Blood Glucose Is Derived From The Diet Gluconeogenesis Glycogenolysis

The digestible dietary carbohydrates yield glucose, galactose, and fructose that are transported via the hepatic portal vein to the liver where galactose and fructose are readily converted to glucose (Chapter 20).

Metabolic & Hormonal Mechanisms Regulate the Concentration of the Blood Glucose

The maintenance of stable levels of glucose in the blood 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 (via the GLUT 2 transporter), whereas cells of extrahepatic tissues (apart from pancreatic B islets) are relatively impermeable, and their glucose transporters are regulated by insulin. As a result, uptake from the bloodstream is the rate-limiting step in the utilization of glucose in extrahepatic tissues. The role of various glucose transporter proteins found in cell membranes, each having 12 transmembrane domains, is shown in Table 19-2.

Glucokinase Is Important in Regulating Blood Glucose After a Meal

Hexokinase has a low Km for glucose and in the liver is saturated and acting at a constant rate under all normal conditions. Glucokinase has a considerably higher Km (lower affinity) for glucose, so that its activity increases over the physiologic range of glucose concentrations (Figure 19-5). It promotes hepatic uptake of large amounts of glucose at the high concentrations found in the hepatic portal vein after a carbohydrate meal. It is absent from the liver of ruminants, which have little

BLOOD

BLOOD

Liver Glut Transporter Bidirectional

Figure 19-4. The lactic acid (Cori) cycle and glucose-alanine cycle.

Glucose is formed from two groups of compounds that undergo gluconeogenesis (Figures 16-4 and 19-1): (1) those which involve a direct net conversion to glucose without significant recycling, such as some amino acids and propionate; and (2) those which 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 re-forms glucose, which again becomes available via the circulation for oxidation in the tissues. This process is known as the Cori cycle, or lactic acid cycle (Figure 19-4). Triacylglycerol glycerol in adipose tissue is derived from blood glucose. This triacylglycerol is continuously undergoing hydrolysis to form free glycerol, which cannot be utilized by adipose tissue and is converted back to glucose by gluconeogenic mechanisms in the liver and kidney (Figure 19-1).

Of the amino acids transported from muscle to the liver during starvation, alanine predominates. The glu-cose-alanine cycle (Figure 19-4) transports glucose from liver to muscle with formation of pyruvate, followed by transamination to alanine, then transports alanine to the liver, followed by gluconeogenesis back to glucose. A net transfer of amino nitrogen from muscle to liver and of free energy from liver to muscle is effected. The energy required for the hepatic synthesis of glucose from pyruvate is derived from the oxidation of fatty acids.

Glucose is also formed from liver glycogen by glycogenolysis (Chapter 18).

Figure 19-4. The lactic acid (Cori) cycle and glucose-alanine cycle.

Table 19-2. Glucose transporters.

Tissue Location

GLUT 1

ive bidirectional transporters

Brain, kidney, colon, placenta, erythrocyte

Uptake of glucose

GLUT 2

Liver, pancreatic B cell, small intestine, kidney

Rapid uptake and release of glucose

GLUT 3

Brain, kidney, placenta

Uptake of glucose

GLUT 4

Heart and skeletal muscle, adipose tissue

Insulin-stimulated uptake of glucose

GLUT 5

Small intestine

Absorption of glucose

Sodium

SGLT 1

-dependent unidirectional transporter

Small intestine and kidney

Active uptake of glucose from lumen of intestine and reabsorption of glucose in proximal tubule of kidney against a concentration gradient

glucose entering the portal circulation from the intestines.

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

Insulin Plays 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 B cells of the islets of Langerhans in the pancreas in response to hyper-glycemia. The B islet cells are freely permeable to glu-

S 50

S 50

"max 100

Gluconeogenesis Glycogenolysis

Blood glucose (mmol/L)

Figure 19-5. Variation in glucose phosphorylating activity of hexokinase and glucokinase with increase of blood glucose concentration. The Km for glucose of hexokinase is 0.05 mmol/L and of glucokinase is 10 mmol/L.

Blood glucose (mmol/L)

Figure 19-5. Variation in glucose phosphorylating activity of hexokinase and glucokinase with increase of blood glucose concentration. The Km for glucose of hexokinase is 0.05 mmol/L and of glucokinase is 10 mmol/L.

cose 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. Increase in [ATP] inhibits ATP-sensitive K+ channels, causing depolarization of the B 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, free 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 (NIDDM, non-insulin-dependent diabetes mellitus); they act by inhibiting the ATP-sensitive K+ channels. Epinephrine and norepinephrine block the release of insulin. Insulin lowers 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 uptake into the liver directly, insulin does enhance long-term uptake as a result of its actions on the enzymes controlling glycolysis, glycogenesis, and gluconeogenesis (Chapter 18).

Glucagon Opposes the Actions of Insulin

Glucagon is the hormone produced by the A cells of the pancreatic islets. Its secretion is stimulated by hypoglycemia. In the liver, it stimulates glycogenolysis by activating 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 (Table 19-1). Both hepatic glycogenolysis and gluconeogenesis contribute to the

"max 100

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.

Other Hormones Affect Blood Glucose

The anterior pituitary gland secretes hormones that tend to elevate the blood glucose and therefore antagonize the action of insulin. These are growth hormone, ACTH (corticotropin), and possibly other "diabetogenic" hormones. Growth hormone secretion is stimulated by hypoglycemia; it decreases glucose uptake in muscle. Some of this effect may not be direct, since it stimulates mobilization of free fatty acids from adipose tissue, which themselves inhibit glucose utilization. The glucocorticoids (11-oxysteroids) are secreted by the adrenal cortex and increase gluconeogenesis. This is a result of enhanced hepatic uptake of amino acids and increased activity of aminotransferases 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.

Epinephrine is secreted by the adrenal medulla as a result of stressful stimuli (fear, excitement, hemorrhage, hypoxia, hypoglycemia, etc) and leads to glycogenolysis in liver and muscle owing to stimulation of phosphory-lase via generation of cAMP. In muscle, glycogenolysis results in increased glycolysis, whereas in liver glucose is the main product leading to increase in blood glucose.

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Responses

  • arlie albury
    Can amino acids derive from glucose?
    5 years ago
  • Bilcuzal
    How to cure hyper gluconeogenesis?
    4 years ago
  • Lena
    What does blood glucose derive from?
    4 years ago
  • Katariina
    Is glucose freely permeable to liver?
    2 years ago
  • Aurelio
    Why is hepatic cell freely permeable to glucoe?
    1 year ago

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