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  • Various strategies have been pursued in the search for GIPR

    2021-10-26

    Various strategies have been pursued in the search for GIPR antagonists. Antibodies raised against both GIP(1–42) [14], [15] or the GIPR [16], [17], a small molecule antagonist [18], amino chembridge substitutions of GIP(1–42) [19], and various GIP(1–42) truncations and modifications such as e.g. Pro3(GIP) [20], [21], [22], [23], [24] have all been reported to be effective, but none have been found suitable for human studies. In 2006, we showed that the dipeptidyl peptidase-4 (DPP-4)-mediated metabolite, porcine GIP(3–42), antagonized porcine GIP(1–42)-mediated cAMP accumulation, but had no antagonistic effects in anesthetized pigs at physiological concentrations [22]. Recently, an alternative processing of the precursor protein pro-GIP was shown to occur in the α-cells of the pancreas and in a subset of the K-cells of the small intestine, which potentially leads to the secretion of GIP(1–30)NH2 [25], [26]. We combined the previously reported N-terminal truncation GIP(3–42) with this C-terminally truncated GIP(1–30)NH2 to design the GIP(3–30)NH2 (which is a naturally occurring metabolite of the DPP-4 cleaved GIP(1–30)NH2), and demonstrated that GIP(3–30)NH2 is an effective competitive antagonist on the human GIPR [27]. In fact, it was superior to other truncations of the N-terminus (GIP(2-, 4-, 5-, 6-, 7-, 8-, and 9–30)NH2) and to GIP(3–42) in terms of basic binding affinity and antagonistic properties of the human GIPR in vitro. In the present study, we determine whether GIP(3–30)NH2 is sufficiently active in the rat model system to be used for studies elucidating the role of GIP in physiology and pathophysiology.
    Materials and methods
    Results
    Discussion Our study demonstrates that rat GIP(3–30)NH2 is a high affinity competitive antagonist on the rat GIPR in vitro and in the surviving perfused rat pancreas, whereas human GIP(3–30)NH2 displays much lower affinity and a consequent lower antagonistic potency on the rat GIPR. This indicates that human GIP(3–30)NH2 is irrelevant in the rat GIP system, whereas rat GIP(3–30)NH2 can be used as a tool to study the GIP physiology when using the rat as a model system. To substantiate this, we show that rat GIP(3–30)NH2 inhibits GIP(1–42)-mediated hormone release from the intact pancreas as evident from the strong inhibition of GIP(1–42)-mediated insulin, glucagon, and somatostatin release from β-, α-, and δ-cells of the pancreas (Fig. 5). This establishes GIP(3–30)NH2 as an effective antagonist in a physiological system.
    Conflicts of interest
    Acknowledgements This work was supported by the Novo Nordisk Foundation Center for Basic Metabolic Research and the University of Copenhagen.
    Introduction Parkinson's disease is a complex and progressive neurodegenerative disorder caused by degeneration of dopaminergic neurons in the basal ganglia. Accumulation of the Lewy bodies comprising of mutated proteins, α-synuclein, parkin and synphilin-11, are the pathological hallmarks of Parkinson's disease (Chung et al., 2001). Degeneration of the dopaminergic neurons causes dopamine deficiency in the basal ganglia circuit leading to the classical symptomatology of Parkinson's disease, namely, resting state tremors, bradykinesia, rigidity, and dementia in advanced stages (Emre, 2004, Goetz, 2011). Management strategies for the disorder are predominantly dopaminergic therapies and are associated with side effects like dyskinesia and hallucinations (Cotzias et al., 1969, Rascol et al., 2000). Disease modification still remains elusive and presents as a major unmet medical need in Parkinson's disease, highlighting the need for newer therapeutic interventions (Kalia et al., 2015). One of the most consistent findings leading to the cell dysfunction and death in the neurons of the nigrostriatal pathway has been neuroinflammation and mitochondrial oxidative stress (Schapira, 2008). Other potential causes of neuronal damage are protein aggregation, protein misfolding, excitotoxicity and the loss of trophic support (Yacoubian and Standaert, 2009). Lower levels of neurotrophic factors like brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), their reduced synthesis and defective transport, has been documented in Parkinson's disease brains, raising the possibility that endogenous brain trophic factors are either not abundant or may not be able to protect the neuronal survival after disease onset (Parain et al., 1999).