Elucidating novel biological actions of the incretin hormones GLP-1 and GIP
By: by Tanya Hansotia.
Published: 2006
Language: eng
Number of pages: 209
ISBN-13: 9780494158371
Description: Incretins are hormones that are released from the gastrointestinal tract and potentiate glucose-stimulated insulin secretion from the endocrine pancreas. The two predominant peptides which have been identified as incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent evidence implicates GLP-1 receptor (GLP-1R) signalling for enhancing beta-cell mass by stimulating beta-cell proliferation and islet neogenesis. We examined whether GLP-1R signalling modifies the cellular susceptibility to apoptosis both in vitro and in vivo. Our findings demonstrate that activation of GLP-1R signalling inhibits beta-cell apoptosis, and provides a novel mechanism whereby GLP-1 is able to enhance or preserve beta-cell mass.Despite the importance of the incretin hormones for glucose homeostasis, elimination of incretin receptor action in GLP-1R-/- or GIPR -/- mice produces only modest impairment in glucose tolerance, possibly due to compensatory up-regulation of the remaining incretin. To assess the consequences of disruption of incretin receptor signalling for glucose homeostasis in the absence of compensation by the complementary incretin, we generated double incretin receptor knockout (DIRKO) mice. Our data indicate that chronic disruption of incretin receptor signalling is not associated with marked perturbations in glucose homeostasis.GLP-1 and GIP regulate glucose homeostasis through overlapping actions on the islet beta-cell. However, GLP-1 also exerts important 'non-incretin' effects, which contribute to its ability to lower glucose, including inhibition of gastric emptying, food intake and glucagon secretion. We examined whether disruption of dual incretin receptor signalling is associated with increased susceptibility to beta-cell metabolic stress imposed by high-fat feeding. Our results indicate that incretin receptors are essential for regulation of glucose homeostasis not only through effects on the beta-cell, but independently via modulation of the adipocyte response to excess over-nutrition.Both GLP-1 and GIP are rapidly inactivated by the protease, dipeptidyl peptidase IV (DPP-IV), which may limit their therapeutic potential. Inhibition of DPP-IV activity could thus provide a means to increase the half-life of GLP-1 and GIP. However, DPP-IV could also act on potential other substrates that are important for glucoregulation. Our studies in DIRKO mice delineate a critical role for incretin receptors as essential targets for the acute glucoregulatory actions of DPP-IV inhibitors.
Notes: Source: Dissertation Abstracts International, Volume: 67-06, Section: B, page: 2997.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.