Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

May 28, 2010Journal of cellular physiology

Active GLP-1 receptor in bone-forming cells that works separately from the usual cAMP-linked receptor

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Abstract

Specific binding of [(125)I]-GLP-1 to MC3T3-E1 cells was observed to be time- and temperature-dependent, peaking at 30 minutes.

GLP-1 binding to MC3T3-E1 cells is dissociable and can be partially displaced by GLP-2, but not by exendin-4, exendin-9, glucagon, or insulin.
Scatchard analysis reveals the presence of high and low affinity binding sites for GLP-1.
GLP-1 induces immediate hydrolysis of glycosylphosphatidylinositols (GPIs), producing short-lived inositolphosphoglycans (IPGs).
GLP-1 increases activities of phosphatidylinositol-3 kinase (PI3K) and mitogen activated protein kinase (MAPK).
GLP-1 decreases Runx2 gene expression while increasing osteocalcin gene expression in MC3T3-E1 cells.
These cells do not express the pancreatic GLP-1 receptor, suggesting GLP-1 may interact via a different pathway.

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Glucagon-like peptide 1 (GLP-1) controls glucose metabolism in extrapancreatic tissues through receptors other than the pancreatic cAMP-linked GLP-1 receptor; also, GLP-1 induces an insulin- and PTH-independent bone anabolic action in insulin-resistant and type-2 diabetic rats. Here we searched for the presence and characteristics of GLP-1 receptors in osteoblastic MC3T3-E1 cells. [(125)I]-GLP-1 specific binding to MC3T3-E1 cells was time- and temperature-dependent, reaching maximal value at 30 min at 25 degrees C; in these conditions, [(125)I]-GLP-1 binding was dissociable, and displaced by GLP-1, partially by GLP-2, but not by exendin-4 (Ex-4), exendin-9 (Ex-9), glucagon or insulin; Scatchard analysis of the unlabeled GLP-1 data showed high and low affinity binding sites; cross-linking of GLP-1 binding revealed an estimated 70 kDa band, almost undetectable in the presence of 10(-6) M GLP-1. GLP-1, Ex-9, insulin or glucagon failed to modify cellular cAMP content, while GLP-2 and Ex-4 increased it. However, GLP-1 induced an immediate hydrolysis of glycosylphosphatidylinositols (GPIs) generating short-lived inositolphosphoglycans (IPGs), and an increase in phosphatidylinositol-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) activities; Ex-4 also affected GPIs, but its action was delayed with respect to that of GLP-1. This incretin was found to decrease Runx2 but increased osteocalcin gene expression, without affecting that of osteoprotegerin or the canonical Wnt pathway activity in MC3T3-E1 cells which do not express the pancreatic GLP-1 receptor. Our data demonstrate for the first time that GLP-1 can directly and functionally interact with osteoblastic cells, possibly through a GPI/IPG-coupled receptor.

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Presence of a functional receptor for GLP‐1 in osteoblastic cells, independent of the cAMP‐linked GLP‐1 receptor

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