title: Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy.
abstract: Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 and PC1/3 together with significant amounts of GLP-1 and GIP were detected in alpha cells. Knockout of GLP-1R abolished these islet adaptations and paradoxically decreased pancreatic insulin, GLP-1 and GIP. This was associated with abolition of normal pregnancy-induced increases in plasma GIP, L-cell numbers, and intestinal GIP and GLP-1 stores. These data indicate that GLP-1 but not GIP is a key mediator of beta cell mass expansion and related adaptations in pregnancy, triggered in part by generation of intra-islet GLP-1.
authors.affiliation: SAAD centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, Northern Ireland.
authors.forename: R Charlotte
authors.initials: RC
authors.lastname: Moffett
authors.affiliation: SAAD centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, Northern Ireland.
authors.forename: Srividya
authors.initials: S
authors.lastname: Vasu
authors.affiliation: Centre for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.affiliation: The Lunenfield - Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: SAAD centre for Pharmacy and Diabetes, University of Ulster, Cromore Road, Coleraine, Northern Ireland.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D048429:Cell Size; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D055786:Gene Knockout Techniques; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics* / Q000378:metabolism
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor