title: Ectopic expression of GIP in pancreatic β-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides.
abstract: Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Fukami
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Seino
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozaki
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Chisato
authors.initials: C
authors.lastname: Sugiyama
authors.forename: Eriko
authors.initials: E
authors.lastname: Sakamoto-Miura
authors.forename: Tatsuhito
authors.initials: T
authors.lastname: Himeno
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takagishi
authors.forename: Shin
authors.initials: S
authors.lastname: Tsunekawa
authors.forename: Safina
authors.initials: S
authors.lastname: Ali
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D005749:Gastric Inhibitory Polypeptide / Q000096:biosynthesis* / Q000235:genetics; D017353:Gene Deletion; D055879:Gene Knock-In Techniques; D000067757:Glucagon-Like Peptide-1 Receptor; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D052336:Proglucagon / Q000032:analysis / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics; D018027:Receptors, Glucagon / Q000378:metabolism
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D007328:Insulin; D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D052336:Proglucagon; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP