Glucagon plays an important role in amino acid metabolism, and experimental variation of circulating glucagon across the physio logical range causes inverse changes of plasma concentrations of amino acids in humans. This effect is most pronounced for glucogenic amino acids, and is associated with increased urinary excretion of nitrogen and enhanced glucose production, supporting a link between glucagon- induced amino acid catabolism and gluconeogenesis. In mice, genetic deletion of the GCGR, or its antagonism with a blocking antibody, causes downregulation of genes encoding proteins involved in amino acid catabolism and the urea cycle, and an increase in circulating amino acids. Acute blockade of the GCGR caused an almost immediate increase in circulating glucagon, and induced α- cell hyperplasia within several days. A profound increase in islet α cells along with hyperaminoacidaemia and hyperglucagonaemia are cardinal features of mice with genetic deletion of GCGR; each of these abnormalities is at least partially corrected with liver- specific re- expression of GCGR. Considered together, findings from studies of humans and mice suggest a physiological connection between the liver and α cell mediated by amino acids.

Understanding of the liver–α- cell axis has become an area of active investigation. Recently two groups independently reported the importance of the amino acid transporter Slc38a5 for mediating amino acid–induced hyperplasia of α cells. This specific transporter actively transports several amino acids into α cells, including glutamine, alanine, and glycine, three prevalent species that increase markedly with interruption of glucagon signalling to the liver. Expression of Slc38a5 is increased with GCGR blockade or deletion and is necessary for the full manifestation of α- cell hyperplasia in these settings. l- glutamine seems to be the key amino acid driving α- cell hyperplasia, a process that is dependent on mechanistic target of rapamycin (mTOR) signalling, a fundamental pathway connecting energy and amino acid availability with cell growth.

The liver–α- cell axis may be involved in the pathogenesis of metabolic liver disease and type 2 diabetes. Individuals with obesity and greater hepatic steatosis than lean individuals had hyperaminoacidaemia, hyperglucagonaemia, and downregulation of hepatic expression of genes involved in amino acid transport and metabolism. When given infusions of exogenous glucagon, circulating amino acids were reduced in lean individuals but not those with obesity. Based on these results, as well as supporting findings that people with non- alcoholic fatty liver disease (NAFLD) have increased plasma levels of glucagon and amino acids, it has been proposed that impairment of the liver–α- cell axis may link hepatic steatosis and dysregulated glucose metabolism.

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مواضيع ذات صلة

Glucagon actions in the liver: glucose and lipid metabolism

Regulation of α- cell secretion

Regulation of insulin secretion by non- nutrients

Regulation of insulin secretion

Islet structure and function

الجلوكاجون Glucagon

هرمون الانسولين

المرض السكري (Diabetes Mellitus)

الغدة البنكرياسيةThe Pancreas