The digestible dietary carbohydrates yield glucose, galactose, and fructose that are transported to the liver via the hepatic portal vein. Galactose and fructose are readily converted to glucose in the liver .

Glucose is formed from two groups of compounds that undergo gluconeogenesis: (1) those that involve a direct net conversion to glucose, including most amino acids and propionate and (2) those that are the products of the metabolism of glucose in tissues. Thus, lactate, formed by glycolysis in skeletal muscle and erythrocytes, is transported to the liver and kidney where it reforms glucose, which again becomes available via the circulation for oxidation in the tissues. This process is known as the Cori cycle, or the lactic acid cycle (Figure 1).

Fig1. The lactic acid (Cori cycle) and glucose-alanine cycles.

In the fasting state, there is a considerable output of alanine from skeletal muscle, far in excess of the amount in the muscle proteins that are being catabolized. It is formed by transamination of pyruvate produced by glycolysis of muscle glycogen, and is exported to the liver, where, after transamination back to pyruvate, it is a substrate for gluconeogenesis. This glucose alanine cycle (see Figure 1) provides an indirect way of utilizing muscle glycogen to maintain blood glucose in the fasting state. The glycerol released by adipose tissue is another source of gluconeogenic carbon along with the lactate released by muscle. The ATP required for the hepatic synthesis of glucose from pyruvate (or glycerol) is formed by the oxidation of fatty acids derived from adipose tissue lipolysis. Glucose is also formed from liver glycogen by glycogenolysis .

Metabolic & Hormonal Mechanisms Regulate the Concentration of Blood Glucose

The maintenance of a stable blood glucose concentration is one of the most finely regulated of all homeostatic mechanisms, involving the liver, extrahepatic tissues, and several hormones. Liver cells are freely permeable to glucose in either direction (via the GLUT 2 transporter), whereas cells of extra hepatic tissues (apart from pancreatic β-islets) are relatively impermeable, and their unidirectional glucose transporters are regulated by insulin. As a result, uptake from the blood stream is an important, but not rate limiting under all settings, determinant of the utilization of glucose in extrahepatic tissues. The role of various glucose transporter proteins found in cell membranes is shown in Table1.

Table1. Major Glucose Transporters

Glucokinase Is Important in Regulating Blood Glucose After a Meal

Hexokinase has a low K_m for glucose, and in the liver it is saturated with low capacity and acting at a constant rate under all normal conditions. It thus acts to ensure an adequate rate of glycolysis to meet the liver’s needs. Glucokinase is an allosteric enzyme with a considerably higher apparent Km (lower affinity) for glucose, so that its activity increases with increase in the con centration of glucose in the hepatic portal vein (Figure 2). In the fasting state, glucokinase is located in the nucleus. In response to an increased intracellular concentration of glucose it migrates into the cytosol, mediated by the carbohydrate response element-binding protein (CREBP). It permits hepatic uptake of large amounts of glucose after a carbohydrate meal, for glycogen and fatty acid synthesis. While the concentration of glucose in the hepatic portal vein may reach 20 mmol/L after a meal, that leaving the liver into the peripheral circulation does not normally exceed 8 to 9 mmol/L. Glucokinase is absent from the liver of ruminants, which have little glucose entering the portal circulation from the intestines.

Fig2. Variation in glucose phosphorylating activity of hexokinase and glucokinase with increasing blood glucose concentration. The Km for glucose of hexokinase is 0.05 mmol/L and of glucokinase is 10 mmol/L.

At normal peripheral blood glucose concentrations (4.5-5.5 mmol/L), the liver is a net producer of glucose. How ever, as the glucose level rises, the output of glucose ceases, and there is a net uptake .

Insulin & Glucagon Play a Central Role in Regulating Blood Glucose

In addition to the direct effects of hyperglycemia in enhancing the uptake of glucose into the liver, the hormone insulin plays a central role in regulating blood glucose. It is produced by the β cells of the islets of Langerhans in the pancreas in response to hyperglycemia. The β-islet cells are freely permeable to glucose via the GLUT 2 transporter, and the glucose is phosphorylated by glucokinase. Therefore, increasing blood glucose increases metabolic flux through glycolysis, the citric acid cycle, and the generation of ATP. The increase in [ATP] inhibits ATP-sensitive K⁺ channels, causing depolarization of the cell membrane, which increases Ca²⁺ influx via voltage-sensitive Ca²⁺ channels, stimulating exocytosis of insulin. Thus, the concentration of insulin in the blood parallels that of the blood glucose. Other substances causing release of insulin from the pancreas include amino acids, nonesterified fatty acids, ketone bodies, glucagon, secretin, and the sulfonylurea drugs tolbutamide and glyburide. These drugs are used to stimulate insulin secretion in Type 2 diabetes mellitus via the ATP-sensitive K⁺ channels. Drugs that augment glucagon-like-peptide signals increase cyclic-AMP, which potentiate glucose-stimulated insulin secretion. Epinephrine and norepinephrine block the release of insulin. Insulin acts to lower blood glucose immediately by enhancing glucose transport into adipose tissue and muscle by recruitment of glucose transporters (GLUT 4) from the interior of the cell to the plasma membrane. Although it does not affect glucose transport activity in the liver, it directly augments liver glucose uptake and glycogen deposition likely through effects on glucokinase and glycogen synthase and phosphorylase activity. Insulin and other hormones modulate long-term uptake as a result of their actions on transcriptional signals to change an entire enzyme portfolio controlling glycolysis, glycogenesis, and gluconeogenesis (see Table 2).

Glucagon is the hormone produced by the α cells of the pancreatic islets in response to hypoglycemia. In the liver, it stimulates glycogenolysis by activating glycogen phosphorylase. Unlike epinephrine, glucagon does not have an effect on muscle phosphorylase. Glucagon also enhances gluconeogenesis from amino acids and lactate. In all these actions, glucagon acts via generation of cAMP (see Table 2). Both hepatic glycogenolysis and gluconeogenesis contribute to the hyperglycemic effect of glucagon, whose actions oppose those of insulin. Most of the endogenous glucagon (and insulin) is cleared from the circulation by the liver (Table 3).

Table2. Regulatory & Adaptive Enzymes Associated With Carbohydrate Metabolism

Table3. Tissue Responses to Insulin & Glucagon

Other Hormones Affect Blood Glucose

 The anterior pituitary gland secretes hormones that tend to elevate blood glucose and therefore antagonize the action of insulin. These are growth hormone, adrenocorticotropic hormone (ACTH), and possibly other “diabetogenic” hormones. Growth hormone secretion is stimulated by hypoglycemia; it decreases glucose uptake in muscle. Some of this effect may be indirect, since it stimulates mobilization of nonesterified fatty acids from adipose tissue, which themselves inhibit glucose utilization. The glucocorticoids (11-oxysteroids) are secreted by the adrenal cortex, and are also synthesized in an unregulated manner in adipose tissue. They act to increase gluconeogenesis as a result of enhanced hepatic catabolism of amino acids, due to induction of aminotransferases (and other enzymes such as tryptophan dioxygenase) and key enzymes of gluconeogenesis. In addition, glucocorticoids inhibit the utilization of glucose in extrahepatic tissues. In all these actions, glucocorticoids act in a manner antagonistic to insulin. A number of cytokines secreted by macrophages infiltrating adipose tissue also have insulin antagonistic actions; together with glucocorticoids secreted by adipose tissue, this explains the insulin resistance that commonly occurs in obese people.

Epinephrine is secreted by the adrenal medulla because of stressful stimuli (fear, excitement, hemorrhage, hypoxia, hypoglycemia, etc.) and leads to glycogenolysis in liver and muscle owing to stimulation of phosphorylase via generation of cAMP. In muscle, glycogenolysis results in increased glycolysis and lactate release, whereas in liver, it results in the release of glucose into the bloodstream. Epinephrine is a potent stimulator of gluconeogenesis because of the robust increase in substrate supply.

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مواضيع ذات صلة

Glycolysis & gluconeogenesis share the same pathway but in opposite directions, & are reciprocally regulated

Glucose-1-Phosphate & Glycogen

Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis

Gluconeogenesis & the Control of Blood Glucose: Biomedical Importance

Glycogen Metabolism is Regulated by A Balance in Activities Between Glycogen Synthase & Phosphorylase

cAMP Activates Glycogen Phosphorylase

Cyclic AMP Integrates The Regulation of Glycogenolysis & Glycogenesis

Glycogenolysis is not the Reverse of Glycogenesis, it is A Separate Pathway

Glycogenesis Occurs Mainly in Muscle & Liver

The Oxidation of Pyruvate to Acetyl-COA is The Irreversible Route from Glycolysis to The Citric Acid Cycle

Glycolysis is Regulated at Three Nonequilibrium Reactions

Tissues That Function Under Hypoxic Conditions or have Intrinsically High Rates of Glucose Oxidation Produce Lactate