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  • In conclusion enhanced glucagon action of

    2022-06-29

    In conclusion, enhanced glucagon action of the beta cell results in improved beta cell function after glucose stimulation, but simultaneously dissociated responses to both glucose-dependent and non-glucose secretagogues evolve. This shows that the glucagon receptor is complexly involved in beta cell function and therefore that a potential overexpression of the glucagon receptor in T2D may have complex influences involving both augmented beta-cell secretion and impaired beta-cell function [9]. There is thus dissociation in secretory beta-cell effects by glucose versus GLP-1 when glucagon receptors are overexpressed in beta Cholesterol which may have dissociated consequences in the fine tuning of beta cell function during fasting, after meal ingestion and after activation of the autonomic nerves.
    Acknowledgements The authors would like to acknowledge Lena Kvist, Lillian Bengtsson, Kristina Andersson and Catarina Blennow of Lund University for their excellent technical assistance. We would also like to acknowledge Erica Nishimura of Novo Nordisk (Målöv, Denmark) for provision of the RIP-Gcgr mouse line. B.A.O. performed data analysis and wrote the manuscript. M.S.W. performed experimental work and data analysis. B.A. performed data analysis, study design and contributed to the writing of the manuscript. B.A. is the guarantor of this work and as such has had access to the full access to all data throughout the study. This work was carried out with grant funding from the Swedish Research Council, Region Skåne/ALF and Lund University Medical Faculty. The authors have nothing to disclose.
    Proglucagon and secretin-like peptides The proglucagon (GCG) gene encodes hormones that have essential and differing roles in mammalian physiology. The three major hormones encoded by proglucagon are glucagon and the two glucagon-like peptides glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) (Kieffer and Habener, 1999, Drucker, 2005). Glucagon is the counter-regulatory hormone to insulin and induces glucose production by the liver when blood glucose levels are low (Jiang and Zhang, 2003, Ramnanan et al., 2011). GLP-1 is a major incretin hormone that potentiates insulin release by pancreatic islet beta cells in response to eating a meal (Meier and Nauck, 2005, Holst, 2007, Baggio and Drucker, 2007). GLP-2 has important roles in maintaining intestinal function (Drucker, 2001, Baggio and Drucker, 2007). The major actions of these hormones are non-overlapping and demonstrate the diverging functions of related sequences (Kieffer and Habener, 1999, Drucker, 2005). In addition to these major physiological functions, these three glucagon-like hormones produced from proglucagon have additional important activities, many of which are involved in feeding behavior (Alvarez et al., 1996, Lovshin et al., 2004, Baggio and Drucker, 2007). The processing of proglucagon to produce the glucagon-like hormones also yields additional peptides, e.g., intervening peptide-1 (IP1), which may have additional physiological functions (Kieffer and Habener, 1999, Drucker, 2005). The proglucagon-derived hormones are members of a larger family of secretin-like hormones that are found to play diverse physiological roles in many metazoan species (Hoyle, 1998, Sherwood et al., 2000, Roch et al., 2009). Mammalian genomes contain six genes that encode a total of 10 secretin-like hormones (Hoyle, 1998, Sherwood et al., 2000, Roch et al., 2009). In addition to the proglucagon (GCG) gene, which encodes three secretin-like sequences (glucagon, GLP-1 and GLP-2), the adenylate cyclase activating peptide (ADCYAP) and vasoactive intestinal peptide (VIP) genes each encode two secretin-like sequences. ADCYAP encodes the hormones PACAP (pituitary adenylate cyclase activating protein) and PACAP-related peptide (PRP; sometimes called growth hormone releasing hormone-like peptide, GHRH-LP) while VIP encodes VIP and peptide histidine methionine (PHM) or peptide histidine isoleucine (PHI) (depending upon whether last amino acid of the hormone in the species is methionine or isoleucine). The three remaining human genes each encode a single secretin-like sequence, and they are the genes for secretin (SCT), growth hormone releasing hormone (GHRH) and glucose-dependent insulinotropic peptide (GIP). Additional secretin-like sequences have been identified in some vertebrate species including the exendins (Hoyle, 1998), which were first identified in the reptile Gila monster and relatives (Heloderma suspectum and Heloderma horridum) (Raufman, 1996). Recently putative orthologs of the gene encoding exendin have been identified in other vertebrates, including other reptiles, birds, amphibians and fish, but not in mammals (Irwin and Prentice, 2011, Irwin, 2012, Wang et al., 2012, Park et al., 2013). This gene has also been called glucagon-like (Gcgl) (Wang et al., 2012) and glucagon-related peptide (Gcrp) (Park et al., 2013).