Fractose and galactose Metabolism Dr. Abdulrahman Al-Ajlan

Fractose and galactose Metabolism About 15% to 20% of the calories contained in the western diet are supplied by fructose (about 100g/day). The major source of fructose is Disacchariede sucrose (table sugar). Fructose is also found as a free monosaccharide in many fruits and vegetables and in honey. Entry of fructose into cells is not insulin dependent.

Continue … Fructose is metabolized in the liver where it is converted to pyruvate or under fasting conditions to glucose. In mild or treated diabetes, fructose is suitable source of energy because its metabolism is insulin-independent and the oxidation of fructose via glycolysis and TCA cycle is favored. In severe diabetes, the flux is towards the synthesis of glucose, and fructose instead of being helpful will be detrimental to the patient. In the eye lens, sorbitol synthesized from the excess glucose may promote cataract development.

Metabolism of galactose: The major dietary source of galactose is the disaccharide lactose found in milk or milk products. Some galactose can also be obtained by degradation of complex carbohydrates such as glycoproteins and glycolipids, which are important membrane components. UDP-galactose may be reacting with glucose in the mammary gland to produce the milk sugar lactose.

Galactosemia: The appearance of high concentration of galactose in the blood after lactose ingestion may be due to galactokinase deficiency or to an uridyl transferase deficiency. In both condition, excess galactose may reduce to galactitol in nerve tissue, lens, liver and kidney causing severe liver damage, severe mental retardation and cataract.

Babies with this deficiency have severe vomiting and diarrhea. Therapy: rapid diagnosis and removal of galactose and lactose from the diet. The uridyl transferase deficiency is more severe, causing elevation of galactose 1-p which inhibits phosphoglucomutase, intering with glycogen synthesis and degradation.

Glycogen Metabolism Glycogen is large, branched polymer consisting of D-glucose residues. The linkage between glucose residues is α-1, 4 except at branch points where the linkage is α-1, 6. On the average, there is a branch every 8 to 10 residues.

Glycogen synthesis and degradation : The fate of glucosyl units released from glycogen: In the liver, glycogen is degraded to maintain blood glucose. Glucose-1-P is converted by phosphoglucomutase to glucose-6-P. Inorganic phosphate is released by glucose 6-phoaphatse, and free glucose enters the blood.

In muscle, glycogen is degraded to provide energy for contraction In muscle, glycogen is degraded to provide energy for contraction. Phosphoglucomutase converts glucose- 1-P to glucose-6-P, which enters the pathway of glycolysis and is converted either to lactate or to CO2 and H2O, generating ATP. Remark: Muscle does not contain glu-6- phosphatase. Therefore, does not contribute to maintenance of blood glucose.

Regulation of Glycogen stores: Glucagon acts on liver cells and epinephrine (adrenaline) acts on both liver and muscle cells to stimulate glycogen degradation. Glycogen degradation in liver In liver, glucagon(during fasting) and epinephrine(during exercise or stress) stimulate glycogen breakdown. The free glucose that is produced is used to maintain blood glucose levels

Glycogen degradation in muscle In muscle, epinephrine stimulate glycogen breakdown to glu-1-P, which is converted to glu-6-P, which enters glycolysis and generate ATP for muscle contraction. Remark: Muscle does not breakdown glycogen in response to glucagon.

Glycogen synthesis Insulin, which is elevated after a meal, stimulates the synthesis of glycogen in both liver and muscle. Insulin stimulates the uptake of glucose by muscle, providing increased substrate for glycogen synthesis.

Glucose metabolism and diabetes mellitus Carbohydrate is digested to simple monosaccharides which are then absorbed. Starch provides glucose directly, while fructose( from dietary sucrose) and galactose (from dietary lactose) are absorbed and also converted into glucose in the liver. Glucose is the common carbohydrate currency of the body.

Insulin Insulin It is a small protein synthesized in the beta cells of the islets of langerhans of the pancreas. It acts through membrane receptors and its main target tissues are liver, muscle and adipose tissue.

Action of insulin  Glucose can not enter the cells of most body tissues in the absence of insulin. The effects of insulin are opposed by other hormones, glucagons, adrenaline, glucocorticoids and growth hormone. The blood glucose concentration is the result of a balance between these different endocrine.  

Insulin stimulate glucose uptake in muscle and adipose tissue Insulin stimulate glycolysis Insulin stimulate glycogen synthesis Insulin stimulate protein synthesis Insulin stimulate uptake of ions (especially K+ ) Insulin stop proteolysis Insulin stop lipolysis Insulin stop gluconeogensis Insulin stop glycogenolysis

Clinical Notes: Diabetes mellitus It is defined as a syndrome characterized by hyperglycemia due to an absolute or relative lake of insulin and or insulin resistance. Types of diabetes mellitus Insulin-dependent diabetes mellitus (IDDM), it is called type 1 may accounts for 15% of all diagnosed cases of diabetes. It can occur at any age but most common in early teenage years (9- 14 yrs). In type 1 the pancreas makes little or no insulin due to autoimmune destruction of insulin producing β-cells, genetic and environmental factors such as a viral infection. The presence of islet cell antibodies in serum predicts future development of diabetes.

Type 2 (NIDDM), may account for 85% of all diagnosed cases of diabetes and most often occurs in adult (40-80 years). Risk factors for type 2 diabetes include older age, obesity, and family history of diabetes. In type 2 the insulin level may be normal or even high. Obesity is the most commonly associated clinical feature. Gestational diabetes; It develops in 2 to 5% of all pregnancies but disappears when a pregnancy is over. Women who have had gestational diabetes are increased risk for later developing type 2 diabetes. Nearly 40% of women with a history of gestational diabetes develop diabetes in future.

What are the symptoms of diabetes? People who think they might have diabetes must visit a physician for diagnosis. They might have some or none of the following symptoms. fatigue polyuria (frequent urination) polydipsia (excessive thirst) polyphagia blurred vision (retinopathy may lead to blindness) or sudden vision changes. Nephropathy leads to renal failure. Weigh loss Dry mouth and very dry skin Sores that are slow to heal More infections than usual impotence

2- Galactosemia The appearance of high concentration of galactose in the blood after lactose ingestion may be due to galactokinase deficiency or to an uridyl transferase deficiency. In both condition, excess galactose may reduce to galactitol in nerve tissue, lens, liver and kidney causing severe liver damage, severe mental retardation and cataract. Babies with this deficiency have severe vomiting and diarrhea. Therapy: rapid diagnosis and removal of galactose and lactose from the diet. The uridyl transferase deficiency is more severe, causing elevation of galactose 1-p which inhibits phosphoglucomutase, intering with glycogen synthesis and degradation.

3- Essential fructosuria Fructokinase is deficient, so fructose can not be metabolized as rapidly as normal. Blood fructose level rise and fructose may be appearing in the urine. This condition is benign.  Essential fructosuria results from a lack of fructokinase in the liver. Fructokinase is deficient, so fructose can not be metabolized as rapidly as normal. Blood fructose levels rise and fructose may appear in the urine. This condition is benign.

4- Hereditary fructose intolerance (fructose poisoning): Absence of aldolase B lead to accumulates of fructose 1-phosphate. Causes severe hypoglycemia (inhibits glucose production) if fructose is ingested, vomiting, jaundices, and hemorrhage. Also, can cause hepatic failure. Therapy: rapid detection and removal of fructose and sucrose from the diet.

5- Phenyl Ketonuria (PKU) The reaction above, catalyzed by phenyl alanine hydroxylase, It the first reaction in catabolism of phenyl alanine. Deficiency of phenyl hydroxylase, phenyl accumulates and it converted to compound such as the phenyl ketone, which give the urine a musty odor, mental retardation, failure to walk or talk, hyperactivity and failure to grow occurs. PKU is treated by restriction of Phe in diet. The complete neuralgic damage can be prevented.

Gluconeogenesis: Gluconeogenesis is the synthesis of glucose from compounds that are not carbohydrate. It occurs mainly in the liver. In human, the major precursors for gluconeogenesis are lactate, amino acids, and glycerol, fatty acids do not produce any net glucose.

It is important for the following reasons; To maintain blood glucose concentration, and provide energy for glucose- dependent tissues (e.g. red blood cells, brain, and renal medulla). Glucose is the source of glyceride glycerol in the adipose tissue (because no glycerokinase in adipose tissue, free glycerol can not be utilized readily in this tissue for triacylglycerol synthesis). In the mammary gland, glucose is required for lactose synthesis. The gluconeogenic pathway helps to clear from the blood metabolic products of other tissues (e.g. lactate produced by muscle and RBC, and glycerol produced by adipose tissue).

Lipid Metabolism Lipids are a heterogeneous group of organic biomolecules soluble in non- polar solvents, such as ether and benzene. Compounds that are related.

Triacylglyceroles ( triglycerides): Triacylglycerols are esters of fatty acids and the trihydroxy sugar alcohol glycerol. Triglycerids, containing 9 calories per gram, are obtained from the diet or are synthesized in the liver after a meal. They are transported in the blood as lipoproteins and stored in adipose tissue. The major class of blood lipoproteins include: Chylomicrons. VLDL (very low density lipoproteins) IDL (intermediate density lipoproteins) LDL (low density lipoproteins) HDL (high density lipoproteins)

In addition to triglycerides they contain proteins, phospholipids, cholesterol, and cholesterol esters. Of these lipoproteins, the highest triacylglycerol (TG) concentrations are found in chylomicrons and VLDL (85% and 60% of the total composition respectively) and a much lower TG concentration is in LD and HDL (about 15% of total). 45% of total composition of HDL is protein and consider the highest among lipoproteins. While chylomicrons and VLDL contains the lowest amounts of protein. Lipoproteins function both to keep lipids soluble as they transport them in the plasma and for delivering their lipid contents to the tissues.

In human, a gradual deposition of lipid, especially cholesterol in tissues. When the lipid deposition contributes to plaque formation, causing the narrowing of blood vessels- a condition known as atherosclerosis. HDL particles are synthesized in the liver and are released into the bloodstream. Functions HDL is excellent acceptors of unesterified cholesterol from the surface of cell membranes and from other circulating lipoproteins (HDL uptake of free cholesterol). Esterification of free cholesterol. During fasting, fatty acids, derived from adipose triglyceride stores, can be oxidized to co2 and H2O by various tissues, producing energy in the form of ATP. In the liver during fasting, fatty acids are converted to ketone bodies, which are released into the blood, taken up by tissues such as muscle and kidney, and oxidized.

Cholesterol metabolism: Cholesterol is synthesized in most tissues of the human body, where it serve as a component of cell membrane. It produced mainly in the liver and intestine. In the liver, cholesterol may be converted to bile salts. In endocrine tissues, cholesterol is may be converted to steroid hormones. A precursor of cholesterol may be converted by a series of tissues to the active form of Vit D Cholesterol is stored in tissues as cholesterol esters and is transported in this form in the blood lipoprotein, which also carry free cholesterol. All the carbons of cholesterol are derived from acetyl co A