title: Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)-Deficient Mice.
abstract: Hepatocyte nuclear factor-1α (HNF1α) is a transcription factor expressed in tissues of endoderm origin. Mutations in HNF1A are associated with maturity-onset diabetes of the young 3 (MODY3). Mice deficient for Hnf1α are hyperglycemic, with their pancreatic β-cells being defective in glucose-sensing insulin secretion. The specific mechanisms involved in this defect are unclear. Gut hormones control glucose homeostasis. Our objective was to explore whether changes in these hormones play a role in glucose homeostasis in the absence of Hnf1α. An increase in ghrelin gene transcript and a decrease in glucose-dependent insulinotropic polypeptide (GIP) gene transcripts were observed in the gut of Hnf1α-null mice. These changes correlated with an increase of ghrelin and a decrease of GIP-labeled cells. Ghrelin serological levels were significantly induced in Hnf1α-null mice. Paradoxically, GIP levels were also induced in these mice. Treatment of Hnf1α-null mice with a ghrelin antagonist led to a recovery of the diabetic symptoms. We conclude that upregulation of ghrelin in the absence of Hnf1α impairs insulin secretion and can be reversed by pharmacological inhibition of ghrelin/GHS-R interaction. These observations open up on future strategies to counteract ghrelin action in a program that could become beneficial in controlling non-insulin-dependent diabetes.
authors.affiliation: Department of Anatomy and Cell Biology, Université de Sherbrooke, Quebec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Brial
authors.affiliation: Department of Anatomy and Cell Biology, Université de Sherbrooke, Quebec, Canada.
authors.forename: Carine R
authors.initials: CR
authors.lastname: Lussier
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Belleville
authors.affiliation: Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Department of Anatomy and Cell Biology, Université de Sherbrooke, Quebec, Canada francois.boudreau@usherbrooke.ca.
authors.forename: François
authors.initials: F
authors.lastname: Boudreau
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics* / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D054439:Ghrelin / Q000235:genetics* / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; C520836:GHRP-6, Lys(3)-; D054439:Ghrelin; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D007328:Insulin; D009842:Oligopeptides; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D005749:Gastric Inhibitory Polypeptide