Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.
Diabetes is a disease of increasing prevalence in the general population and of unknown cause. Diabetes is manifested as hyperglycemia due to a relative deficiency of the production of insulin by the pancreatic beta-cells. One determinant in the development of diabetes is an inadequate mass of beta-cells, either absolute (type 1, juvenile diabetes) or relative (type 2, maturity-onset diabetes). Earlier, we reported that the intestinal hormone glucagon-like peptide I (GLP-I) effectively augments glucose-stimulated insulin secretion. Here we report that exendin-4, a long-acting GLP-I agonist, stimulates both the differentiation of beta-cells from ductal progenitor cells (neogenesis) and proliferation of beta-cells when administered to rats. In a partial pancreatectomy rat model of type 2 diabetes, the daily administration of exendin-4 for 10 days post-pancreatectomy attenuates the development of diabetes. We show that exendin-4 stimulates the regeneration of the pancreas and expansion of beta-cell mass by processes of both neogenesis and proliferation of beta-cells. Thus, GLP-I and analogs thereof hold promise as a novel therapy to stimulate beta-cell growth and differentiation when administered to diabetic individuals with reduced beta-cell mass.
Xu
G
G
Elliott P. Joslin Research Laboratories, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Stoffers
D A
DA
Habener
J F
JF
Bonner-Weir
S
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000819:agonists / Q000032:analysis; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D010180:Pancreatectomy; D010446:Peptide Fragments / Q000819:agonists; D010455:Peptides / Q000494:pharmacology*; D011498:Protein Precursors / Q000819:agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000235:genetics; D014688:Venoms / Q000494:pharmacology
D001786:Blood Glucose; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide