Clinical Chemistry Chapter 1- Carbohydrates PDF

Al- Balqa' Applied University (BAU) Zarqa University College Dept. Of Allied Medical Sciences Clinical Chemistry Chapter 1: Carbohydrate : Normal and abnormal carbohydrate metabolism By : Dr Laila Alsawalha Lecture overview Structure of Carbohydrate...

Al- Balqa' Applied University (BAU) Zarqa University College Dept. Of Allied Medical Sciences Clinical Chemistry Chapter 1: Carbohydrate : Normal and abnormal carbohydrate metabolism By : Dr Laila Alsawalha Lecture overview Structure of Carbohydrate Glucose Metabolism Hormonal regulation of glucose in blood by Insulin Insulin Mechanism of action Carbohydrates Carbohydrates, including sugars and starch, are widely distributed in plants and animals They perform multiple functions, such as being structural components as in RNA and DNA ( ribose and deoxyribose sugars) and providing a source of energy ( glucose) Glucose is derived from: 1- the breakdown of carbohydrates in the diet or in body stores. 2- endogenous synthesis from protein or from the glycerol moiety of triglycerides When energy intake exceeds expenditure, the excess is converted to fat and glycogen for storage in adipose tissue and liver or muscle, respectively. When energy expenditure exceeds caloric intake, endogenous glucose formation occurs from the breakdown of carbohydrate stores and from non carbohydrate sources ( amino acids, lactate, and glycerol) Insulin, glucagon, and epinephrine maintain the glucose concentration in the blood within a fairly narrow interval under diverse conditions ( feeding, fasting, or severe exercise) Classification and Structure 1) Monosaccharides (simple sugars) : Can be classified by one of two methods: A) According to the number of carbon atoms : Trioses, Tetroses, Pentoses, Hexoses, Heptoses, Octoses. 4 B) According to the characteristic carbonyl group: Aldehyde group or ketone group a) Aldo sugars: Aldoses : Monosaccharaides containing aldehyde group e.g. glucose, ribose. b) Keto sugars: Ketoses : Monosaccharaides containing ketone group e.g. fructose, ribulose. 5 2) Disaccharide contain Two monosaccharide units. 3) Oligosaccharides contain from three to about ten monosaccharide units. 4) Polysaccharides contain more than ten monosaccharide units and can be hundreds of sugar units in length. 6  Complex carbohydrates Carbohydrates can be attached by glycosidic bonds to non-carbohydrate structures, including: purines and pyrimidines (found in nucleic acids), aromatic rings (such as those found in steroids and bilirubin), proteins (found in glycoproteins and glycosaminoglycan) lipids (found in glycolipids). 7  A. Digestion of carbohydrates begins in the mouth The major dietary polysaccharides are of animal (glycogen) and plant origin (starch, composed of amylose and amylopectin). During mastication, salivary α-amylase acts briefly on dietary starch in a random manner, breaking some α(1- 4) bonds. 8 9 10 B. Further digestion of carbohydrates by pancreatic enzymes occurs in the small intestine When the acidic stomach contents reach the small intestine, they are neutralized by bicarbonate secreted by the pancreas, and pancreatic α- amylase continues the process of starch digestion. 11  C- Digestion by intestinal enzymes: The final digestive processes occur primarily at the mucosal lining of upper jejunum and include the action of several disacchardases. For example, Isomaltase cleaves the α(1→6) bond in isomaltose to two glucose molecules Maltase converts maltose to two glucose molecules Sucrase converts sucrose to glucose and fructose. Lactase converts lactose to glucose and galactose. Trehalase converts trehalose found in mushrooms and other fungi to two glucose molecules. 12  D. Absorption of monosaccharides by intestinal mucosal cells The duodenum and upper jejunum absorb the bulk of the dietary sugars. However, different sugars have different mechanisms of absorption. 1. galactose and glucose are transported into the mucosal cells by an active, energy-requiring process that requires a concurrent uptake of sodium ions; the transporter protein is the sodium-dependent glucose cotransporter 1 (SGLT-1). 13 Fate of glucose Glucose is the only carbohydrate to be either directly utilized for energy or stored as glycogen After glucose enters the cell, it is quickly shunted into 1 of 3 possible metabolic pathways depending on the availability of substrates or the nutritional status of the cell The first step for all 3 pathways requires glucose to be converted to G-6-p using ATP, this reaction is catalyzed by the enzyme hexokinase. G-6-p can enter the Embden-Meyerhof pathway or the hexose monophosphate shunt, or can be converted to glycogen. The first 2 pathways are important for the generation of energy from glucose, the latter pathway is important for the storage of glucose Glycogenesis is the name for the conversion of glucose to glycogen, the reverse process, the breakdown of glycogen to glucose is termed glycogenolysis. The formation of glucose from noncarbohydrate sources, such as aa, glycerol or lactate is termed gluconeogenesis. 14  During a brief fast, a decline in blood glucose concentration is prevented by breakdown of glycogen stored in the liver and synthesis of glucose in the liver. A small amount of glucose also may be derived from synthesis within the kidneys. These organs contain glucose-6-phosphatase which is necessary to produce glucose from G-6-p In cases of more prolonged fasting ( >42h), gluconeogenesis accounts for essentially all the glucose production. In contrast, after a meal the absorbed glucose is converted to glycogen or fat Normal glucose disposal depends on: 1.The ability of the pancreas to secrete insulin 2.The ability of insulin to promote uptake of glucose into peripheral tissues 3.The ability of insulin to suppress hepatic glucose production 15 Regulation of glucose metabolism Hormonal regulation Hormones function at several levels and in many different tissues. Their actions can affect the entry of glucose into the cell and can also influence the fate of glucose once it has entered the cell Control of blood glucose is under 2 major hormones: insulin and glucagon. Other hormones and neuroendocrine substances also exert some control over blood glucose concentrations The endocrine system must assist in the meeting of 3 requirements: 1- a steady supply of glucose must be available under all normal circumstances 2- Excess glucose must be safely stored to prevent it from causing alterations in fluid and electrolyte balance or being lost 3- Stored glucose must be used to supply the ECF when glucose is not being absorbed by the gut 16 ❖ Insulin Insulin is a peptide hormone that is synthesized in the β cells of the pancreatic islets of langerhans. Insulin is the primary hormone responsible for the entry of glucose into cells, so insulin production and release increases after a meal, when ECF glucose concentration are increasing This hormone is synthesized and stored in vesicles in the cytosol of the β cells until it is needed It is an anabolic hormone that stimulates the uptake of glucose into fat and muscle, promotes the conversion of glucose to glycogen or fat for storage, inhibits glucose production by the liver, stimulates protein synthesis and inhibits protein breakdown Human insulin consists of 51 aa in 2 chains A and B joined by 2 disulfide bridges with a third one within the A chain 17 Insulin structure  Insulin Preproinsulin, a protein of about 100aa is not detectable in the circulation under normal conditions because it is enzymatically cleaved and converted to proinsulin Proinsulin is stored in secretory granules in the Golgi complex of the β cells, where proteolytic cleavage to insulin and C-peptide occurs. This process is catalyzed by 2 Ca-regulated endopeptidases, namely prohormone convertases 1 and 2 At the cell membrane, the insulin and the C-peptide are released into the circulation into equimolar amounts 19 Insulin Although insulin and C-peptide are secreted into the portal circulation in equimolar amounts, fasting concentrations of C-peptide are 5-10 fold higher than those of insulin due to the longer half-life of C-peptide ( about 35 min). C-peptide is removed from the circulation by the kidneys and degraded, with a fraction excreted unchanged in the urine - Insulin release in response to an increase in ECF glucose concentration is biphasic. There is an initial small rapid increase in circulating insulin that is additional to the prolonged release of insulin from the β cell, insulin release is stopped when ECF glucose concentration begin to decrease - Insulin binds to a cell surface receptor of most cells except neurons, RBCs and retinal epithelium ( these cells obtain glucose without endocrine control) - On all other cells, H-R complex initiates a chain of events in the cell, which first increases the number of glucose transporters on the cell surface and then increases glycogenesis Insulin action Insulin action Effects of insulin on hepatocytes Insulin has 4 major effects on liver cells: 1. Insulin promotes glycogen synthesis from glucose by enhancing the transcription of glucokinase and by activating glycogen synthase, 22 Insulin action - additionally, insulin inhibits glycogen breakdown to glucose by decreasing the activity of glycogen phosphorylase and glucose-6-phosphatase Insulin effect on carbohydrate oxidation 2. Insulin promotes glycolysis and carbohydrate oxidation by increasing the activity of glucokinase, phosphofructokinase and pyruvate kinase Insulin action Insulin also promotes glucose metabolism via the hexose monophosphate shunt, in addition to that, insulin promotes the oxidation of pyruvate by stimulating pyruvate dehydrogenase. Insulin inhibits gluconeogenesis by inhibiting the activity of phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase Insulin action 3. Insulin promotes the synthesis and storage of fats by increasing the activity of acetyl CoA carboxylase and fatty acid synthase,  insulin also indirectly inhibits fat oxidation because the increased levels of enzyme which is responsible for the transport of fatty acids into the mitochondria where fat oxidation occurs 4. By mechanisms that are not well understood, insulin promotes protein synthesis and inhibits protein breakdown Chapter1-Carbohydrates Effects of insulin on muscle cells Insulin has 4 major effects on muscle cells: ❑Insulin promotes glucose uptake by recruiting GLUT4 transporters to the plasma membrane ❑Insulin promotes glycogen synthesis from glucose ❑Insulin promotes glycolysis and carbohydrate oxidation Note: There is little or no gluconeogenesis in muscles ❑Insulin promotes protein synthesis and inhibits protein breakdown Chapter1-Carbohydrates Effects of insulin on adipocytes Insulin promotes glucose uptake by recruiting GLUT4 transporters to the plasma membrane - Insulin also promotes the conversion of pyruvate to free fatty acids by stimulating pyruvate dehydrogenase and acetyl CoA carboxylase - Insulin promotes the esterification of α-glycerol-phosphate with free fatty acids to form triglycerides which the adipocytes stores in fat droplets, insulin inhibits hormone-sensitive triglyceride lipase which would break the triglycerides down into glycerol and free fatty acids