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    • Until now various reports have

    2021-11-23

    Until now, various reports have demonstrated the therapeutic potential of enzyme-resistant forms of GIP in experimental diabetic animal models , , . In essence, structural modifications performed at the Tyr residue in GIP generate analogues that are completely resistant to the actions of DPP-IV and have markedly enhanced insulinotropic and antihyperglycaemic activity , . Substitution of Ala produced analogues with varying degrees of DPP-IV resistance and biological activity, however, their efficacy was not as impressive as that of the Tyr-modified analogues , , , , . Such ‘super GIP’ analogues may be useful for the treatment of T2DM, by acting mostly through the stimulation of insulin secretion, analogous to the actions of GLP-1 but without effects on gastric emptying , . An exciting finding has been the development of a GIP receptor antagonist through the substitution of Glu with a Pro residue . (Pro)GIP is completely resistant to the actions of DPP-IV and even more notably, effectively and specifically countered the insulin-releasing actions of the native hormone , . Recent evidence has demonstrated that genetic knockout of GIP can prevent insulin resistance in high-fat fed mice . Furthermore, a recent paper published from our laboratory has shown that chemical ablation of GIP receptor action with daily (Pro)GIP administration ameliorated insulin resistance and significantly improved urb597 sale tolerance, pancreatic β-cell function and disturbances of islet morphology in mice . Comparable to the therapeutic actions of metformin and other insulin sensitisers, specific GIP receptor antagonists are currently being considered as an unexpected new class of drugs for alleviation of insulin resistance and treatment of T2DM . In the present study, five Glu-substituted GIP analogues were designed, synthesised and tested for their ability to serve as effective GIP receptor antagonists. The enzyme stability of each analogue together with their abilities to affect cAMP production and insulin secretion was investigated. Furthermore, the insulin-releasing and antihyperglycaemic activities of all GIP analogues were examined in obese diabetic mice. Materials and methods
    Results
    Discussion Glucose-dependent insulinotropic polypeptide (GIP) is presently under renewed interest as a potential therapeutic drug candidate for the treatment of T2DM [1], [2]. One of the key advantages in exploiting GIP as a therapeutic option stems from its ability to potentiate glucose-induced insulin secretion, thereby negating the risk of hypoglycaemic episodes due to excessive insulin-release from the pancreatic β-cells. In addition to its actions on the pancreas, GIP also exerts myriad extrapancreatic actions in a range of peripheral tissues which further augment its ability to lower blood glucose concentrations [1]. However, the major disadvantage in developing GIP as a therapeutic molecule is its relatively short biological half-life in the circulation due to degradation by the ubiquitous enzyme, DPP-IV, and additionally, its rapid elimination from the kidneys [25]. Several studies have reported the metabolic stability and biological activity of a wide range of GIP analogues modified at positions Tyr1 and Ala2 within the GIP molecule [23], [24], [25], [26], [27], [28]. In general, analogues of GIP modified at positions Tyr1 and Ala2 displayed increased metabolic stability to DPP-IV and enhanced biological activity compared with native GIP when tested in several biological systems. These properties translate into significant antihyperglycaemic actions in vivo. Substitution of Glu3 in GIP with a proline residue rendered the peptide completely stable to the actions of DPP-IV [34]. Unexpectedly though, this proline-substituted analogue, (Pro3)GIP, exhibited potent antagonist actions at the GIP receptor when tested in vitro and in vivo[33], [34]. Furthermore, chronic, as opposed to acute, administration of (Pro3)GIP significantly improved glucose tolerance and ameliorated insulin resistance and abnormalities of islet structure in ob/ob mice [36]. These observations suggest that development of GIP receptor antagonists may provide a new class of drug offering a safe and exciting therapeutic approach to T2DM [1], [36].