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  • Besides its established insulinotropic actions GIP


    Besides its established insulinotropic actions, GIP has been shown to possess other direct beneficial effects on the beta cell, including stimulation of growth, differentiation, proliferation and survival.21, 22, 23 It has also been shown to stimulate proinsulin gene transcription and translation. Moreover, a stable GIP analogue has been shown to enhance functional differentiation of mouse embryonic stem cells into cells expressing islet-specific genes and hormones. In addition to its effects on pancreatic beta cells, GIP also possesses glucose-lowering extrapancreatic effects, which have been reviewed elsewhere.*26, 27, 28 These include inhibition of hepatic glucose production, promotion of glucose uptake in isolated muscle, increase of fatty Betulinic Acid mg synthesis, stimulation of lipoprotein lipase activity and reduction Betulinic Acid mg of hepatic insulin extraction.*26, 27, 28 These actions combined, and given that GIP stimulates insulin secretion only under hyperglycaemic conditions, highlight GIP as a potential therapeutic agent for type 2 diabetes. The glucose-dependent mode of action of incretin hormones is not offered by other insulin-releasing drugs, such as the sulphonylureas or meglitinides, and therefore provides a key advantage in minimising unwanted episodes of hypoglycaemia.12, 29
    GIP and type 2 diabetes The incretin effect is severely reduced in patients with type 2 diabetes. Current opinion would suggest that two distinct mechanisms underlie this phenomenon. Firstly, the postprandial secretion of GLP-1 is decreased in type 2 diabetes. Secondly, there is a resistance to the insulinotropic action of native GIP in type 2 diabetic patients. Whilst the former is accepted in the scientific community, the importance attached to the latter is a more contentious issue. Although several early studies showed blunted early insulin responses to GIP infusion in type 2 diabetes (with conflicting degrees of beta-cell resistance, however), these employed GIP infusion rates that produced physiological rather than therapeutic concentrations. The once-postulated specific defect in GIP stimulation of insulin secretion in type 2 diabetic patients is now recognised to extend to several factors, including the key beta-cell regulator glucose and GLP-1.33, 34 In addition, the reported decreased insulinotropic effect of GIP in patients with type 2 diabetes was shown to be much less evident following pulse administration as opposed to intravenous infusion. GIP has also been shown to effectively potentiate the hypoglycaemic effect of glibenclamide and to directly reduce hepatic insulin extraction. To further compound the notion of a genetic component to the reduced effectiveness of GIP in the pathogenesis of type 2 diabetes, recent observations in first-degree relatives and women with gestational diabetes, both with increased risk of developing type 2 diabetes, revealed no defect in GIP secretion or action.38, 39 More recent studies have shown that the reduction of hyperglycaemia with insulin in type 2 diabetic subjects restores GIP-stimulated insulin secretion. Furthermore, the administration of sulphonylurea to induce KATP channel closure has been shown to ameliorate the impaired insulinotropic effect of GIP in patients with type 2 diabetes. This, combined with various observations in animal models of diabetes, indicates that desensitisation of GIP-R is not caused by an inherent or genetic defect but is a consequence of hyperglycaemia on KATP channel activity per se.40, 41, 42 Various studies indicate that decreased GIP-R expression might also be involved.43, 44 Overall, this work suggests that the augmentation of GIP action is an appropriate goal for the treatment of type 2 diabetes, especially in combination with other glucose-lowering drugs and using engineered dipeptidyl peptidase IV (DPP IV)-resistant GIP analogues with enhanced potency.*26, 27, 28
    DPP IV and GIP metabolism GIP is secreted particularly in response to carbohydrate- and lipid-rich meals, typically fasting GIP concentrations are in the region of 10pmoll−1 with peaks occurring (70–150pmoll−1) approximately 60min after meal ingestion. Following release into the circulation, GIP undergoes rapid degradation by DPP IV where it cleaves the first two amino acids, Tyr1–Ala2 of GIP, resulting in the truncated metabolite GIP(3–42).. The truncation of GIP(1–42) to GIP(3–42) eliminates insulinotropic activity, but only reduces receptor affinity fourfold. The importance of DPP IV in curtailing the insulinotropic action of GIP has been shown in animal studies using selective DPP IV inhibitors.48, 49 Furthermore, mice with a targeted deletion of the DPP IV gene show enhanced insulin secretion and glucose tolerance. However, DPP IV is a complex and widely expressed enzyme which can be found either membrane bound or solubilised in blood. It has numerous other roles, such as activation of T-lymphocytes and cleavage of numerous physiological peptides, including GLP-1 and peptide YY (PYY) as detailed elsewhere.51, 52 The physiological inactivation of GIP by DPP IV has been a major obstacle to its clinical implementation and is overcome by two new pharmacological strategies, namely: (i) the development of specific DPP IV inhibitors and (ii) the engineering of DPP IV-resistant forms.