The long acting GLP-1 analogue, liraglutide, induces beta cell differentiation during normal human pancreas development

Hanley, K.P., Gray, S., Dijkstra, I.M.E., Hearn, T., Williams, L., Wilson, D.I. and Hanley, N.A. (2006) The long acting GLP-1 analogue, liraglutide, induces beta cell differentiation during normal human pancreas development. Diabetologia, 49 (Supplement 1), 288-289. (doi:10.1007/s00125-006-0358-5).

Abstract

Background and Aims: Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion; the primary reason long-acting analogues have been developed for use in Type 2 diabetes. In rodents and tumour cell lines, GLP-1 signaling has also increased beta cell F mass_ by promoting beta cell neogenesis, proliferation and inhibiting apoptosis. However, little is known about the role of GLP-1 during normal human beta cell differentiation. We have investigated GLP-1 signaling, via the long-acting analogue Liraglutide (Novo Nordisk A/S) in the developing human pancreas.
Materials and Methods: With ethical approval and informed consent, human fetal material was collected from first trimester termination and processed for fixed tissue, RNA and protein analysis. In vitro culture models were established to interrogate beta cell differentiation. Insulin positivecells were expressed as a percentage of total epithelial cell number.
Results: Human pancreas was isolated at 8 weeks post conception (wpc), immediately prior to significant beta cell differentiation (Piper et al, J Endocrinology, 181,11–23, 2004). GLP-1, along with its receptor, was expressed in the developing pancreas and duodenum. In 7-day explant culture, Liraglutide increased insulin positive cell number by 68% (n=6), but had no effect on beta cell proliferation or apoptosis. Consistent with this implication of de novo differentiation, exposure to Liraglutide decreased epithelial progenitor cell proliferation by 24%. The effects of Liraglutide on beta cell number were abrogated by co-incubation with 10-fold molar excess of the GLP-1 receptor antagonist, Exendin 9–39, restoring insulin-positive cell number to just below 100% of control. The use of Exendin 9–39 alone reduced insulin-positive cells by 26%.
Conclusion: Liraglutide increases human primary betacell number, via GLP-1 receptor signaling that most likely enhances beta cell differentiation. For Exendin 9–39 to decrease insulin-positive cell number by itself suggests that native GLP-1 signaling is very important during early human development. Furthermore, our data suggest that altering the cell cycle status of progenitor cells may be an underlying mechanism that regulates human beta cell differentiation. Clinically, Liraglutide may increase human beta cell mass in Type 2 diabetes. In addition, modulating the GLP-1 pathway may be a potent mechanism for manipulating stem cells to betacells as an ambitious transplantation therapy in Type 1 diabetes.
Supported by Novo Nordisk

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