Glucagon action is mediated by the glucagon receptor (GCGR), a family B G- protein–coupled receptor that is highly conserved across mammalian species. Binding of glucagon to the GCGR activates adenylyl cyclase through the Gs subtype G- protein generating cAMP and activating protein kinase A (PKA) as one major mode of intracellular signalling [74]. However, the GCGR also couples to Gq, suggesting access to a wider range of downstream signalling pathways. The richest source of glucagon binding is in the liver and kidney; lesser binding occurs in heart, adipose tissue, the CNS, adrenal gland, and spleen. Consistent with the relative receptor expression, the liver and kidney play the major role in glucagon clearance, accounting for ~70% of the removal from the circulation. The half- life of glucagon in circulating plasma is relatively short: 2, 5, and 7 minutes in rats, dogs, and humans, respectively.

The first known action of glucagon, to increase hepatic glucose production, was recognized nearly 100 years ago. Subsequent work demonstrated effects of glucagon to counter hypoglycaemia and led to the general principle that it has a role opposing that of insulin to maintain plasma glucose in times of stress, fasting, or exercise. The endocrine mechanism of glucagon action is based on the effects of exogenous glucagon to increase hepatic glucose output in animals, humans, and several in vitro systems, as well as the observation that removal of circulating glucagon with a neutralizing antibody reduces blood glucose.

The cAMP/PKA signalling pathway is critical for the ability of glucagon to regulate hepatic glucose production. The downstream activation of phosphorylase kinase and its target glycogen phosphorylase activates glycogenolysis and inhibits glycogenesis. However, insulin also regulates these pathways. Thus, a long- held view is that the balance between glycogen breakdown and synthesis results from the relative insulin and glucagon effects on hepatocytes, the degree of cAMP signalling, and the level of glycogen stores. Strategies that increase glycogen synthesis relative to glycogenolysis promote glucose tolerance and are potential therapeutic targets for hyperglycaemia. GCGR signalling also regulates the flux between glucose- 6- phosphate and fructose bisphosphate via action on fructose 2,6 bisphosphatase and its inhibition of pyruvate kinase activity. The result of cAMP signalling is rapid inhibition of hepatic glucose metabolism and mobilization of stored glucose to deliver glucose to peripheral tissues.

However, another critical aspect of glucagon- induced regulation of hepatic glucose production is through enhancement of the gluconeogenic pathway, an action mediated by PKA activation of CREB and Forkhead box (FOXO1). Glucagon upregulates phos phoenolpyruvate carboxykinase (Pepck) gene transcription, which varies with the metabolic state, increasing during fasting and decreasing in response to insulin. PEPCK catalyses a key step in gluconeogenesis by converting oxaloacetate, a product of the tri carboxylic acid (TCA) cycle, into phosphoenolpyruvate. In animal models, gluconeogenesis is increased by overexpression of Pepck and conversely decreased by deletion of Pepck . Other key genes involved in glucose production, including peroxisome proliferator- activated receptor- γ coactivator 1 (PGC- 1) and glucose- 6- phosphatase (G6P), are also activated by glucagon signalling. Overall, glucagon regulates several processes within the gluconeogenic pathway that enable sustained glucose production, an effect that is enhanced in the face of limited glycogen supply. Gluconeogenesis is an energy- demanding process, requiring six moles of high- energy phosphate bonds for each mole of glucose produced, and is tightly linked to TCA cycle activity and lipid oxidation for sources of ATP. Indeed, glucagon contributes to hepatic fatty acid oxidation and ketogenesis at several metabolic steps, and elimination of glucagon action increases liver triglyceride content during fasting. A recent study has shown the centrality of the inositol triphosphate receptor 1 to mediate fatty acid mobilization and oxidation downstream of the GCGR. Taken with previous work, these new findings support a model whereby glucagon has broad effects on hepatic fuel metabolism, generating energy from lipids to support glucose production.

The effects of glucagon on hepatic glucose and lipid metabolism may also lead to pathological consequences if they are not counter balanced by appropriate levels of insulin action. Increased glucagon during extended periods of fasting or uncontrolled type 1 diabetes stimulates fatty acid oxidation and contributes to ketogenesis.

The transcription factor FOXA2 may play a central role in this process. FOXA2 controls the expression of genes involved in fatty acid oxidation and ketogenesis and is activated by both fasting and glucagon. Insulin has opposing effects on FOXA2, presenting yet another example of coordinated and inverse regulation by insulin and glucagon on glucose and lipid metabolism, with glucagon more active in the fasted state and insulin predominating during and after feeding.

Studies in humans using somatostatin to inhibit insulin and glucagon secretion, with selective replacement of one or both hormones, are consistent with the knowledge gained from pre- clinical animal studies. Glucagon is necessary to support normal fasting glucose levels and basal insulin replacement without glucagon results in hypoglycaemia. However, physio logical regulation of hepatic glucose production by glucagon occurs against a backdrop of constant but variable hepatic insulin action. At glucose levels of 4.5–5.5 mmol/l, plasma glucagon levels are relatively low and unchanging, while changes in glycaemia within this range can affect insulin secretion. This suggests that the effect of glucagon to promote glycogenolysis and initiate gluconeogenesis during fasting occurs tonically, with the absolute level of fasting blood glucose determined by variations of hepatic insulin action. At a cellular level, this can be conceived as glucagon maintaining a threshold of cAMP, or other signalling mediators, that can be modulated by changes in hepatic insulin signalling.

Although glucagon- driven hepatic glucose production includes both glycogenolysis and gluconeogenesis, these two processes follow different temporal patterns. As fasting progresses, the contribution of glycogenolysis to total hepatic glucose output wanes such that glycogenolysis contributes ~50% of liver glucose output in the postabsorptive state but less than 10% after 36 hours of fasting. In acute experiments, where glucagon action can be selectively increased, glycogenolytic effects predominate. This is because activation of gluconeogenesis by glucagon requires a supply of glucose precursors, primarily lactate, alanine, and glycerol. Increased delivery of these compounds to the liver is not directly regulated by glucagon and requires a longer period of fasting to reduce plasma insulin and disinhibit lipolysis and proteolysis. With extended periods of starvation, gluconeogenesis becomes even more tightly controlled by precursor supply as preservation of protein stores becomes essential.

The hallmark of glucagon action in homeostasis is to increase hepatic glucose production during hypoglycaemic counter- regulation (Figure 1). Glycogenolysis provides the most rapid source of glucose. However, the rise in catecholamines that also occurs with hypoglycaemia provides a supply of glucose pre cursors for gluconeogenesis as well as direct stimulation of hepatic glucose production through hepatic adrenergic receptors. Thus, there is an integrated, synergistic effect of catecholamines and hypoglycaemia to stimulate glucagon release and glucagon action to return glucose levels to normal.

Fig1. Counter- regulatory actions in response to hypoglycaemia. A decrease in glycaemia initiates multiple events in order to restore euglycaemia. In the islet, a low blood glucose decreases insulin secretion from β cells and increases glucagon secretion from α cells. Hypoglycaemia also initiates neuronal sympathetic tone, which increases glucagon, cortisol, and epinephrine secretion. The changes in hormone concentrations in response to hypoglycaemia are summarized in the middle of the figure. These hormonal changes increase glycaemia by enhancement of glucose production by the liver and kidney, reduction of glucose uptake into peripheral tissues, and efflux of amino acids (AAs) and lipid products from skeletal muscle and adipose tissue, respectively. The increased concentrations of AAs, lactate, and glycerol facilitate gluconeogenesis to further increase hepatic glucose output. AA, amino acid; FFA, free fatty acid; SNS, sympathetic nervous system.

Glucagon also contributes to the maintenance of blood glucose during exercise, another metabolic stressor. Similar to hypoglycaemia, increasing catecholamines and glucagon in response to exercise, combined with the usually low circulating levels of insulin, enhance glucagon action and ensure adequate glucose output to maintain glucose supply to peripheral working muscles. With prolonged exercise, the impact of glucagon to pro mote lipid oxidation becomes increasingly important to preserve limited glucose and provide energy.

Although the physiology of glucagon to regulate hepatic glucose and lipid metabolism is based on a large base of experimental evidence accumulated over many years, several recent reports have raised questions about the fundamental aspects of the consensus model. The pre- eminence of Gs/cAMP signalling as the basis for driving hepatic glucose production has been challenged by pre- clinical studies that implicate signalling through Gi as increasing glycogenolysis and gluconeogenesis. A similar challenge to traditional thinking is based on studies in mice showing that glucagon is dispensable for the ketosis induced by starvation or SGLT- 2 inhibitor treatment. Finally, an effect of hepatic glucagon receptor signalling to improve insulin- stimulated glucose uptake in skeletal muscle and brown fat has been described in mice, suggesting a broader role for glucagon on glucose dis position through indirect mechanisms. These findings suggest that there remain significant gaps in understanding glucagon action, and that further study could provide insights into disease and potential for therapeutic development.

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مواضيع ذات صلة

Glucagon actions in the liver: amino acid metabolism and the hepatic–α- cell axis

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