Glucagon and glucagon receptor in PET
Glucagon is a 29-amino acid neuropeptide hormone that belongs to the secretin family. Glucagon and insulin regulate glucose and amino acid metabolism. Preproglucagon gene transcription is seen in α-cells in the islets of Langerhans, L-cells of intestinal mucosa, and in neurons in nucleus of solitary tract. In addition to glucagon, preproglucagon gene sequence contains coding regions for GLP-1, GLP-2, oxyntomodulin, glicentin, glicentin-related pancreatic polypeptide (GRPP), and major proglucagon fragment (MPGF). The entire amino acid sequence of glucagon is found in glicentin and oxyntomodulin (Sandoval & D'Alessio, 2015). Glucagon is processed from proglucagon, a 180-amino acid precursor, by prohormone convertase 2 (PC2, or, neuroendocrine convertase 2, NEC2) in the pancreatic α-cells. GLP-1, GLP-2, oxyntomodulin and glicentin are processed from proglucagon by PC1 (or NEC1) in intestine and brain (Habegger et al., 2010).
From the pancreatic islets, glucagon-containing blood goes to pancreatic acinar cells (insulo-acinar portal system), enabling the hormones released in the islet to directly affect the exocrine system through a second capillary system. Blood is then drained from pancreas and other abdominal visceral organs and gastrointestinal tract via the portal vein into the liver, enabling glucagon to rapidly counteract the functions of insulin by inhibiting hepatic glycogen synthesis, stimulating glycogenolysis, enhancing gluconeogenesis, and increasing glucose concentration in the blood (Authier & Desbuquois, 2008; Sandoval & D'Alessio, 2015; Wewer Albrechtsen et al., 2016). For many of functions of glucagon, glucagon/insulin ratio in the plasma seems to be more important than the concentration of glucagon (Bankir et al., 2018). In addition to pancreas, glucagon is also secreted from elsewhere, probably gut, because oral nutrient administration elicits glucagon secretion in totally pancreatectomised patients while intravenous glucose administration does not (Wewer Albrechtsen et al., 2016; Lund & Knop, 2019). Most of the glucagon is removed from blood by the liver and kidneys, mainly through glucagon receptor mediated endocytosis. In addition, glucagon is degraded enzymatically in the vasculature and cell membranes. Half-life of circulating glucagon is 7 min in humans (Sandoval & D'Alessio, 2015).
In pancreatic islets, β- and δ-cells release factors that inhibit glucagon secretion (Gylfe & Gilon, 2014). Insulin inhibits glucagon secretion, but glucagon stimulates insulin secretion. Adrenaline inhibits insulin secretion and stimulates glucagon secretion. Glucagon release is increased during exercise and prolonged fasting, promoting lipolysis and oxidation of lipids. The morning fast period is a basal condition for glucagon levels (Bankir et al., 2018). After a meal, small intestine and proximal colon release GLP-1, which, when bound to pancreatic GLP-1R, inhibits the release of glucagon. Protein-rich meal, and GIP, enhances glucagon secretion. Pancreatic α-cells can directly respond to decreasing blood concentration of glucose or increasing concentration of amino acids by secreting glucagon. Amino acids stimulate secretion of both glucagon and insulin. Acutely dangerous hypoglycaemia may develop if glucagon secretion is not sufficiently increased in response to low glucose level. In type 2 diabetes glucagon release is not suppressed, contributing to postbrandial hyperglycemia (Borghi et al., 1984; Shah et al., 2002; Geary, 2017).
The activity of glucagon is mediated by glucagon receptor (GCGR), which is a 62 kDa protein, belonging to the class B GPCRs. Glucagon receptor, and glucagon itself, are highly conserved across mammals. GCGRs are abundant in hepatocytes and kidneys, but are also found in the heart, adipose tissue, central nervous system, adrenal glands, ovaries, and spleen, and in pancreatic islets, including the β-cells. Exposure to chronically elevated glucagon decreases GCGR expression in the liver and pancreatic islets, while increased glucose level increases expression of the receptor. (Authier & Desbuquois, 2008; Sandoval & D'Alessio, 2015.
In the liver, activation of GCGR activates adenylate cyclase, leading to increased concentration of cAMP. While cAMP usually functions as an intracellular second messenger, in the case of hepatocytes most of produced cAMP is released into the circulation.
Glucagon receptor antagonists and agonists are being studied for treatment of T2D. Several dual GCGR/GLP-1R agonists have been developed: pancreatic GLP-1R activation decreases blood glucose levels, and hepatic GCGR activation increases energy expenditure and induces weight loss.
[68Ga]Ga-DO3A-S01-GCG is a promising PET tracer targeting the glucagon receptor. Preclinical studies show that binding is specific, and can not be blocked by GLP-1R agonist (Velikyan et al., 2019).
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Updated at: 2019-03-04
Created at: 2019-02-20
Written by: Vesa Oikonen