Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas.
Diabetes is caused by a failure of the pancreas to produce insulin in amounts sufficient to meet the body's needs. A hallmark of diabetes is an absolute (type 1) or relative (type 2) reduction in the mass of pancreatic beta-cells that produce insulin. Mature beta-cells have a lifespan of approximately 48-56 days (rat) and are replaced by the replication of preexisting beta-cells and by the differentiation and proliferation of new beta-cells (neogenesis) derived from the pancreatic ducts. Here, we show that the insulinotropic hormone glucagon-like peptide (GLP)-1, which is produced by the intestine, enhances the pancreatic expression of the homeodomain transcription factor IDX-1 that is critical for pancreas development and the transcriptional regulation of the insulin gene. Concomitantly, GLP-1 administered to diabetic mice stimulates insulin secretion and effectively lowers their blood sugar levels. GLP-1 also enhances beta-cell neogenesis and islet size. Thus, in addition to stimulating insulin secretion, GLP-1 stimulates the expression of the transcription factor IDX-1 while stimulating beta-cell neogenesis and may thereby be an effective treatment for diabetes.
Stoffers
D A
DA
Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, USA.
Kieffer
T J
TJ
Hussain
M A
MA
Drucker
D J
DJ
Bonner-Weir
S
S
Habener
J F
JF
Egan
J M
JM
D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology; D000077270:Exenatide; D005934:Glucagon / Q000819:agonists*; D052216:Glucagon-Like Peptide 1; D018398:Homeodomain Proteins; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000819:agonists*; D010455:Peptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011498:Protein Precursors / Q000819:agonists*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014688:Venoms
D018398:Homeodomain Proteins; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide