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    • br Are incretins the only mediators of

    2021-05-13


    Are incretins the only mediators of the anti-hyperglycaemic effects of DPP-4 inhibitors? Even though both GLP-1 and GIP were identified as substrates for DPP-4 early on [17], [19], [20], [22], and DPP-4 inhibition in vivo raises levels of the intact endogenous forms of both of them [43], [44], from the outset, the glucose-lowering effects of DPP-4 inhibitors in patients with T2DM were believed to be mainly due to the effects of GLP-1. This was largely because the insulinotropic effects of GIP in these individuals were well-known to be impaired [45]. However, in mice, both incretins seem to be involved in mediating the anti-hyperglycaemic effects of DPP-4 inhibition, since the glucose-lowering effects of valine-pyrrolidide were still evident in mice with a genetic Afatinib dimaleate of either the GLP-1 or the GIP receptor, but were lost when both receptors were deleted [46]. More recent evidence indicates that also in humans, the antidiabetic effects of DPP-4 inhibitors must involve more than enhancing the actions of only GLP-1. Thus, around half of the glucose-lowering effects of DPP-4 inhibition with sitagliptin [47] or vildagliptin [48] are still evident when endogenous GLP-1 signalling is blocked using the GLP-1 receptor antagonist, exendin 9–39, pointing towards the involvement of additional substrate(s). GIP could still play a role, because even though its actions are impaired in T2DM, they can be, at least partially, restored after a period of strict glycaemic control. Thus, its insulinotropic effects are improved following 4 weeks of near-normalisation of glucose levels using insulin [49], while the reduction in HbA1c levels following a 12 week intervention with sitagliptin was also shown to be associated with a greater insulin-stimulating effect of GIP [50]. These results are compatible with the finding that in rats, hyperglycaemia is associated with down-regulation of incretin hormone receptor expression and impairment in their insulinotropic actions, which are reversed if normoglycaemia is restored [51], [52]. In humans also, the induction of insulin resistance and glucose intolerance results in an impaired incretin effect [53], [54] and a reduction in the insulinotropic effects of GLP-1 and GIP [55]. Accordingly, while GLP-1 may be the primary mediator of the effects of DPP-4 inhibition during the initial period, it is reasonable to speculate that once glycaemic control starts to be improved and glucotoxicity is lessened, the effects of GIP may gradually improve and begin to contribute to the actions of DPP-4 inhibitors [50], but the relative contribution of GIP and whether additional mediators are also involved is still unclear. Although the DPP-4 enzyme is an amino-dipeptidase with relatively strict substrate requirements, preferring a proline or alanine residue in the penultimate position at the N-terminus, numerous other substrates of DPP-4 have been identified [56], [57]. Many of these are peptide hormones, the majority of which have only been identified as substrates from in vitro studies, often using high, pharmacological peptide concentrations, and it is unclear how many are truly physiological substrates, since the involvement of DPP-4 in the degradation of the endogenous peptides in vivo has not been demonstrated for most of them. Moreover, a number of other factors should be considered in the context of whether other potential factors might be involved in mediating the effects of DPP-4 inhibitors. These include (i) whether DPP-4 is a key enzyme in their metabolism, (ii) whether alternative routes of clearance for them also exist (i.e. will DPP-4 inhibition affect plasma levels or will other enzymes take over if DPP-4 activity is blocked?), and (iii) whether cleavage by DPP-4 actually has any effect on their biological activity. Nonetheless, these factors (peptide hormones, neuropeptides, chemokines, cytokines – see [56], [57]), identified as biochemical DPP-4 substrates, influence a number of physiological processes, with some of them regulating metabolic processes. Although the weight of data (Table 1) is not as strong as for the incretin hormones, there is evidence to suggest that levels of some of them, at least, might be influenced by DPP-4 activity, supporting that some of them might also be physiological substrates, and could possibly contribute to some of the clinical effect of DPP-4 inhibitors (Fig. 1).