Glucagon-like peptide-1.

  • Doyle M
  • Egan J
  • 17

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Abstract

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.

Author-supplied keywords

  • Age Factors
  • Aged
  • Aging
  • Animals
  • Biological
  • Cell Line
  • Diabetes Mellitus
  • Glucagon
  • Glucagon-Like Peptide 1
  • Glucagon: physiology
  • Glucokinase
  • Glucokinase: metabolism
  • Glucose Transporter Type 2
  • Homeodomain Proteins
  • Humans
  • Insulin
  • Insulin: metabolism
  • Islets of Langerhans
  • Islets of Langerhans: metabolism
  • Messenger
  • Messenger: metabolism
  • Models
  • Monosaccharide Transport Proteins
  • Monosaccharide Transport Proteins: metabolism
  • Peptide Fragments
  • Peptide Fragments: physiology
  • Protein Precursors
  • Protein Precursors: physiology
  • RNA
  • Rats
  • Time Factors
  • Trans-Activators
  • Trans-Activators: metabolism
  • Type 2
  • Type 2: metabolism
  • Up-Regulation
  • Wistar

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Authors

  • M E Doyle

  • J M Egan

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