title: Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes.
abstract: The system that regulates insulin secretion from beta-cells in the islet of Langerhans has a capsaicin-sensitive inhibitory component. As calcitonin gene-related peptide (CGRP)-expressing primary sensory fibers innervate the islets, and a major proportion of the CGRP-containing primary sensory neurons is sensitive to capsaicin, the islet-innervating sensory fibers may represent the capsaicin-sensitive inhibitory component. Here, we examined the expression of the capsaicin receptor, vanilloid type 1 transient receptor potential receptor (TRPV1) in CGRP-expressing fibers in the pancreatic islets, and the effect of selective elimination of capsaicin-sensitive primary afferents on the decline of glucose homeostasis and insulin secretion in Zucker diabetic fatty (ZDF) rats, which are used to study various aspects of human type 2 diabetes mellitus. We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1. Furthermore, we also found that systemic capsaicin application before the development of hyperglycemia prevents the increase of fasting, non-fasting, and mean 24-h plasma glucose levels, and the deterioration of glucose tolerance assessed on the fifth week following the injection. These effects were accompanied by enhanced insulin secretion and a virtually complete loss of CGRP- and TRPV1-coexpressing islet-innervating fibers. These data indicate that CGRP-containing fibers in the islets are capsaicin sensitive, and that elimination of these fibers contributes to the prevention of the deterioration of glucose homeostasis through increased insulin secretion in ZDF rats. Based on these data we propose that the activity of islet-innervating capsaicin-sensitive fibers may have a role in the development of reduced insulin secretion in human type 2 diabetes mellitus.
authors.affiliation: Research and Development, Novo Nordisk A/S, Novo Nordisk Park, F6.1.30, DK-2760 Måløv, Denmark. dxg@novonordisk.com
authors.forename: Dorte X
authors.initials: DX
authors.lastname: Gram
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Istvan
authors.initials: I
authors.lastname: Nagy
authors.forename: Uffe B
authors.initials: UB
authors.lastname: Olsen
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Frank
authors.initials: F
authors.lastname: Sundler
authors.forename: René
authors.initials: R
authors.lastname: Tabanera
authors.forename: Ove
authors.initials: O
authors.lastname: Svendsen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carr
authors.forename: Peter
authors.initials: P
authors.lastname: Santha
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Anker J
authors.initials: AJ
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000473:pathology*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test / Q000379:methods; D006442:Glycated Hemoglobin / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000097:blood / Q000172:deficiency*; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D050916:TRPV Cation Channels / Q000378:metabolism; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D006442:Glycated Hemoglobin; D007328:Insulin; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat