Sustained expression of exendin-4 does not perturb glucose homeostasis, beta-cell mass, or food intake in metallothionein-preproexendin transgenic mice.
Activation of glucagon-like peptide (GLP)-1 receptor signaling promotes glucose lowering via multiple mechanisms, including regulation of food intake, glucose-dependent insulin secretion, and stimulation of beta-cell mass. As GLP-1 exhibits a short t(12) in vivo, the biological consequences of prolonged GLP-1 receptor signaling remains unclear. To address this question, we have now generated metallothionein promoter-preproexendin (MT-Ex) transgenic mice. MT-Ex mice process preproexendin correctly, as is made evident by detection of circulating plasma exendin-4 immunoreactivity using high pressure liquid chromatography and an exendin-4-specific radioimmunoassay. Despite elevated levels of exendin-4, fasting plasma glucose and glucose clearance following oral and intraperitoneal glucose tolerance tests are normal in MT-Ex mice. Induction of transgene expression significantly reduced glycemic excursion during both oral and intraperitoneal glucose tolerance tests (p < 0.05) and increased levels of glucose-stimulated insulin following oral glucose administration (p < 0.05). Despite evidence that exendin-4 may induce beta-cell proliferation, beta-cell mass and islet histology were normal in MT-Ex mice. MT-Ex mice exhibited no differences in basal food intake or body weight; however, induction of exendin-4 expression was associated with reduced short term food ingestion (p < 0.05). In contrast, short term water intake was significantly reduced in the absence of zinc in fluid-restricted MT-Ex mice (p < 0.05). These findings illustrate that sustained elevation of circulating exendin-4 is not invariably associated with changes in glucose homeostasis, increased beta-cell mass, or reduction in food intake in mice in vivo.
Baggio
L
L
Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario M5G 2C4.
Adatia
F
F
Bock
T
T
Brubaker
P L
PL
Drucker
D J
DJ
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002149:Energy Intake; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018027:Receptors, Glucagon / Q000378:metabolism; D015398:Signal Transduction; D014688:Venoms
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D008668:Metallothionein; D000077270:Exenatide; D005947:Glucose