Physiology, Glucagon

Article Author:
Senthil Venugopal
Article Editor:
Ishwarlal Jialal
Updated:
1/13/2019 11:10:51 PM
PubMed Link:
Physiology, Glucagon

Introduction

The recognition of glucagon as a hormone followed the pioneering work of Unger reporting on its quantitation by radioimmunoassay.[1] Unger first reported the glycogenolytic, gluconeogenic and ketogenic effects of glucagon in dogs.[2] Glucagon, manufactured by the alpha cells in the pancreatic islets, stimulates glucose production through glycogenolysis and gluconeogenesis. The proglucagon gene encodes it, and the proglucagon peptide is processed by prohormone convertase-2 (PC2) to produce the 29-amino acid mature peptide. Enhancement of glucagon transcription is by amino acids and cyclic AMP in the pancreas and intestinal cells, and Wnt signaling in the intestine.[3] Elevated plasma concentrations of glucagon and hyperglucagonemia contribute to the hyperglycemia of diabetes. Hyperglucagonemia also occurs in other clinical conditions such as non-alcoholic fatty liver disease, glucagon-producing tumors and after gastric bypass surgery.[4] In this brief review, we cover the relevant biochemistry, physiology, measurement and clinical relevance of glucagon.

Issues of Concern

Glucagon and insulin work together to maintain euglycemia and glucose transport to the tissues. The blood glucose levels determine whether glucagon or insulin is activated or inhibited. Low plasma glucose stimulates glucagon secretion which in turn promotes hepatic gluconeogenesis and glycogenolysis to normalize plasma glucose levels. Excessive glucagon might result from a tumor in the tail or the body of the pancreas, potentially leading to the glucagonoma syndrome, comprising weight loss, necrolytic migratory erythema (NME), diabetes, and mucosal abnormalities including stomatitis, cheilitis, and glossitis.[5]

Cellular

Glucagon plays a role in hepatic glucose production after blocking endogenous glucagon and insulin production.[6] Proglucagon is cleaved by prohormone convertase 2 (PC2) to form fully processed bioactive glucagon and gets secreted from the pancreatic alpha cells in response to hypoglycemia or increasing concentrations of amino acids. Its secretion is enhanced by oxyntomodulin and glucose-dependent insulinotropic polypeptide (GIP), while inhibited by glucagon-like peptide-1 (GLP-1).[7] The autonomous nervous system may also play an important role in glucagon secretion. Paracrine factors were shown to regulate glucagon production from pancreatic alpha cells. In the islets, GABA, somatostatin, and insulin inhibit glucagon secretion.[8][9][10] Increasing glucose levels also inhibit glucagon secretion while hypoglycemia stimulates glucagon and other counter-regulatory hormones, such as epinephrine and cortisol, to correct the hypoglycemia and avoid its serious sequelae. The incretin hormone GLP-1 also inhibits glucagon secretion. Gluconeogenic amino acids such as alanine stimulate glucagon secretion. Although it remains unknown whether glucagon feedback to alpha cells is in an autocrine manner, according to recent studies, alpha cells do not express glucagon receptor (GCGR), and it may thus regulate its own secretion by activating insulin.[11]

Organ Systems Involved

Similar to insulin, glucagon secretion is tightly regulated depending on blood glucose levels. Hypoglycemia stimulates the pancreatic alpha cells to secrete glucagon. In the pancreas, the prohormone proprotein convertase 2 processes proglucagon (160 amino acids (aa)) to the glicentin-related pancreatic polypeptide (GRPP, 1–30 aa), glucagon (33–61 aa), intervening peptide-1 (IP-1) and major proglucagon fragment (72–158 aa). In the intestine, proglucagon is processed by PC1/3 activity to glicentin (1–69 aa), GLP-1 (78–107 aa), IP-2 and GLP-2 (152–158 aa). Glicentin is further cleaved into GRPP (1–30 aa) and oxyntomodulin (33–69 aa). In the intestine, glucagon with N-terminally elongated form (1–61 aa) also forms. Hence, the entire amino acid sequence of proglucagon is also present in oxyntomodulin and glicentin, which the intestinal L-cells secrete in response to food intake. Reports exist of extra-pancreatic glucagon secretion after pancreatectomy in humans and dogs.[12][13] Also, a molecule with a molecular weight similar to that of pancreatic glucagon has reported production in the gastrointestinal tract of several species.[14]

Function

The primary function of glucagon is to increase the hepatic glucose output, thereby restoring euglycemia. Administration of glucagon increases glucose levels via gluconeogenesis and glycogenolysis in fasted or fed animals and in humans.[3] Incubation of glucagon-induced glucose output from primary hepatocytes in culture. Inhibition of glucagon signaling leads to decreased plasma glucose concentrations.[15]

Mechanism

Glucagon binds to its membrane-bound receptor, a seven-pass transmembrane G-protein-coupled receptor. Glucagon receptor gene (GCGR) encodes the receptor and has an abundant expression in liver and kidney and less expression in the heart, adipocytes, lymphoblasts, spleen, pancreas, brain, retina, adrenal gland and the gastrointestinal tract.[16] Upon glucagon binding, the receptor stimulates adenylate cyclase, which induces cAMP levels and the activation of protein kinase A (PKA) pathway. Other studies also have shown that glucagon could activate other pathways involving 5’-AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK).

Glucagon signaling while promoting glycogenolysis, it inhibits glycogen synthesis in the liver. Upon glucagon stimulation, activated PKA phosphorylates glycogen phosphorylase kinase, which phosphorylates serine-14 residue of glycogen phosphorylase. This activated glycogen phosphorylase phosphorylates glycogen, resulting in increased glycogenolysis and the production of glucose 6 phosphate. Glucose 6 phosphate is converted to glucose by glucose 6 phosphatase, resulting in increased glucose levels in plasma. Glucagon modulated glucose-6-phosphatase activity via PKA-dependent PGC-1 activation.

In addition to promoting glycogenolysis, glucagon also inhibits glycogenesis in the liver at the same time. Glycogen synthase is a significant regulatory enzyme in the glycogenesis pathway. This enzyme catalyzes the transfer of a glucosyl residue from UDP-glucose to a nonreducing end of the branched glycogen molecule. Glucagon induces phosphorylation of glycogen synthase and thereby inhibits glycogen synthase activity in the liver. Phosphorylation of glycogen synthase by multiple kinases including PKA and other serine/threonine kinases leading to a graded inactivation, which leads to decreased glycogen synthesis and therefore increases the glucose output to the blood.[17][18] Glucagon-induced phosphoenolpyruvate carboxykinase (PEPCK) is the enzyme in a rate-limiting step in the hepatic gluconeogenesis. PKA activation leads to the activation of CREB, leading to the increased synthesis of PGC-1 protein. Both PGC-1 and HNF-4 together increase the transcription of the PEPCK gene. Glucagon-induced glucose-6-phosphatase. In addition to the above functions, glucagon inhibits glycolysis by inhibiting phosphofructokinase-1.

Glucagon also stimulates lipolysis and ketogenesis, and the ratio of glucagon to insulin perceived by the liver is a critical signal for the liver to convert fatty acids to ketone bodies as in diabetic hyperglycemic coma.[19]

Related Testing

Glucagon has a half-life of 3-6 minutes. Hence, the sample collection should be in chilled tubes with a proteolytic enzyme inhibitor. In adults and children, the normal levels in plasma are less than 120 pg/ml, while in cold blood the levels can go as high as 215 pg/ml. Sample collection should be in chilled ethylenediaminetetraacetate  (EDTA) or dipotassium EDTA plus aprotinin tubes after overnight fasting. Storage pending the taking of measurements should be at -70C after separation from the cells.

In patients with kidney failure, there may be increased levels of  N-terminally elongated proglucagon (1-61 aa); thus, glucagon measurements in subjects with impaired kidney function may lead to an overestimation of endogenous glucagon secretion. The stability of the glucagon molecule and the sensitivity of the assay must are considerations when measuring glucagon levels.

Pathophysiology

In patients with type 2 diabetes mellitus (T2DM), elevated plasma glucagon levels are observed in the fasting state and defective suppression in the postprandial state, resulting in high glucagon levels in the blood.[20] This defective state has led to the bi-hormonal hypothesis and the importance of glucagon in the pathogenesis of diabetes.

Hyperglucagonemia has been observed in patients with pancreatic neuroendocrine tumors.[21] Hyperglucagonemia due to N-terminally elongated forms of the glucagon molecule may be found in patients with renal dysfunction.[22]

Clinical Significance

Although the measurement of plasma glucagon levels is not recommended in the diagnosis and management of diabetes, the role played by glucagon in the pathogenesis of diabetes, particularly T2DM, has been confirmed by drugs that modulate the incretin axis such as GLP-1 receptor agonists that inhibit glucagon and decrease hyperglycemia and the DPP4 inhibitors that increase endogenous GLP-1 and hence inhibit glucagon and hyperglycemia.


References

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