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Hormones of the Pancreas
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Glucagon is a 29-amino-acid polypeptide (molecular weight, 3485 Da), which antagonizes the actions of insulin, and is synthesized as proglucagon in α-cells of the islets. Proglucagon is processed to glucagon in the pancreas. Glucagon has a plasma half-life of 5–10 minutes and is degraded by the liver. Proglucagon is processed to GLP-1 in intestinal cells in response to a high concentration of glucose in the intestinal lumen. GLP-1 is an incretin because it enhances the release of insulin from β cells in response to an increase in blood glucose.
Mahvash Disease
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Glucagon (abbreviated from glucose agonist) is a 29-aa, 3.485 kDa polypeptide generated from the cleavage of proglucagon by proprotein convertase 2 in pancreatic islet α cells. Alternate source of proglucagon comes from intestinal L cells, including glicentin, GLP-1 (an incretin), IP-2, and GLP-2 (promotes intestinal growth). While hypoglycemic conditions induce α-cell secretion of glucagon, hyperglycemic conditions increase β-cell release of insulin.
The Enteroinsular Axis
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Varun Pathak, Nigel Irwin, Peter R. Flatt
OXM is a 37-amino acid peptide co-secreted with GLP-1 from enteroendocrine L-cells in response to feeding [102]. Similar to GLP-1, it is a PC1/3-derived, post-translational product of the proglucagon gene [12]. Interestingly, the amino acid sequence of OXM comprises the full sequence of glucagon with a C terminal octa-peptide extension [103]. To date, no specific OXM receptor(s) has been identified, and biological effects are attributed to interactions with GLP-1 and glucagon receptors [104]. As such, studies in rodents suggest that glucagon receptor activation by OXM increases energy expenditure, leading to reduced fat mass and improved metabolic control [104]. Thus, although T2DM is characterized by hyperglucagonemia [105], and glucagon antagonism has been suggested as a possible therapeutic avenue in this regard [106,107], centrally mediated actions of glucagon may actually help to improve metabolic control through modulation of energy balance [108]. In addition, simultaneous activation of GLP-1 receptors by OXM to induce well-characterized insulinotropic and body weight–lowering effects add to these beneficial anti-obesity and -diabetic actions [15]. Accordingly, rodent and clinical studies with OXM have demonstrated key advantages, such as reduced food intake and gastric emptying, as well as increased energy expenditure, with an overall lowering of body weight [3,109,110; Table 3.1; Figure 3.1].
GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2023
Ryan A. Lafferty, Peter R. Flatt, Nigel Irwin
GLP-1 is a gut-derived, 29 amino acid residue hormone, released post-prandially from intestinal L-cells, particularly following meals rich in fat and carbohydrate [19,20]. GLP-1 secretion is biphasic, with an early phase occurring 10–15 min after meal ingestion and a second, more prolonged, phase occurring 30–60 min post meal [21]. The primary biologically active form of the peptide is GLP-1(7-36)-amide, generated by tissue-specific post-translational processing of the proglucagon gene by prohormone convertase enzymes [22]. Upon binding to the GLP-1 receptor (GLP-1 R) on pancreatic beta-cells, GLP-1 promotes glucose-dependent insulin secretion via stimulation of intracellular cAMP-mediated events and also encourages glucose-induced biosynthesis of insulin, resulting in replenishment of insulin stores within beta cells [21, 23; Figure 1]. Furthermore, there is evidence to suggest that GLP-1 R activation enhances pancreatic beta-cell growth and survival, at least in rodents [24, 25; Figure 1]. In addition, GLP-1 is also known to suppress glucagon secretion, with some debate as to whether this is related to a direct effect on alpha cells or mediated indirectly through increased somatostatin secretion from islet delta-cells [26]. As a result of these combined positive effects on glucose modulating islet-derived hormones, sustained activation of GLP-1 R has seen successful clinical application in the management of T2DM.
Misrouting of glucagon and stathmin-2 towards lysosomal system of α-cells in glucagon hypersecretion of diabetes
Published in Islets, 2022
Farzad Asadi, Savita Dhanvantari
In the present study, we observed that the relationship between glucagon and Stmn2 was disrupted, indicated by increased glucagon and decreased Stmn2 cell content. An altered balance between glucagon and Stmn2 has also been reported in islets from patients with diabetes; α-cell RNA sequencing analysis showed a higher Gcg: Stmn2 gene expression ratio in islets from people with type 2 diabetes compared to healthy subjects.36 Proglucagon gene transcription, glucagon synthesis and secretion are all highly responsive to prevailing glucose concentrations,16,37–39 reflecting the hyperglucagonemic state of diabetes. However, it appears that Stmn2 mRNA and protein levels may not be responsive to glucose concentrations. A BLAST search of the promoter region of the Stmn2 gene (GeneBank: AH000817; mouse Stmn2 complete cds) against the sequence of the glucose response element in the mouse glucagon receptor gene40 (GeneBank: AF229079.1; mouse Gcgr complete cds), did not reveal any sequence homology. Thus, the enhanced secretion of Stmn2 in diabetes may reflect an elevation in exocytotic activity in hyperglucagonemia,38 and not increases in mRNA or protein synthesis.
Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1
Published in Islets, 2021
Scott A. Campbell, Janyne Johnson, Peter E. Light
The proglucagon gene GCG is expressed in pancreatic alpha cells, intestinal L-cells, and neurons in the nucleus tractus solitarus.1 Differential processing of proglucagon by Prohormone Convertase 2 (PC2, encoded by the PCSK2 gene) yields glucagon, whereas PC1/3 (encoded by the PCSK1 gene) yields GLP-1 and GLP-2.2,3 It is generally accepted that glucagon production and secretion are largely restricted to the alpha cells within pancreatic islets, whereas GLP-1 production and secretion are confined to the enteroendocrine L-cells and the central nervous system. However, as early as 1985, GLP-1 expression was predicted in both the gastrointestinal tract and pancreas.4 Moreover, GLP-1 expression was documented in human pancreatic extracts and proglucagon-producing pancreatic tumors,5 and early HPLC analysis of human and porcine alpha cell extracts identified glucagon and small quantities of N-terminally extended GLP-1.6 Subsequent papers have identified GLP-1 in the human pancreas where it is co-packaged within the glucagon secretory granules of an alpha cell subpopulation.7–9 Conversely, recent evidence suggests that L-cells can secrete glucagon.10 This relatively unexpected pancreatic source of GLP-1 suggests a potential paracrine role for alpha cell-derived GLP-1 and suggests plasticity in the differential processing of the proglucagon peptide in both alpha cells and L-cells.