Despite potent biological actions the native

Despite potent biological actions, the native hormone undergoes degradation by the enzyme dipeptidylpeptidase-IV (DPP-IV) [17] and is rapidly cleared from the bloodstream by renal filtration [18]. One such approach to prolong the biological half-life of GIP is through conjugation with a polyethylene glycol (PEG) residue. PEGylation of peptides has been shown to decrease renal clearance and improve proteolytic stability [12] whilst also offering reduced immunogenicity [3] and restricted blood-brain barrier penetration [27]. Furthermore, a recent study in our laboratory has shown that conjugation of a mini-PEG residue to the C-terminus of GIP, GIP[mPEG], results in DPP-IV stability, significantly enhanced in vitro potency and the ability to counter pancreatic beta-cell dysfunction in mice with high-fat diet-induced obesity [10]. Thus, the present study has utilized GIP[mPEG] to examine possible beneficial effects of prolonged GIP receptor activation on glucose homeostasis and beta-cell function in mice with age-related glucose intolerance.
Materials and methods
Results
Acknowledgements
Over the last number of years, glucose-dependent insulinotropic polypeptide (GIP) has come forward as a promising candidate for diabetes therapy , . GIP is a 42 amino acid hormone secreted from enteroendocrine K-cells in response to food and nutrient 516 3 sale . Upon release, the primary action of GIP is the stimulation of glucose-dependent insulin secretion through interaction with specific heterotrimeric G-protein-coupled GIP receptors on pancreatic β-cells . This glucose-dependent action on insulin secretion means there is a significantly reduced likelihood of hypoglycaemic episodes often associated with other insulin-releasing agents used in the treatment of T2DM . Additionally, the pleiotropic nature of GIP acting synergistically as both a growth and anti-apoptotic factor for pancreatic β-cells , , , , further support its possible therapeutic application in T2DM. One of the crucial difficulties in attempting to develop GIP as a therapeutic agent is its short biological half-life, which is primarily due to degradation by the ubiquitous enzyme dipeptidyl peptidase-IV (DPP-IV) . DPP-IV (CD26; E.C.3.4.14.5) is a homodimeric class II protein belonging to the prolyl oligopeptidase family , ubiquitously expressed in mammalian tissues and organs . It is important to note that DPP-IV action is not specific to GIP alone as natural substrates also include cytokines, chemokines, endomorphins and almost all members of the PACAP/glucagon peptide superfamily, including the sister incretin hormone GLP-1 . DPP-IV, therefore, appears to play an important role in the regulation of a number of key physiological processes, which include effects on pain regulation, metabolism, cell adhesion, immune response and the cardiovascular system. Due to the rapid inactivation of GLP-1 and GIP, DPP-IV inhibitors are currently being developed as a strategy to prolong the biological activity of incretin hormones. Encouraging effects have been reported with several inhibitors, including improvements in glucose tolerance, hyperinsulinaemia, β-cell glucose responsiveness and peripheral insulin sensitivity , , , . One important advantage of DPP-IV inhibitors is the prospect that they can be administered orally. However, one major disadvantage is that they also pose a possible threat from long-term administration and undesirable side effects, due to prolonged inhibition of other DPP-IV mediated processes , , . Thus although DPP IV inhibitors in clinical development show good specificity, non-selective inhibition of the DPP-IV related enzymes, DPP-8 and DPP-9, has been shown to result in toxicity in preclinical species . Hence, given that information concerning the substrate specificity of DPP-IV is well documented, an attractive alternative approach involves the generation of specific GLP-1 and GIP analogues modified in the region around the enzyme cleavage site to impart improved DPP-IV resistance , , , . The potential of this approach is demonstrated by the stable GLP-1 mimetic exendin 1–39 (Byetta), which has been approved for the clinical treatment of T2DM .