title: Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus.
abstract: Glucose in the gut lumen activates gut endocrine cells to release 5-HT, glucagon-like peptide 1/2 (GLP-1/2), and glucose-dependent insulinotropic polypeptide (GIP), which act to change gastrointestinal function and regulate postprandial plasma glucose. There is evidence that both release and action of incretin hormones is reduced in type 2 diabetes (T2D). We measured cellular activation of enteroendocrine and enterochromaffin cells, enteric neurons, and vagal afferent neurons in response to intestinal glucose in a model of type 2 diabetes mellitus, the UCD-T2DM rat. Prediabetic (PD), recent-diabetic (RD, 2 wk postonset), and 3-mo diabetic (3MD) fasted UCD-T2DM rats were given an orogastric gavage of vehicle (water, 0.5 ml /100 g body wt) or glucose (330 μmol/100 g body wt); after 6 min tissue was removed and cellular activation was determined by immunohistochemistry for phosphorylated calcium calmodulin-dependent kinase II (pCaMKII). In PD rats, pCaMKII immunoreactivity was increased in duodenal 5-HT (P < 0.001), K (P < 0.01) and L (P < 0.01) cells in response to glucose; glucose-induced activation of all three cell types was significantly reduced in RD and 3MD compared with PD rats. Immunoreactivity for GLP-1, but not GIP, was significantly reduced in RD and 3MD compared with PD rats (P < 0.01). Administration of glucose significantly increased pCaMKII in enteric and vagal afferent neurons in PD rats; glucose-induced pCaMKII immunoreactivity was attenuated in enteric and vagal afferent neurons (P < 0.01, P < 0.001, respectively) in RD and 3MD. These data suggest that glucose sensing in enteroendocrine and enterochromaffin cells and activation of neural pathways is markedly impaired in UCD-T2DM rats.
authors.affiliation: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, California 95616, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Bethany P
authors.initials: BP
authors.lastname: Cummings
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Martin
authors.forename: James W
authors.initials: JW
authors.lastname: Sharp
authors.forename: James L
authors.initials: JL
authors.lastname: Graham
authors.forename: Kimber L
authors.initials: KL
authors.lastname: Stanhope
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
authors.forename: Helen E
authors.initials: HE
authors.lastname: Raybould
mesh_terms: D000344:Afferent Pathways / Q000503:physiopathology*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004759:Enterochromaffin Cells / Q000378:metabolism / Q000473:pathology; D019858:Enteroendocrine Cells / Q000378:metabolism* / Q000473:pathology; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D004763:Glucagon-Like Peptides / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D012701:Serotonin / Q000378:metabolism; D014630:Vagus Nerve / Q000503:physiopathology*
chemical_list: D012701:Serotonin; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose