Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • The findings in this study may represent an example of

    2021-09-23

    The findings in this study may represent an example of a more general phenomenon, namely that the exquisite specificity of the G protein-coupled receptors that mediate the physiological actions of the SC75741 receptor family hormones in mammals may have arisen relatively late in evolution. In non-mammalian vertebrates, the receptors display a lesser degree of selectivity for the peptide ligand and the hormones may activate multiple receptors. While zfGIP may not activate the human glucagon receptor, it has been shown that it will activate a putative glucagon receptor from the zebrafish [13]. Exendin-4 from the reptile Heloderma suspectum, although it shows only 53% sequence identity with human GLP-1, will potently activate the human GLP-1 receptor [2]. Previous studies both in vitro [37] and in vivo [38] have demonstrated that glucagon from the dogfish Scyliorhinus canicula (Elasmobranchii) acts as dual agonist at mammalian glucagon and GLP-1 receptors. Similarly, a receptor has been identified in the goldfish Carassius auratus (Teleostei) that is activated by both goldfish GLP-1 and glucagon and by human GLP-1 and glucagon [39].
    Acknowledgements The authors wish to thank Professor Bernard Thorens (University of Lausanne, Switzerland) for GLP-1 receptor-transfected CHL cells, Professor Cecilia Unson (The Rockefeller University, USA) for glucagon receptor transfected HEK293cells, and Dr Jaqueline Naylor (Cardiovascular and Metabolic Disease, MedImmune, Cambridge, UK) for CRISPR/Cas9-engineered INS-1 cells. The study was supported by the Northern Ireland Department of Education and Learning (DEL), the SAAD Trading and Contracting Company, and Ulster University Strategic Funding.
    Introduction Structurally optimized analogs of glucagon-like peptide 1 (GLP-1) have provided profound therapeutic improvements in management of glucose and body weight to lessen adverse cardiovascular events in T2D patients [1], [2]. In contrast, GIP, despite its role as a physiological incretin and partner with GLP-1, has failed to advance as a therapeutic agent. Notably the insulinotropic effect of GIP receptor agonism is diminished in modest hyperglycemia [3] but purportedly reversed with improved glycemic control [4]. This latter observation served as a catalyst to integrating coagonism at GIP and GLP-1 receptors (GIPR and GLP-1R, respectively) as a strategy in which the latter activity primes the former to achieve a more optimal reversal of the metabolic syndrome [4]. Two different peptides, NNC0090-2746 (MAR709) and LY3298176 (Tirzepatide), with high potency dual incretin agonism have advanced to multi-dose clinical studies. The preclinical and clinical results have demonstrated improvements in glycemic control and body weight that exceeds what is achieved with comparable dosing of benchmark GLP-1R specific agonists [5], [6], [7], [8]. Despite these beneficial clinical results of combinatorial therapy, the pharmacological effect of GIP alone to lower body weight has not been adequately addressed. The role of GIP to regulate systemic metabolism beyond its direct effect at the endocrine pancreas remains controversial and confusing, particularly as it relates to GIP action to promote gain in fat mass (reviewed in [9]). Mouse models of diminished GIP activity, including GIPR knockout mice [10], immunization against GIP [11], [12], enteroendocrine K cell ablation [13], and chemical antagonism [14], [15] have shown reduced or delayed body weight gain in rodents exposed to obesogenic diets. Furthermore, elevated levels of GIP are associated with visceral fat deposition [16], and acute GIP infusion increased adipose tissue vasoactivity and adipogenesis in humans [17]. These rodent loss-of-function studies and experimental human physiology results have fostered beliefs that GIPR antagonism can pharmacologically improve body weight upon chronic administration. On the contrary, there is experimental evidence that amplified GIP action is also beneficial to body weight, including transgenic overexpression of GIP [18], single [19] and combinatorial preclinical pharmacology [5], [20], [21], [22], and genome-wide association studies [23]. However, it has yet to be definitively shown whether chronic pharmacological manipulation of the GIPR system in either direction is beneficial or detrimental for body weight in obese mice, which is instrumental to study the molecular underpinnings of GIP-mediated pharmacological effects. At a minimum, it has been shown that GIPR mono-agonists improve glucose metabolism and clearly do not promote further weight gain in mice with established obesity [5], [21], [24], [25], [26].