Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Carbohydrate and Lipid Metabolism
Regulation of Carbohydrate Metabolism
Regulation of Blood Glucose Levels

Sources of Blood glucose

A. Dietary CARBOHYDRATES.

Most dietary carbohydrates undergo Hydrolysis to yield glucose, galactose, or fructose, which are transported via the portal vein to the Liver. In the liver, galactose and fructose are rapidly converted into glucose (see Figs. 21.2 and 21.3).

B. Various glucose-yielding compounds that enter the gluconeogenic pathway (Fig. 22.2). These compounds can be divided into two groups: (1) compounds that are converted into glucose without being products of its METABOLISM, such as Amino Acids and propionate; and (2) compounds that are products of the partial metabolism of glucose in certain Tissues, which are then transported to The Liver and Kidneys, where glucose is resynthesized from them. For example, lactate produced from glucose in skeletal Muscles and erythrocytes is transported to the liver and kidneys to be reconverted into glucose, which is subsequently released into the blood and tissues. This process is known as the Cori cycle or the lactic acid cycle (Fig. 22.6). Blood Glucose serves as the source of glycerol required for triacylglycerol synthesis in adipose tissue, since the direct utilization of free glycerol in this tissue is limited. Adipose tissue acylglycerols undergo continuous hydrolysis to release free glycerol, which diffuses out of the tissue into the bloodstream. In the liver and kidneys, it enters The Gluconeogenesis pathway and is converted back into glucose. Thus, a continuous cycle operates in which glucose is transported from the liver and kidneys to adipose tissue, while glycerol from this tissue travels to the liver and kidneys to be reconverted into glucose.

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Fig. 22.6. Lactic acid cycle (Cori cycle) and glucose-Alanine cycle.

It should be noted that alanine predominates among the amino acids transported from muscles to the liver during starvation. This observation led to the postulate of the glucose-alanine cycle (Fig. 22.6), whereby glucose is transferred from the liver to muscles, and alanine from muscles to the liver. This pathway facilitates the Transport of Amino nitrogen from muscles to the liver and Free energy from the liver to muscles. The energy required for hepatic glucose synthesis from Pyruvate is derived from Fatty acid oxidation.

C. Liver Glycogen.

Blood glucose concentration

In humans between meals, blood glucose concentration typically ranges from 80 to 100 mg/100 mL. Following a carbohydrate-rich meal, this concentration rises to 120–130 mg/100 mL, whereas during fasting, it drops to approximately 60–70 mg/100 mL. Under normal physiological conditions, blood glucose levels fluctuate within these limits. In ruminants, glucose concentration is considerably lower—about 40 mg/100 mL in sheep and 60 mg/100 mL in cattle. This is presumably because almost all dietary carbohydrates in these animals are fermented into lower (volatile) Fatty acids, which replace glucose as the primary energy source in tissues under normal feeding conditions.

Regulation of blood glucose concentration

The maintenance of blood glucose at a steady level exemplifies one of the most sophisticated homeostatic mechanisms, involving the liver, extrahepatic tissues, and several Hormones. Glucose readily penetrates hepatic Cells, whereas its entry into extrahepatic cells is relatively slow. Consequently, Transport Across the Cell membrane serves as the rate-limiting step in glucose utilization by extrahepatic tissues. Once inside the cells, glucose is rapidly phosphorylated by hexokinase. On the other hand, the uptake and output of glucose by the liver may be more significantly influenced by The activity of other specific Enzymes and the concentrations of key metabolic intermediates. Nevertheless, blood glucose concentration remains a critical factor regulating The rate of glucose uptake by both hepatic and extrahepatic tissues.

Role of glucokinase. It is noteworthy that glucose-6-phosphate inhibits hexokinase and, consequently, the hexokinase-catalyzed, feedback-regulated glucose uptake in extrahepatic tissues. This does not occur in the liver, as glucose-6-phosphate does not inhibit glucokinase. Glucokinase exhibits a higher K_m value (lower affinity) for glucose than hexokinase; its activity increases within the physiological range of glucose concentrations (Fig. 22.7). Following a carbohydrate-rich meal, the enzyme is "tuned" to the high glucose concentrations delivered to the liver via the portal vein. Notably, this enzyme is absent in ruminants, which receive only minimal amounts of intestinal glucose through the portal system.

At normal blood glucose levels (80–100 mg/100 mL), the liver apparently supplies glucose to the bloodstream. Conversely, when blood glucose levels rise, hepatic glucose output ceases, and at sufficiently high concentrations, net uptake of glucose by the liver begins. Experiments with rats have demonstrated that at a portal vein glucose concentration of 150 mg/100 mL, the rates of hepatic glucose uptake and output are equal.

Role of Insulin. In the state of hyperglycemia, glucose uptake is enhanced in both the liver and peripheral tissues. The hormone insulin plays a central role in regulating blood glucose concentration. It is synthesized by the beta Cells of the pancreatic islets of Langerhans, and its secretion into the blood increases during hyperglycemia. The concentration of this hormone in the blood parallels that of glucose, and its administration rapidly induces hypoglycemia. Substances that stimulate insulin secretion include amino acids, free fatty acids, Ketone Bodies, Glucagon, secretin, and the drug tolbutamide, whereas adrenaline and noradrenaline inhibit its release. Insulin rapidly increases glucose uptake by adipose tissue and muscles by accelerating transmembrane glucose transport through the translocation of glucose transporters from the Cytoplasm to The Plasma Membrane. However, insulin exerts no direct effect on glucose penetration into hepatic cells, which is consistent with the finding that the rate of Glucose metabolism in the liver is not limited by transmembrane passage. Instead, insulin acts indirectly by modulating the activities of enzymes involved in Glycolysis and Glycogenolysis (see above).

Fig. 22.7. Dependence of glucose-phosphorylating activity of hexokinase and glucokinase on blood glucose concentration. The K_m value for glucose is 0.05 mmol∙L^-1 (0.9 mg/100 mL) for hexokinase and 10 mmol∙L^-1 (180 mg/100 mL) for glucokinase.

The anterior pituitary secretes hormones that act antagonistically to insulin by elevating blood glucose levels. These include Growth Hormone, ACTH (corticotropin), and presumably other "diabetogenic" factors. Hypoglycemia stimulates growth hormone secretion, which in turn reduces glucose uptake in certain tissues, such as Skeletal Muscle. The action of growth hormone is partly indirect, as it stimulates the mobilization of free fatty acids from adipose tissue, which act as inhibitors of glucose utilization. Prolonged administration of growth hormone leads to diabetes; by inducing hyperglycemia, it stimulates continuous insulin secretion, ultimately resulting in beta-cell exhaustion.

Glucocorticoids (11-hydroxysteroids) are secreted by the adrenal cortex and play a vital role in Carbohydrate Metabolism. Administration of these Steroids enhances gluconeogenesis by accelerating tissue Protein Catabolism, increasing hepatic amino acid uptake, and upregulating transaminases and Other Enzymes involved in hepatic gluconeogenesis. Additionally, glucocorticoids inhibit glucose utilization in extrahepatic tissues, thereby functioning as physiological antagonists to insulin.

Adrenaline is secreted by The adrenal medulla in response to stress (fear, severe anxiety, Hemorrhage, oxygen deficiency, hypoglycemia, etc.). By stimulating phosphorylase, it triggers glycogenolysis in the liver and skeletal muscles. In muscles, due to the absence of glucose-6-phosphatase, glycogenolysis halts at the lactate stage, whereas in the liver, the primary end product of glycogen breakdown is free glucose, which enters the bloodstream and raises its level.

Glucagon is a hormone secreted by the alpha cells of the pancreatic islets of Langerhans, with its release stimulated by hypoglycemia. Upon reaching the liver via the portal vein, glucagon—much like adrenaline—activates phosphorylase and induces glycogenolysis. The majority of endogenous glucagon is retained by the liver. Unlike adrenaline, glucagon has no effect on muscle phosphorylase. This hormone also enhances gluconeogenesis from amino acids and lactate. The hyperglycemic effect of glucagon stems from both hepatic glycogenolysis and gluconeogenesis.

It should be noted that THYROID HORMONES also influence blood glucose levels. Experimental evidence indicates that thyroxine exerts a diabetogenic effect, whereas thyroidectomy prevents the onset of experimental diabetes. Glycogen is reportedly completely absent in the livers of thyrotoxic animals. In humans with hyperthyroidism, fasting blood sugar is elevated, whereas in those with hypothyroidism, it is reduced. In hyperthyroidism, glucose appears to be consumed at normal or accelerated rates, whereas in hypothyroidism, the capacity for glucose utilization is diminished. Furthermore, hypothyroid patients exhibit reduced sensitivity to insulin compared to healthy individuals and hyperthyroid patients.

Renal threshold for glucose, glycosuria

When blood glucose reaches a relatively high level, the kidneys become involved in its regulation. Glucose is filtered by the renal glomeruli and is normally completely reabsorbed back into the blood in the renal tubules. This reabsorption process requires ATP consumption within the renal tubular cells. The maximum reabsorptive capacity for glucose in the renal tubules is approximately 350 mg∙min^-1. When blood glucose is elevated, the glomerular filtrate contains more glucose than the tubules can reabsorb. The excess glucose is excreted in the urine, resulting in glycosuria. In healthy individuals, glycosuria occurs when venous blood glucose exceeds 170–180 mg/100 mL; this level is referred to as the renal threshold for glucose.

Glycosuria can be experimentally induced in laboratory animals using phlorhizin, which inhibits renal tubular glucose reabsorption. Such glycosuria, caused by impaired glucose reabsorption, is termed renal glycosuria. Renal glycosuria may stem from an inherited renal defect or develop secondary to various pathologies. Glycosuria frequently serves as a primary indicator of Diabetes Mellitus.

Fig. 22.8. Glucose tolerance test. Blood glucose curves in a healthy individual and a diabetes patient following the ingestion of 50 g of glucose. Note that the baseline Blood Glucose Level is elevated in the patient with diabetes. A return to the baseline blood glucose level within two hours is indicative of normal glucose tolerance.

Glucose tolerance

The body's ability to utilize glucose can be assessed by its tolerance to it. Following the administration of a specific amount of glucose, blood glucose curves are plotted (Fig. 22.8) to characterize glucose tolerance. In diabetes mellitus, glucose tolerance is impaired due to a reduced secretion of insulin; this condition leads to elevated blood glucose levels (hyperglycemia), glucosuria, and potential alterations in Lipid Metabolism. Impaired glucose tolerance occurs not only in diabetes, but also in certain conditions associated with hepatic dysfunction, various infectious diseases, obesity, the administration of certain drugs, and occasionally in atherosclerosis. Reduced glucose tolerance may also be observed in pituitary or adrenal cortex hyperfunction due to the antagonism between hormones secreted by these Endocrine glands and insulin.

Insulin enhances the body's tolerance to glucose. Its administration lowers blood glucose levels while increasing glucose uptake and its storage as glycogen in the liver and muscles. An excess of insulin can precipitate severe hypoglycemia accompanied by convulsions; unless glucose is administered promptly in this state, it can be fatal. In humans, hypoglycemic convulsions occur when blood glucose levels drop rapidly to 20 mg/100 ml. Increased glucose tolerance is observed in hypofunction of the Pituitary Gland or the adrenal cortex, resulting from a diminished antagonistic effect of the hormones secreted by these glands against insulin. As a consequence, the "relative level" of insulin in the body increases.

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