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    • Given the actions of GIP

    2022-01-14

    Given the actions of GIP analogues administered as a single dose to ob/ob mice, studies were performed to assess their ability to act in vivo as antagonists of GIP-induced insulinotropic and antihyperglycaemic actions. (Ala3)GIP, (Phe3)GIP, (Tyr3)GIP and (Pro3)GIP all counteracted the glucose-lowering actions of native GIP, being associated with correspondingly decreased insulin responses. The acute inhibitory actions were most pronounced with (Pro3)GIP, which also inhibited the insulinotropic response to glucose alone. This together with worsening of glucose tolerance by both (Pro3)GIP and (Phe3)GIP indicates a permissive action of raised endogenous GIP in ob/ob mice on insulin secretion and glucose disposal, including effects at extrapancreatic sites [44], [45], [46]. In contrast to other analogues, (Lys3)GIP and (Trp3)GIP did not modify the antihyperglycaemic actions of native GIP. This effect of (Trp3)GIP is entirely consistent with its profile of actions. However, the lack of GIP antagonism by (Lys3)GIP is surprising given its marginally enhanced resistance to DPP-IV degradation and ability to inhibit GIP-mediated cAMP production and insulin secretion in vitro. Conversely, (Ala3)GIP and (Tyr3)GIP failed to inhibit these acute cellular actions of GIP but proved to be highly effective antagonists of GIP action in ob/ob mice. A better understanding of the full range of biological effects of GIP at pancreatic and extrapancreatic sites might help explain such observations. In summary, we have reported the characteristics of a range of Glu3-substituted analogues of GIP. The analogues designed all showed poor resistance to DPP-IV degradation with only (Lys3)GIP showing moderately increased stability. Of the analogues tested, (Ala3)GIP, (Phe3)GIP and (Tyr3)GIP demonstrated significant GIP-R antagonist activity in ob/ob mice. Their inhibitory actions though were much less pronounced than the already well-established GIP-R antagonist, (Pro3)GIP, which has the additional benefit of being completely resistant to the actions of DPP-IV. By exploring further strategies to increase enzyme stability and duration of action, for example, through fatty Demethoxycurcumin derivatisation, such analogues may be developed into more powerful GIP-R antagonists. As illustrated elsewhere GIP-R antagonists may have potential for development into a new class of drugs for the long-term treatment of T2DM.
    Acknowledgments These studies were supported by University of Ulster Strategic Research Funding. The authors thank Professor Bernard Thorens (University of Lausanne, Switzerland) for kindly providing CHL cells transfected with the GIP receptor and Professor Cliff Bailey (Aston University, UK) for ob/ob mice.
    Introduction Obesity is an overwhelming health problem in many societies linked to sedentary lifestyle and consumption of energy rich high fat diets [1]. The accompanying induction of insulin resistance necessitates beta cell compensation to stave off the progression to hyperglycaemia, but when the capacity of beta cell adaptation is exceeded overt diabetes ensues. This scenario is well illustrated by the age-related progression of diabetes in relation to changes of islet morphology in C57BL/KsJ db/db mice [2]. Thus, in contrast to high fat fed wild-type controls, these animals rapidly succumb to beta cell exhaustion and destruction following short compensatory period of beta cell expansion and hyperactivity [3]. In the present study, we have used normal C57BL/6 mice together with GIPRKO mice on same genetic background to evaluate the role of glucose-dependent insulinotropic polypeptide (GIP) in islet compensation to prolonged high fat feeding. Although discovered many years ago and originally named gastric inhibitory polypeptide [4], GIP underwent a long period of being the ‘neglected incretin’ [5] overshadowed by the advent of molecular biology which led to the discovery and extensive characterisation of proglucagon-derived GLP-1 released from intestinal L-cells following cleavage of the precursor peptide by PC1/3 [6]. More recent studies have revisited GIP alongside GLP-1 [7], [8] and indicate that both peptides have important physiological effects that can be exploited for treatment of diabetes using either GLP-1 mimetics or DPPIV inhibitors which enhance the bioactivity of both incretin peptides by inhibiting their rapid in vivo degradation [8], [9].