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Int. J. Mol. Sci. 2018, 19(2), 575; https://doi.org/10.3390/ijms19020575

The Biased G-Protein-Coupled Receptor Agonism Bridges the Gap between the Insulin Receptor and the Metabolic Syndrome

1
Postgraduate Medical Education, Graduate Diploma and Professional Master in Medical Sciences, School of Medicine, Queen’s University, Kingston, ON K7L 3L4, Canada
2
Department of Biomedical and Molecular Science, Queen’s University, Kingston, ON K7L 3N6, Canada
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 1 February 2018 / Revised: 11 February 2018 / Accepted: 15 February 2018 / Published: 17 February 2018
(This article belongs to the Special Issue Insulin and Insulin Receptor in Diseases)
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Abstract

Insulin signaling, as mediated through the insulin receptor (IR), plays a critical role in metabolism. Aberrations in this signaling cascade lead to several pathologies, the majority of which are classified under the umbrella term “metabolic syndrome”. Although many of these pathologies are associated with insulin resistance, the exact mechanisms are not well understood. One area of current interest is the possibility of G-protein-coupled receptors (GPCRs) influencing or regulating IR signaling. This concept is particularly significant, because GPCRs have been shown to participate in cross-talk with the IR. More importantly, GPCR signaling has also been shown to preferentially regulate specific downstream signaling targets through GPCR agonist bias. A novel study recently demonstrated that this GPCR-biased agonism influences the activity of the IR without the presence of insulin. Although GPCR-IR cross-talk has previously been established, the notion that GPCRs can regulate the activation of the IR is particularly significant in relation to metabolic syndrome and other pathologies that develop as a result of alterations in IR signaling. As such, we aim to provide an overview of the physiological and pathophysiological roles of the IR within metabolic syndrome and its related pathologies, including cardiovascular health, gut microflora composition, gastrointestinal tract functioning, polycystic ovarian syndrome, pancreatic cancer, and neurodegenerative disorders. Furthermore, we propose that the GPCR-biased agonism may perhaps mediate some of the downstream signaling effects that further exacerbate these diseases for which the mechanisms are currently not well understood. View Full-Text
Keywords: insulin receptor signaling; G protein-coupled receptors; metabolic syndrome; GPCR biased agonism; angiotensin; bradykinin; gut microbiota; ghrelin; polycystic ovarian syndrome; pancreatic cancer; Alzheimer’s insulin receptor signaling; G protein-coupled receptors; metabolic syndrome; GPCR biased agonism; angiotensin; bradykinin; gut microbiota; ghrelin; polycystic ovarian syndrome; pancreatic cancer; Alzheimer’s
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Liauchonak, I.; Dawoud, F.; Riat, Y.; Qorri, B.; Sambi, M.; Jain, J.; Kalaydina, R.-V.; Mendonza, N.; Bajwa, K.; Szewczuk, M.R. The Biased G-Protein-Coupled Receptor Agonism Bridges the Gap between the Insulin Receptor and the Metabolic Syndrome. Int. J. Mol. Sci. 2018, 19, 575.

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