|Topic:||Regulation of Blood Glucose Levels .|
|Details:|| If for no other reason, it is because of the demands of the brain for oxidizable glucose that the human body exquisitely regulates the level of glucose circulating in the blood. This level is maintained in the range of 5mM (90mg/dL) during normal between meal fasting.
Nearly all carbohydrates ingested in the diet are converted to glucose following transport to the liver. Catabolism of dietary or cellular proteins generates carbon atoms that can be utilized for glucose synthesis via gluconeogenesis. Additionally, other tissues besides the liver that incompletely oxidize glucose (predominantly skeletal muscle and erythrocytes) provide lactate that can be converted to glucose via gluconeogenesis.
Maintenance of blood glucose homeostasis is of paramount importance to the survival of the human organism. The predominant tissue responding to signals that indicate reduced or elevated blood glucose levels is the liver. Indeed, one of the most important functions of the liver is to produce glucose for the circulation. Both elevated and reduced levels of blood glucose trigger hormonal responses to initiate pathways designed to restore glucose homeostasis. Low blood glucose triggers release of glucagon from pancreatic α-cells. High blood glucose triggers release of insulin from pancreatic β-cells.
Additional hormonal signals, such as via ACTH and growth hormone, released from the pituitary, act to increase blood glucose by inhibiting its uptake by extrahepatic tissues such as adipose tissue and skeletal muscle. Glucocorticoids also act to increase blood glucose levels by inhibiting glucose uptake (also primarily at the level of adipose tissue and skeletal muscle) and by stimulation of gluconeogenesis. Cortisol, the major glucocorticoid released from the adrenal cortex, is secreted in response to the increase in circulating ACTH. Within the liver, cortisol binding to the glucocorticoid receptor (GR), results in transcriptional activation of the PEPCK gene, thereby, resulting in increased rates of gluconeogenesis and glucose output to the blood.
The adrenal medullary hormone, epinephrine, stimulates production of glucose by activating hepatic glycogenolysis and gluconeogenesis. These effects are exerted via the presence of α1 and β2 adrenergic receptor subtypes on hepatocytes. Epinephrine also exerts an effect on skeletal muscle glycogenolysis in response to stressful stimuli. Within skeletal muscle, epinephrine exerts its effects primarily through activation of the β2 adrenergic receptor but a small percentage of the total adrenergic receptor subtypes in skeletal muscle includes the β1 subtype (7–10% of the total).
The significance of adrenergic (epinephrine primarily) receptor function to the control of blood glucose can be seen by the consequences of several identified receptor mutations. For example, mutations in either the β1 or the β3 adrenergic receptors are highly correlated to insulin resistance associated with type 2 diabetes. In addition, mutations in all three β-adrenergic receptors are associated with hyperlipidemia (which exacerbates the hyperglycemia of diabetes) as well as the associated pathophysiology of the metabolic syndrome. Mutations in all three β-receptors are also associated with increased risk for obesity.
Glucagon binding to its receptors on the surface of liver cells triggers an increase in cAMP production leading to an increased rate of glycogenolysis by activating glycogen phosphorylase via the PKA-mediated cascade. This is the same response hepatocytes have to epinephrine binding to the β2 adrenergic receptors on hepatocytes. The resultant increased levels of G6P in hepatocytes is hydrolyzed to free glucose, by glucose-6-phosphatase, which then diffuses to the blood. The glucose enters extrahepatic cells where it is re-phosphorylated by hexokinase. Since all tissues, excluding liver, kidney, and small intestine, lack glucose-6-phosphatase, the glucose-6-phosphate product of hexokinase is retained and oxidized by these tissues.
In opposition to the cellular responses to glucagon, cortisol, and epinephrine, insulin stimulates extrahepatic uptake of glucose from the blood and inhibits glycogenolysis in extrahepatic cells and conversely stimulates glycogen synthesis. As the glucose enters hepatocytes it binds to and inhibits glycogen phosphorylase activity. The binding of free glucose stimulates the dephosphorylation of phosphorylase thereby, inactivating it. Why is it that the glucose that enters hepatocytes is not immediately phosphorylated and oxidized? Hepatocytes express the isoform of hexokinase called glucokinase. Glucokinase has a much lower affinity for glucose than does hexokinase. Therefore, it is not fully active at the physiological ranges of blood glucose. Additionally, glucokinase is not inhibited by its product G6P, whereas, hexokinase is inhibited by G6P.
Hepatocytes, unlike most other cells, are essentially freely permeable to glucose and are, therefore, not directly affected by the action of insulin at the level of increased glucose uptake. When blood glucose levels are low, the liver does not compete with other tissues for glucose since the extrahepatic uptake of glucose is stimulated in response to insulin. Conversely, when blood glucose levels are high extrahepatic needs are satisfied and the liver takes up glucose for conversion into glycogen for future needs. Under conditions of high blood glucose, liver glucose levels will be high and the activity of glucokinase will be elevated. The G6P produced by glucokinase is rapidly converted to G1P by phosphoglucomutase, where it can then be incorporated into glycogen.
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