Glucagon-like peptide-1.
There is a progressive impairment in beta-cell function with age. As a result, 19 percent of the U.S. population over the age of 65 is diagnosed with type 2 diabetes mellitus (DM). Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue that has multiple synergetic effects on the glucose-dependent insulin secretion pathways of the beta-cell. This peptide and its longer-acting analog exendin-4 are currently under review as treatments for type 2 DM. In our work on the rodent model of glucose intolerance in aging, we found that GLP-1 is capable of rescuing the age-related decline in beta-cell function. We have shown that this is due to the ability of GLP-1 to 1) recruit beta-cells into a secretory mode; 2) upregulate the genes of the beta-cell glucose-sensing machinery; and 3) cause beta-cell differentiation and neogenesis. Our investigations into the mechanisms of action of GLP-1 began by using the reverse hemolytic plaque assay to quantify insulin secretion from individual cells of the RIN 1046-38 insulinoma cell line in response to acute treatment with the peptide. GLP-1 increases both the number of cells secreting insulin and the amount secreted per cell. This response to GLP-1 is retained even in the beta cell of the old (i.e., 22-month), glucose-intolerant Wistar rat, which exhibits a normal, first-phase insulin response to glucose following an acute bolus of GLP-1. Preincubation with GLP-1 (24 hours) potentiates glucose- and GLP-1-dependent insulin secretion and increases insulin content in the insulinoma cells. Treatment of old Wistar rats for 48 hours with GLP-1 leads to normalization of the insulin response and an increase in islet insulin content and mRNA levels of GLUT 2 and glucokinase. PDX-1, a transcriptional factor activator of these three genes, also is upregulated in the insulinoma cell line in aged rats and diabetic mice following treatment with GLP-1. Administration of GLP-1 to old rats leads to pancreatic cell proliferation, insulin-positive clusters, and an increase in beta-cell mass. This evidence led us to believe that GLP-1 is an endocrinotrophic factor. We used an acinar cell line to show that GLP-1 can directly cause the conversion of a putative pro-endocrine cell into an endocrine one. Thus, the actions of GLP-1 on the beta-cell are complex, with possible benefits to the diabetic patient that extend beyond a simple glucose-dependent increase in insulin secretion. The major limitation to GLP-1 as a clinical treatment is its short biological half-life. We have shown that the peptide exendin-4, originating in the saliva of the Gila monster, exhibits the same insulinotropic and endocrinotrophic properties as GLP-1 but is more potent and longer acting in rodents and humans.
Diabetes Section, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
M E
ME
Doyle
J M
JM
Egan
D000367:Age Factors; D000368:Aged; D000375:Aging; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005934:Glucagon / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase / Q000378:metabolism; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology*; D011498:Protein Precursors / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation
D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005941:Glucokinase