title: Glucagon-like peptide-2 receptor modulates islet adaptation to metabolic stress in the ob/ob mouse.
abstract: OBJECTIVE
  Glucagon-like peptide-2 (GLP-2) is a gut hormone that increases gut growth, reduces mucosal cell death, and augments mesenteric blood flow and nutrient absorption. Exogenous GLP-2(1-33) also stimulates glucagon secretion and enhances gut barrier function with implications for susceptibility to systemic inflammation and subsequent metabolic dysregulation. We examined the importance of GLP-2 receptor (GLP-2R) signaling for glucose homeostasis in multiple models of metabolic stress, diabetes, and obesity.
  
  
  METHODS
  Body weight, islet function, glucose tolerance, and islet histology were studied in wild-type, high-fat fed, lean diabetic, Glp2r(-/-) and ob/ob:Glp2r(-/-) mice.
  
  
  RESULTS
  GLP-2 did not stimulate glucagon secretion from isolated pancreatic islets in vitro, and exogenous GLP-2 had no effect on the glucagon response to insulin-induced hypoglycemia in vivo. Glp2r(-/-) mice exhibit no change in glycemia, and plasma glucagon levels were similar in Glp2r(-/-) and Glp2r(+/+) mice after hypoglycemia or after oral or intraperitoneal glucose challenge. Moreover, glucose homeostasis was comparable in Glp2r(-/-) and Glp2r(+/+) mice fed a high-fat diet for 5 months or after induction of streptozotocin-induced diabetes. In contrast, loss of the GLP-2R leads to increased glucagon secretion and alpha-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced beta-cell mass, and decreased islet proliferation in ob/ob:Glp2r(-/-) mice.
  
  
  CONCLUSIONS
  Our results show that, although the GLP-2R is not critical for the stimulation or suppression of glucagon secretion or glucose homeostasis in normal or lean diabetic mice, elimination of GLP-2R signaling in obese mice impairs the normal islet adaptive response required to maintain glucose homeostasis.
authors.affiliation: Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Bahrami
authors.forename: Christine
authors.initials: C
authors.lastname: Longuet
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.forename: Karen
authors.initials: K
authors.lastname: Li
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005934:Glucagon / Q000097:blood; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism*; D000067758:Glucagon-Like Peptide-2 Receptor; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D005951:Glucose Tolerance Test; D007003:Hypoglycemia / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018027:Receptors, Glucagon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D007328:Insulin; D018027:Receptors, Glucagon; D005934:Glucagon