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    • br Preclinical development of GIP agonists Since the action

    2021-11-12


    Preclinical development of GIP agonists Since the action of DPP IV is not limited to GIP, the most specific pharmacological approach for GIP would be modification at the N-terminus to disrupt DPP IV-mediated degradation. Indeed, it has been shown that GIP analogues with N-terminal modifications are not cleaved by DPP IV, resulting in peptides with increased potency and prolonged duration of biological action. Several novel Tyr1-modified GIP analogues have been developed, including the use of N-acetyl, N-Fmoc, N-gluticol and N-pyroglutamyl groups.*26, 53, 54, 55, 56 All the analogues modified at Tyr1 exhibited complete resistance to DPP IV and enhanced bioactivity compared to the native peptide. Further to this, a series of Ala2-substituted GIP analogues has been synthesised, including (Abu2)GIP, (Gly2)GIP, (Sar2)GIP, (Ser2)GIP and (d-Ala2)GIP.*26, 57, 58 In GS-7340 to Tyr1-modified analogues, Ala2-substituted analogues were not completely resistant to the actions of DPP IV and their efficacy was not as impressive as Tyr1-modified analogues. The effects of modification at position Tyr1 and Ala2 in GIP have been reviewed extensively elsewhere.*26, *59 In addition to DPP IV inactivation, GIP and related analogues are still susceptible to in vivo renal filtration.
    Clinical potential of GIP agonists There is good reason to consider GIP as an attractive agent for the treatment of human type 2 diabetes, especially since diminished insulinotropic action of GIP is now recognised as an acquired rather than a primary feature of type 2 diabetes.33, 34, 35 The GIP resistance has been shown to be reversible, particularly when GIP is given with beta-cell depolarising agents.40, 41, 42 The proven efficacy of DPP IV inhibitors, which act through potentiation of both GLP-1 and GIP action48, 49, also indicates that these agents might partly or fully restore GIP responsiveness in humans. In addition, GIP and GLP-1 have complimentary insulinotropic effects and thus should be appropriate for use as combination therapies. Interestingly, Amylin Pharmaceuticals has recently reported the development of a long-acting GIP analogue, AC163794, with enhanced insulin-releasing activity in normal and diabetic rats. A small, pilot clinical study indicated prolonged insulin-releasing activity of a longer-acting GIP analogue in type 2 diabetic patients. However, detailed clinical trials with GIP are needed, similar to those carried out for GLP-1, to discover the true therapeutic promise of GIP-related peptide drugs.
    Emerging actions of GIP An exciting aspect of recent research in incretin biology is the increasing realisation that GIP has actions outside of the pancreas and the GI tract. Most significant of these is the demonstration of functional GIP-R on adipocytes. The established effects of GIP on adipocytes include increase of lipoprotein lipase, stimulation of lipogenesis, enhancement of fatty acid and glucose uptake, augmentation of insulin-induced fatty acid incorporation and inhibition of both glucagon- and adrenergic-receptor-mediated lipolysis.*26, 27 Furthermore, the ingestion of fat has been shown to be a potent stimulus of GIP secretion77, 78, GIP levels are increased in obesity79, 80 and consumption of high-fat diets induce K-cell hyperplasia and increased GIP gene expression and intestinal GIP.*81, 82 GIP, therefore, appears to be a key regulator of adipocyte biology and lipid metabolism, ensuring efficient deposition of fat in body stores. Thus, an unexpected therapeutic channel for exploiting GIP-R antagonism for treatment of obesity and associated metabolic abnormalities induced by high-fat ‘Western’ diets has emerged [Fig. 1].
    GIP receptor antagonism A number of potential GIP-R antagonists have undergone systematic metabolic testing, with (Pro3)GIP identified as the most potent antagonist to date. Thus, amino acid modification/substitution at Tyr1/Ala2 of GIP results in enhanced agonist activity, whereas substitution of Glu3 provides antagonist effects. (Pro3)GIP is a stable, specific and potent antagonist of the GIP-R shown to effectively antagonise the acute insulinotropic effect of GIP in vitro and in vivo, resulting in impaired glucose tolerance.84, 85 In normal mice, sustained longer-term genetic or chemical knockout of GIP-R signalling resulted in mild impairments of insulin secretion and glucose homeostasis, presumably through disruption of the incretin effect.86, 87 However, an entirely different scenario emerges when GIP-R signalling is compromised for longer term in animal models of obesity-diabetes, especially those fed high-fat diets [Fig. 1]. Thus, in well-established insulin-resistant obesity-related diabetes, the beneficial effects of GIP-R blockade on lipid metabolism and fat deposition take pre-eminence and considerably outweigh loss of the insulin-releasing GIP component of the entero-insular axis. Indeed, as discussed earlier, the insulinotropic effect of native GIP and other similar secretagogues is already compromised in type 2 diabetes.