title: Incretin hormone receptors are required for normal beta cell development and function in female mice.
abstract: The incretin hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), potentiate insulin secretion and are responsible for the majority of insulin secretion that occurs after a meal. They may also, however, have a fundamental role in pancreatic beta cell development and function, independently of their role in potentiating insulin secretion after a meal. This has led to observations that a loss of GIP or GLP-1 action affects normal beta cell function, however each one of the incretin hormones may compensate when the action of the other is lost and therefore the overall impact of the incretin hormones on beta cell function is not known. We therefore utilized a mouse line deficient in both the GLP-1 and GIP receptor genes, the double incretin receptor knockout (DIRKO), to determine the consequences of a lifelong, complete lack of incretin hormone action on beta cell function, in vivo, in intact animals. We found that DIRKO mice displayed impaired glucose tolerance and insulin secretion in response to both oral glucose and mixed meal tolerance tests compared to wild-type mice. Assessment of beta cell function using the hyperglycemic clamp technique revealed an 80% decrease in first phase insulin response in DIRKO mice, but a normal second phase insulin secretion. A similar decline was seen when wild-type mice were given acute intravenous injection of glucose together with the GLP-1 receptor antagonist Ex9-39. Ex vivo assessments of the pancreas revealed significantly fewer islets in the pancreata of DIRKO mice despite no differences in total pancreatic mass. Insulin secretion from isolated islets of DIRKO mice was impaired to a similar extent to that seen during the hyperglycemic clamp. Insulin secretion in wild-type islets was impaired by acute treatment with Ex9-39 to a similar extent as the in vivo intravenous glucose tolerance tests. In conclusion, a loss of the action of both incretin hormones results in direct impairment of beta cell function both in vivo and in vitro in a process that appears to be independent of the intestinally secreted incretin hormones. We therefore conclude that the incretin hormones together significantly impact both beta-cell function and beta-cell development.
authors.affiliation: Department of Clinical Sciences, Medicine, Lund University, Sölvegatan 19, 22184 Lund, Sweden. Electronic address: bilal.omar@med.lu.se.
authors.forename: Bilal
authors.initials: B
authors.lastname: Omar
authors.affiliation: Department of Clinical Sciences, Medicine, Lund University, Sölvegatan 19, 22184 Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Ahlkvist
authors.affiliation: Graduate School of Medicine, Akita University, Akita, Japan.
authors.forename: Yuchiro
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Yutaka Seino Distinguished Center for Diabetes Research, Kensai Electric Power Medical Research Institute, Kobe, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Seino
authors.affiliation: Department of Clinical Sciences, Medicine, Lund University, Sölvegatan 19, 22184 Lund, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D002478:Cells, Cultured; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010179:Pancreas / Q000166:cytology / Q000254:growth & development; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; C041086:gastric inhibitory polypeptide receptor
keywords: Clamp; GIP; GLP-1; Glucose; Insulin