Harper’s Illustrated Biochemistry, 29th Edition (2012)

Chapter 20. Gluconeogenesis & the Control of Blood Glucose

David A. Bender, PhD & Peter A. Mayes, PhD, DSc

OBJECTIVES

After studying this chapter, you should be able to:

Explain the importance of gluconeogenesis in glucose homeostasis.

Describe the pathway of gluconeogenesis, how irreversible enzymes of glycolysis are bypassed, and how glycolysis and gluconeogenesis are regulated reciprocally.

Explain how plasma glucose concentration is maintained within narrow limits in the fed and fasting states.

BIOMEDICAL IMPORTANCE

Gluconeogenesis is the process of synthesizing glucose or glycogen from noncarbohydrate precursors. The major substrates are the glucogenic amino acids (Chapter 29), lactate, glycerol, and propionate. Liver and kidney are the major gluconeogenic tissues; the kidney may contribute up to 40% of total glucose synthesis in the fasting state and more in starvation. The key gluconeogenic enzymes are expressed in the small intestine, but it is unclear whether or not there is significant glucose production by the intestine in the fasting state.

A supply of glucose is necessary especially for the nervous system and erythrocytes. After an overnight fast, glycogenolysis (Chapter 19) and gluconeogenesis make approximately equal contributions to blood glucose; as glycogen reserves are depleted, so gluconeogenesis becomes progressively more important.

Failure of gluconeogenesis is usually fatal. Hypoglycemia causes brain dysfunction, which can lead to coma and death. Glucose is also important in maintaining the level of intermediates of the citric acid cycle even when fatty acids are the main source of acetyl-CoA in the tissues. In addition, gluconeogenesis clears lactate produced by muscle and erythrocytes, and glycerol produced by adipose tissue. In ruminants, propionate is a product of rumen metabolism of carbohydrates, and is a major substrate for gluconeogenesis.

Excessive gluconeogenesis occurs in critically ill patients in response to injury and infection, contributing to hyperglycemia which is associated with a poor outcome. Hyperglycemia leads to changes in osmolality of body fluids, impaired blood flow, intracellular acidosis and increased superoxide radical production (Chapter 45), resulting in deranged endothelial and immune system function and impaired blood coagulation. Excessive gluconeogenesis is also a contributory factor to hyperglycemia in type 2 diabetes because of impaired sensitivity of gluconeogenesis to downregulation in response to insulin.

GLUCONEOGENESIS INVOLVES GLYCOLYSIS, THE CITRIC ACID CYCLE, PLUS SOME SPECIAL REACTIONS

Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis

Three nonequilibrium reactions in glycolysis (Chapter 18), catalyzed by hexokinase, phosphofructokinase and pyruvate kinase, prevent simple reversal of glycolysis for glucose synthesis (Figure 20–1). They are circumvented as follows.

FIGURE 20–1 Major pathways and regulation of gluconeogenesis and glycolysis in the liver. Entry points of glucogenic amino acids after transamination are indicated by arrows extended from circles (see also Figure 17–4). The key gluconeogenic enzymes are enclosed in double-bordered boxes. The ATP required for gluconeogenesis is supplied by the oxidation of fatty acids. Propionate is of quantitative importance only in ruminants. Arrows with wavy shafts signify allosteric effects; dash-shafted arrows, covalent modification by reversible phosphorylation. High concentrations of alanine act as a “gluconeogenic signal” by inhibiting glycolysis at the pyruvate kinase step.

Pyruvate & Phosphoenolpyruvate

Reversal of the reaction catalyzed by pyruvate kinase in glycolysis involves two endothermic reactions. Mitochondrial pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate, an ATP-requiring reaction in which the vitamin biotin is the coenzyme. Biotin binds CO₂ from bicarbonate as carboxybiotin prior to the addition of the CO₂ to pyruvate (Figure 44–17). The resultant oxaloacetate is reduced to malate, exported from the mitochondrion into the cytosol and there oxidized back to oxaloacetate. A second enzyme, phosphoenolpyruvate carboxykinase, catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate using GTP as the phosphate donor. In liver and kidney, the reaction of succinate thiokinase in the citric acid cycle (Chapter 17) produces GTP (rather than ATP as in other tissues), and this GTP is used for the reaction of phosphoenolpyruvate carboxykinase, thus providing a link between citric acid cycle activity and gluconeogenesis, to prevent excessive removal of oxaloacetate for gluconeogenesis, which would impair citric acid cycle activity.

Fructose 1,6-Bisphosphate & Fructose 6-Phosphate

The conversion of fructose 1,6-bisphosphate to fructose 6-phosphate, for the reversal of glycolysis, is catalyzed by fructose 1,6-bisphosphatase. Its presence determines whether a tissue is capable of synthesizing glucose (or glycogen) not only from pyruvate, but also from triose phosphates. It is present in liver, kidney, and skeletal muscle, but is probably absent from heart and smooth muscle.

Glucose 6-Phosphate & Glucose

The conversion of glucose 6-phosphate to glucose is catalyzed by glucose 6-phosphatase. It is present in liver and kidney, but absent from muscle and adipose tissue, which, therefore, cannot export glucose into the bloodstream.

Glucose 1-Phosphate & Glycogen

The breakdown of glycogen to glucose 1-phosphate is catalyzed by phosphorylase. Glycogen synthesis involves a different pathway via uridine diphosphate glucose and glycogen synthase (Figure 19–1).

The relationships between gluconeogenesis and the glycolytic pathway are shown in Figure 20–1. After transamination or deamination, glucogenic amino acids yield either pyruvate or intermediates of the citric acid cycle. Therefore, the reactions described above can account for the conversion of both lactate and glucogenic amino acids to glucose or glycogen.

Propionate is a major precursor of glucose in ruminants; it enters gluconeogenesis via the citric acid cycle. After esterification with CoA, propionyl-CoA is carboxylated to D-methylmalonyl-CoA, catalyzed by propionyl-CoA carboxylase, a biotin-dependent enzyme (Figure 20–2). Methylmalonyl-CoA racemase catalyzes the conversion of D-methylmalonyl-CoA to L-methylmalonyl-CoA, which then undergoes isomerization to succinyl-CoA catalyzed by methylmalonyl-CoA mutase. In nonruminants, including human beings, propionate arises from the β-oxidation of odd-chain fatty acids that occur in ruminant lipids (Chapter 22), as well as the oxidation of isoleucine and the side chain of cholesterol, and is a (relatively minor) substrate for gluconeogenesis. Methylmalonyl-CoA mutase is a vitamin B₁₂-dependent enzyme, and in deficiency methylmalonic acid is excreted in the urine (methylmalonicaciduria).

FIGURE 20–2 Metabolism of propionate.

Glycerol is released from adipose tissue as a result of lipolysis of lipoprotein triacylglycerol in the fed state; it may be used for reesterification of free fatty acids to triacylglycerol in adipose tissue or liver, or may be a substrate for gluconeogenesis in the liver. In the fasting state, glycerol released from lipolysis of adipose tissue triacylglycerol is used solely as a substrate for gluconeogenesis in the liver and kidneys.

SINCE GLYCOLYSIS & GLUCONEOGENESIS SHARE THE SAME PATHWAY BUT IN OPPOSITE DIRECTIONS, THEY MUST BE REGULATED RECIPROCALLY

Changes in the availability of substrates are responsible for most changes in metabolism either directly or indirectly acting via changes in hormone secretion. Three mechanisms are responsible for regulating the activity of enzymes concerned in carbohydrate metabolism: (1) changes in the rate of enzyme synthesis, (2) covalent modification by reversible phosphorylation, and (3) allosteric effects.

Induction & Repression of Key Enzymes Requires Several Hours

The changes in enzyme activity in the liver that occur under various metabolic conditions are listed in Table 20-1. The enzymes involved catalyze nonequilibrium (physiologically irreversible) reactions. The effects are generally reinforced because the activity of the enzymes catalyzing the reactions in the opposite direction varies reciprocally (see Figure 20–1). The enzymes involved in the utilization of glucose (ie, those of glycolysis and lipogenesis) become more active when there is a superfluity of glucose, and under these conditions the enzymes of gluconeogenesis have low activity. Insulin, secreted in response to increased blood glucose, enhances the synthesis of the key enzymes in glycolysis. It also antagonizes the effect of the glucocorticoids and glucagon-stimulated cAMP, which induce synthesis of the key enzymes of gluconeogenesis.

TABLE 20–1 Regulatory and Adaptive Enzymes Associated with Carbohydrate Metabolism

Covalent Modification by Reversible Phosphorylation Is Rapid

Glucagon and epinephrine, hormones that are responsive to a decrease in blood glucose, inhibit glycolysis and stimulate gluconeogenesis in the liver by increasing the concentration of cAMP. This in turn activates cAMP-dependent protein kinase, leading to the phosphorylation and inactivation of pyruvate kinase. They also affect the concentration of fructose 2,6-bisphosphate and therefore glycolysis and gluconeogenesis, as described below.

Allosteric Modification Is Instantaneous

In gluconeogenesis, pyruvate carboxylase, which catalyzes the synthesis of oxaloacetate from pyruvate, requires acetyl-CoA as an allosteric activator. The addition of acetyl-CoA results in a change in the tertiary structure of the protein, lowering the K_m for bicarbonate. This means that as acetyl-CoA is formed from pyruvate, it automatically ensures the provision of oxaloacetate and, therefore, its further oxidation in the citric acid cycle, by activating pyruvate carboxylase. The activation of pyruvate carboxylase and the reciprocal inhibition of pyruvate dehydrogenase by acetyl-CoA derived from the oxidation of fatty acids explain the action of fatty acid oxidation in sparing the oxidation of pyruvate and in stimulating gluconeogenesis. The reciprocal relationship between these two enzymes alters the metabolic fate of pyruvate as the tissue changes from carbohydrate oxidation (glycolysis) to gluconeogenesis during the transition from the fed to fasting state (see Figure 20–1). A major role of fatty acid oxidation in promoting gluconeogenesis is to supply the ATP required.

Phosphofructokinase (phosphofructokinase-1) occupies a key position in regulating glycolysis and is also subject to feedback control. It is inhibited by citrate and by normal intracellular concentrations of ATP and is activated by 5′ AMP. 5′ AMP acts as an indicator of the energy status of the cell. The presence of adenylyl kinase in liver and many other tissues allows rapid equilibration of the reaction

Thus, when ATP is used in energy-requiring processes resulting in formation of ADP, [AMP] increases. A relatively small decrease in [ATP] causes a several-fold increase in [AMP], so that [AMP] acts as a metabolic amplifier of a small change in [ATP], and hence a sensitive signal of the energy state of the cell. The activity of phosphofructokinase-1 is thus regulated in response to the energy status of the cell to control the quantity of carbohydrate undergoing glycolysis prior to its entry into the citric acid cycle. Simultaneously, AMP activates phosphorylase, increasing glycogenolysis. A consequence of the inhibition of phosphofructokinase-1 is an accumulation of glucose 6-phosphate, which in turn inhibits further uptake of glucose in extrahepatic tissues by inhibition of hexokinase.

Fructose 2,6-Bisphosphate Plays a Unique Role in the Regulation of Glycolysis & Gluconeogenesis in Liver

The most potent positive allosteric activator of phosphofructokinase-1 and inhibitor of fructose 1,6-bisphosphatase in liver is fructose 2,6-bisphosphate. It relieves inhibition of phosphofructokinase-1 by ATP and increases the affinity for fructose 6-phosphate. It inhibits fructose 1,6-bisphosphatase by increasing the K_m for fructose 1,6-bisphosphate. Its concentration is under both substrate (allosteric) and hormonal control (covalent modification) (Figure 20–3).

FIGURE 20–3 Control of glycolysis and gluconeogenesis in the liver by fructose 2,6-bisphosphate and the bifunctional enzyme PFK-2/F-2,6-Pase (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase). (F-1,6-Pase, fructose 1,6-bisphosphatase; PFK-1, phosphofructokinase-1 [6-phosphofructo-1-kinase].) Arrows with wavy shafts indicate allosteric effects.

Fructose 2,6-bisphosphate is formed by phosphorylation of fructose 6-phosphate by phosphofructokinase-2. The same enzyme protein is also responsible for its breakdown, since it has fructose 2,6-bisphosphatase activity. This bifunctional enzyme is under the allosteric control of fructose 6-phosphate, which stimulates the kinase and inhibits the phosphatase. Hence, when there is an abundant supply of glucose, the concentration of fructose 2,6-bisphosphate increases, stimulating glycolysis by activating phosphofructokinase-1 and inhibiting fructose 1,6-bisphosphatase. In the fasting state, glucagon stimulates the production of cAMP, activating cAMP-dependent protein kinase, which in turn inactivates phosphofructokinase-2 and activates fructose 2,6-bisphosphatase by phosphorylation. Hence, gluconeogenesis is stimulated by a decrease in the concentration of fructose 2,6-bisphosphate, which inactivates phosphofructokinase-1 and relieves the inhibition of fructose 1,6-bisphosphatase. Xylulose 5-phosphate, an intermediate of the pentose phosphate pathway (Chapter 21) activates the protein phosphatase that dephosphorylates the bifunctional enzyme, so increasing the formation of fructose 2,6-bisphosphate and increasing the rate of glycolysis. This leads to increased flux through glycolysis and the pentose phosphate pathway and increased fatty acid synthesis (Chapter 23).

Substrate (Futile) Cycles Allow Fine Tuning & Rapid Response

The control points in glycolysis and glycogen metabolism involve a cycle of phosphorylation and dephosphorylation catalyzed by glucokinase and glucose 6-phosphatase; phosphofructokinase-1 and fructose 1,6-bisphosphatase; pyruvate kinase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase; and glycogen synthase and phosphorylase. It would seem obvious that these opposing enzymes are regulated in such a way that when those involved in glycolysis are active, those involved in gluconeogenesis are inactive, since otherwise there would be cycling between phosphorylated and nonphosphorylated intermediates, with net hydrolysis of ATP. While this is so, in muscle both phosphofructokinase and fructose 1,6-bisphosphatase have some activity at all times, so that there is indeed some measure of (wasteful) substrate cycling. This permits the very rapid increase in the rate of glycolysis necessary for muscle contraction. At rest the rate of phosphofructokinase activity is some 10-fold higher than that of fructose 1,6-bisphosphatase; in anticipation of muscle contraction, the activity of both enzymes increases, fructose 1,6-bisphosphatase 10 times more than phosphofructokinase, maintaining the same net rate of glycolysis. At the start of muscle contraction, the activity of phosphofructokinase increases further, and that of fructose 1,6-bisphosphatase falls, so increasing the net rate of glycolysis (and hence ATP formation) as much as a 1000-fold.

THE BLOOD CONCENTRATION OF GLUCOSE IS REGULATED WITHIN NARROW LIMITS

In the postabsorptive state, the concentration of blood glucose in most mammals is maintained between 4.5-5.5 mmol/L. After the ingestion of a carbohydrate meal, it may rise to 6.5–7.2 mmol/L, and in starvation, it may fall to 3.3-3.9 mmol/L. A sudden decrease in blood glucose (eg, in response to insulin overdose) causes convulsions, because of the dependence of the brain on a supply of glucose. However, much lower concentrations can be tolerated if hypoglycemia develops slowly enough for adaptation to occur. The blood glucose level in birds is considerably higher (14.0 mmol/L) and in ruminants considerably lower (approximately 2.2 mmol/L in sheep and 3.3 mmol/L in cattle). These lower normal levels appear to be associated with the fact that ruminants ferment virtually all dietary carbohydrate to short-chain fatty acids, and these largely replace glucose as the main metabolic fuel of the tissues in the fed state.

BLOOD GLUCOSE IS DERIVED FROM THE DIET, GLUCONEOGENESIS, & GLYCOGENOLYSIS

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 (Chapter 21).

Glucose is formed from two groups of compounds that undergo gluconeogenesis (see Figures 17-4 and 20-1) : (1) those which involve a direct net conversion to glucose, including most 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 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 20–4).

FIGURE 20–4 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 its concentration 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 glucosealanine cycle (see Figure 20–4) thus provides an indirect way of utilizing muscle glycogen to maintain blood glucose in the fasting state. The ATP 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 19).

Metabolic & Hormonal Mechanisms Regulate the Concentration of 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 β-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 is shown in Table 20-2.

TABLE 20–2 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 is saturated and acting at a constant rate under all normal conditions. Glucokinase has a considerably higher K_m (lower affinity) for glucose, so that its activity increases with increases in the concentration of glucose in the hepatic portal vein (Figure 20–5). It promotes hepatic uptake of large amounts of glucose after a carbohydrate meal. It is absent from the liver of ruminants, which have little glucose entering the portal circulation from the intestines.

FIGURE 20–5 Variation in glucose phosphorylating activity of hexokinase and glucokinase with increasing blood glucose concentration. The K_m for glucose of hexokinase is 0.05 mmol/L and of glucokinase is 10 mmol/L.

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 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 voltagesensitive 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, noninsulin-dependent diabetes mellitus) via 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 19 and Table 20-1).

Glucagon Opposes the Actions of Insulin

Glucagon is the hormone produced by the α 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 (see Table 20-1). 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 20-3).

TABLE 20–3 Tissue Responses to Insulin and 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, 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 be indirect, 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 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 as a result 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, whereas in liver it results in the release of glucose into the bloodstream.

FURTHER CLINICAL ASPECTS

Glucosuria Occurs When the Renal Threshold for Glucose Is Exceeded

When the blood glucose rises to relatively high levels, the kidney also exerts a regulatory effect. Glucose is continuously filtered by the glomeruli, but is normally completely reabsorbed in the renal tubules by active transport. The capacity of the tubular system to reabsorb glucose is limited to a rate of about 2 mmol/min, and in hyperglycemia (as occurs in poorly controlled diabetes mellitus), the glomerular filtrate may contain more glucose than can be reabsorbed, resulting in glucosuria. Glucosuria occurs when the venous blood glucose concentration exceeds about 10 mmol/L; this is termed the renal threshold for glucose.

Hypoglycemia May Occur During Pregnancy & in the Neonate

During pregnancy, fetal glucose consumption increases and there is a risk of maternal and possibly fetal hypoglycemia, particularly if there are long intervals between meals or at night. Furthermore, premature and low-birth-weight babies are more susceptible to hypoglycemia, since they have little adipose tissue to provide free fatty acids. The enzymes of gluconeogenesis may not be completely functional at this time, and gluconeogenesis is anyway dependent on a supply of free fatty acids for energy. Little glycerol, which would normally be released from adipose tissue, is available for gluconeogenesis.

The Body’s Ability to Utilize Glucose May Be Ascertained by Measuring Glucose Tolerance

Glucose tolerance is the ability to regulate the blood glucose concentration after the administration of a test dose of glucose (normally 1 g/kg body weight) (Figure 20–6). Diabetes mellitus (type 1, or insulin-dependent diabetes mellitus; IDDM) is characterized by decreased glucose tolerance as a result of decreased secretion of insulin as a result of progressive destruction of pancreatic β-islet cells. Glucose tolerance is also impaired in type 2 diabetes mellitus (NIDDM) as a result of impaired sensitivity of tissues to insulin action. Insulin resistance associated with obesity (and especially abdominal obesity) leading to the development of hyperlipidemia, then atherosclerosis and coronary heart disease, as well as overt diabetes, is known as the metabolic syndrome. Impaired glucose tolerance also occurs in conditions where the liver is damaged, in some infections, and in response to some drugs, as well as in conditions that lead to hyperactivity of the pituitary or adrenal cortex because of the antagonism of the hormones secreted by these glands to the action of insulin.

FIGURE 20–6 Glucose tolerance test. Blood glucose curves of a normal and a diabetic person after oral administration of 1 g of glucose/kg body weight. Note the initial raised concentration in the fasting diabetic. A criterion of normality is the return of the curve to the initial value within 2 h.

Administration of insulin (as in the treatment of diabetes mellitus) lowers the blood glucose concentration and increases its utilization and storage in the liver and muscle as glycogen. An excess of insulin may cause hypoglycemia, resulting in convulsions and even in death unless glucose is administered promptly. Increased tolerance to glucose is observed in pituitary or adrenocortical insufficiency, attributable to a decrease in the antagonism to insulin by the hormones normally secreted by these glands.

The Energy Cost of Gluconeogenesis Explains Why Very Low Carbohydrate Diets Promote Weight Loss

Very low carbohydrate diets, providing only 20 g per day of carbohydrate or less (compared with a desirable intake of 100–120 g/day), but permitting unlimited consumption of fat and protein, have been promoted as an effective regime for weight loss, although such diets are counter to all advice on a prudent diet for health. Since there is a continual demand for glucose, there will be a considerable amount of gluconeogenesis from amino acids; the associated high ATP cost must then be met by oxidation of fatty acids.

SUMMARY

Gluconeogenesis is the process of synthesizing glucose or glycogen from noncarbohydrate precursors. It is of particular importance when carbohydrate is not available from the diet. Significant substrates are amino acids, lactate, glycerol, and propionate.

The pathway of gluconeogenesis in the liver and kidney utilizes those reactions in glycolysis that are reversible plus four additional reactions that circumvent the irreversible nonequilibrium reactions.

Since glycolysis and gluconeogenesis share the same pathway but operate in opposite directions, their activities must be regulated reciprocally.

The liver regulates the blood glucose concentration after a meal because it contains the high-K_m glucokinase that promotes increased hepatic utilization of glucose.

Insulin is secreted as a direct response to hyperglycemia; it stimulates the liver to store glucose as glycogen and facilitates uptake of glucose into extrahepatic tissues.

Glucagon is secreted as a response to hypoglycemia and activates both glycogenolysis and gluconeogenesis in the liver, causing release of glucose into the blood.

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