Peptides
JF - Regulatory Peptides
ER -