CARBOHYDRATE METABOLISM Digestion, Absorption and Transport of Carbohydrates The dietary carbohydrate consists of: Polysaccharides: Starch, glycogen and cellulose Disaccharides: Sucrose, maltose and lactose Monosaccharides: Mainly glucose and fructose Digestion in Mouth Salivary glands secrete α-amylase. Acts briefly on dietary starch and glycogen breaking some α-(1 → 4) bonds. α-amylase hydrolyzes starch into dextrins. Action of α-amylase on starch or glycogen Digestion in Stomach Carbohydrate digestion halts temporarily in stomach. Digestion in Intestine There are two phases of intestinal digestion: 1. Digestion due to pancreatic α-amylase 2. Digestion due to intestinal enzymes : Sucrase Maltase Lactase Isomaltase Digestion due to pancreatic α-amylase Pancreatic α-amylase degrades dextrins further into a mixture of : Maltose, Isomaltose and α-limit dextrin. The α-limit dextrins are smaller oligosaccharides containing 3 to 5 glucose units. Digestion due to intestinal enzymes The end products of carbohydrate digestion are: Glucose Fructose Galactose Flow sheet of digestion of carbohydrates. Absorption of Carbohydrates Two mechanisms are responsible for the absorption of monosaccharides: 1. Active transport against a concentration gradient, from a low glucose concentration to a higher concentration. 2. Facilitative transport, with concentration gradient , from a higher concentration to lower conc. Active Transport The transport of glucose and galactose occurs by an active transport. Active transport requires: - Energy - A specific transport protein - Presence of sodium ions Transport of glucose, fructose, galactose, mannose. Facilitative Transport Fructose and mannose are transported by a Na+ independent facilitative diffusion process, requiring specific glucose transporter, GLUT-5. Movement of sugar in facilitative diffusion is strictly from a higher concentration to a lower one until it reaches an equilibrium. Transport of Carbohydrates Sodium independent transporter, GLUT-2 facilitates transport of sugars out of the mucosal cells. Through portal circulation transported to the liver. Lactose Intolerance Intolerance to lactose (the sugar of milk). Due to deficiency of enzyme lactase. lactose undergoes bacterial fermentation with the production of: - H2 and CO2 gases - acetic acid , propionic acid and butyric acid Abdominal cramps and flatulence results from the: -- Accumulation of gases -- Osmotically active products that draw water from the intestinal cells into the lumen resulting in diarrhoea and dehydration. Treatment for this disorder is simply to remove lactose from the diet. GLYCOLYSIS Embden Meyerhof pathway. Definition Glycolysis is the sequence of reactions that converts glucose into pyruvate in the presence of oxygen (aerobic) or lactate in the absence of oxygen (anaerobic) with the production of ATP. Location Glycolysis is found in cytosol of all cells. Reactions Of Glycolysis I st phase: Energy requiring phase. II nd phase: Energy generating phase. Phases of the glycolytic pathway. Anaerobic Glycolysis The re-oxidation of NADH by conversion of pyruvate to lactate by lactate dehydrogenase Tissues that function under hypoxic conditions produce lactate, e.g. skeletal muscle, smooth muscle and erythrocytes. Regulation of Glycolysis Glycolysis is regulated at 3 irreversible steps.These reactions are catalysed by: 1. Hexokinase and glucokinase 2. Phosphofructokinase-I 3. Pyruvate kinase Regulation of phosphofructokinase by fructose-2,6bisphosphate Regulation of liver pyruvate kinase. Significance of Glycolysis Glycolysis is the principal route for glucose metabolism for the production of ATP molecules. Glycolysis provide ATP in the absence of oxygen and allows tissues to survive anoxic episodes. In erythrocytes, glycolysis supplies 2,3-BPG which is required for transport of oxygen by Hb. Generates precursors for biosynthetic pathway: Pyruvate transaminated to amino acid alanine. Pyruvate provides substrate acetyl-CoA for fatty acid biosynthesis. Glycerol-3-phosphate, required for synthesis of triacylglycerol is derived from glycolysis. It also provide pathway for the metabolism of fructose and galactose derived from diet. In mammals, glucose is the only fuel that the brain uses under non-starvation conditions and the only fuel that red blood cells can use at all. Glycolysis & Dental Caries Energetic of Glycolysis The net reaction of aerobic glycolysis of glucose into two molecules pyruvate generates: – 2 molecules of NADH (2.5 x2 = 5) – 4 molecules of ATP at subs level phosphorylation Two molecules of ATP per mole of glucose are consumed The net gain is 7 moles of ATP Under aerobic conditions, 7 molecules of ATP are produced. In anaerobic glycolysis, on the other hand, only 2 moles of ATP are produced per molecule of glucose. Rapoport Lubering Cycle In Rapoport lubering cycle, production of ATP by substrate phosphorylation from 1,3-BPG to 3-BPG is bypassed in the erythrocyte. There is no net production of ATP when glycolysis takes this route. Significance of Rapoport Lubering Cycle It supplies 2,3-BPG required for transport of oxygen by hemoglobin. 2,3-BPG regulates the binding and release of oxygen from hemoglobin 2, 3-BPG present in erythrocytes acts as a buffer. Catabolic fates of pyruvate. Conversion Of Pyruvate To Acetyl-CoA Pyruvate is converted to acetyl CoA by oxidative decarboxylation in mitochondria. Irreversible reaction catalyzed by a multienzyme complex pyruvate dehydrogenase (PDH) PDH requires five coenzymes : thiamine pyrophosphate (TPP), lipoate, coenzyme-A, FAD and NAD+. Oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex. Energetics in conversion of pyruvate to Acetyl Co A One molecule of NADH is produced for each molecule of pyruvate. Oxidation of NADH by electron transport chain results in synthesis of 2.5 ATP molecules Citric Acid Cycle Citric acid cycle or Krebs cycle or tricarboxylic acid (TCA) cycle Definition The citric acid cycle is a series of reactions in mitochondria that brings about the catabolism of acetyl-CoA to CO2 and H2O with generation of ATP. Energetics of Citric Acid Cycle  Three molecules of NADH and one FADH2 are produced  One molecule of ATP is generated at substrate level during the conversion of succinyl-CoA to succinate. Total 10 ATP are generated from one mole of acetyl-CoA. Significance of Citric Acid Cycle  Provide energy in the form of ATP.  Final common pathway for the oxidation of carbohydrates, lipids, and proteins.  Amphibolic (catabolic and anabolic) process , has a dual function.  Pathways originate from the TCA cycle: – Gluconeogenesis – Transamination – Fatty acid synthesis – Heme synthesis. Amphibolic role of the citric acid cycle Regulation of Citric Acid Cycle Citric acid cycle is regulated at three steps by: 1. Citrate synthase 2. Isocitrate dehydrogenase 3. α-ketoglutarate dehydrogenase. Activities of these enzymes are dependent on the energy status of the cycle. Excess of ATP, NADH and succinyl-CoA, which signals high energy status of the cell, inhibit these enzymes. High level of ADP which signals low energy status of the cell stimulates the operation of the cycle. Regulation of citric acid cycle. GLUCONEOGENESIS Synthesis of glucose from non-carbohydrate precursors. Location of Gluconeogenesis Liver is the major tissue During starvation, the kidney is also capable of making glucose by gluconeogenesis. Non-carbohydrate Precursors of gluconeogenesis  Lactate  Glycerol  Glucogenic amino acids  Propionic acid  Intermediates of TCA Major non-carbohydrate substrates and their entry points into gluconeogenesis. Conversion of propionate to succinyl-CoA. Conversion of glycerol to dihydroxyacetone phosphate. Pathway of Cori cycle or lactic acid cycle. Glucose alanine cycle or Cahill cycle. Characteristics of Gluconeogenesis 1. Glycolysis and gluconeogenesis share the same pathway but in opposite direction. 2. Seven reversible reactions of glycolysis are used by gluconeogenesis. 3. Involves glycolysis plus some special reactions. Significance of Gluconeogenesis 1. Maintains blood glucose level when carbohydrate is not available in sufficient amounts from the diet. 2. During starvation glucose is provided to the brain and other tissues like erythrocytes, lens, cornea of the eye and kidney 3. Gluconeogenesis is used to clear the products of metabolism of other tissues from blood. Lactate, produced by muscle and erythrocytes Glycerol produced by adipose tissue Propionyl-CoA produced by oxidation of odd carbon number fatty acids and carbon skeleton of some amino acids. Regulation of Gluconeogenesis Gluconeogenesis regulated by four key enzymes: 1. Pyruvate carboxylase 2. Phosphoenolpyruvate carboxykinase 3. Fructose-1,6-bisphosphatase 4. Glucose-6-phosphatase The hormones glucagon and epinephrine stimulate gluconeogenesis by inducing the synthesis of the key enzymes Insulin inhibits the gluconeogenesis by repressing their synthesis. During starvation and in diabetes mellitus, high level of glucagon stimulates gluconeogenesis. However in well-fed state, insulin suppresses the gluconeogenesis. Glycogen Metabolism  Glycogen metabolism includes: Glycogenesis Glycogenolysis  Glycogenesis and glycogenolysis are both cytosolic processes. Glycogenesis Glycogenesis is the pathway for the formation of glycogen from glucose. This process requires energy, supplied by ATP and uridine triphosphate (UTP). It occurs in muscle and liver. Schematic representation of glycogenesis (mechanism of branching) Schematic representation of glycogenesis (mechanism of branching) Glycogenolysis Degradation of glycogen to glucose-6-phosphate in muscle and to glucose in liver Schematic representation of glycogenolysis (mechanism of debranching) Significance of Glycogenolysis and Glycogenesis In liver Following a meal, excess glucose is removed from the portal circulation and stored as glycogen by glycogenesis. Conversely, between meals, blood glucose levels are maintained within the normal range by release of glucose from liver glycogen by glycogenolysis. In muscle The function of muscle glycogen is to act as a readily available source of glucose within the muscle itself during muscle contraction. The muscle cannot release glucose into the blood, because of the absence of glucose-6-phosphatase Muscle glycogen stores are used exclusively by muscle Regulation of Glycogenesis and Glycogenolysis The principal enzymes controlling glycogen metabolism are: - Glycogen phosphorylase - Glycogen synthase Principal enzymes are regulated reciprocally: - Hormonal regulation - Allosteric regulation. Allosteric regulation of glycogenesis and glycogenolysis Hormonal regulation Regulation of glycogen synthesis by action of protein phosphatase-1. Inactivation of glycogen synthase kinase by insulin. Glycogen Storage Disease Glycogen storage disease is a group of genetic diseases, that result from a defect in enzyme required for either glycogen synthesis or degradation. Characterized by deposition of either normal or abnormal glycogen in the specific tissues Pentose Phosphate Pathway The pentose phosphate pathway is an alternative route for the oxidation of glucose. It is the pathway for formation of pentose phosphate. It is also called hexose monophosphate shunt. Characteristics of Pentose Phosphate pathway A multicyclic process It does not generate ATP. Three molecules of glucose-6-phosphate give rise to three molecules of CO2 and three molecules of 5-carbon sugars Location The enzymes of pentose phosphate pathway are present in cytosol of all cells. Pathway divided in to two phases: 1. Phase I : Oxidative irreversible phase 2. Phase II : Non-oxidative reversible phase. Outline of pentose phosphate pathway. Phase I: Oxidative Phase II Significance of Pentose Phosphate Pathway The pentoses (ribose-5-phosphate) required for the biosynthesis of nucteotide and nucleic acids RNA and DNA are provided by pentose phosphate pathway. It provides a route for the interconversion of pentoses and hexoses It generates NADPH which are required in 1. Biosynthesis of Fatty acids Cholesterol Steroid hormones Neurotransmitters. 2. Detoxification reactions In RBC, NADPH is required to maintain the level of reduced glutathione. The reduced glutathione protects the RBC membrane from toxic effect of H2O2 by reducing H2O2to H2O NADPH also keeps iron of hemoglobin in reduced ferrous (Fe2+) state and prevents the formation of methemoglobin. Role of NADPH and glutathione Macrophage bactericidal activity Regulation of Pentose Phosphate Pathway Glucose-6-phosphate dehydrogenase (G-6-PD) is the rate limiting enzyme. The activity of this enzyme is regulated by cellular concentration of NADPH. NADPH is competitive inhibitor of G-6-PD. An increased concentration of NADPH decreases activity of G-6-PD, for example: – Under well-fed condition, the level of NADPH decreases and pentose phosphate pathway is stimulated. – In starvation and diabetes, the level of NADPH is high and inhibits the pathway. Insulin enhances the pathway by inducing the enzyme G-6-PD and 6-phosphogluconolactone dehydrogenase. Disorders of Pentose Phosphate Pathway Deficiency of Glucose-6-phosphate dehydrogenase (G-6-PD) Glucose 6-phosphate dehydrogenase deficiency is X linked inherited disorder, characterized by hemolytic anemia, due to excessive hemolysis. Most individuals are asymptomatic. However, some individuals with G-6-PD deficiency develop hemolytic anemia if they are exposed to drugs like antibiotic, antipyretic or Antimalarial, e.g. primaquine ,chloroquine A 20-year-old male suffering from malaria was treated with chloroquine and manifested as hemolytic anemia. Provisional diagnosis of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency was made. Questions a. Which reaction is catalyzed by the enzyme G-6-PD? b. How does deficiency of G-6-PD produce hemolytic anemia? c. Name the pathway in which this reaction occurs. G-6-PD deficiency and resistance to malaria Persons with G-6-PD deficiency cannot support growth of the malarial parasite, Plasmodium falciparum and thus are less susceptible to malaria than the normal person. Wernicke-Korsakoff Syndrome A genetic disorder due to reduced activity of the TPP-dependent transketolase enzyme. The reduced activity of transketolase is due to reduced affinity for TPP In the chronic thiamine deficiency the transketolase enzyme has a much reduced activity leading to the Wernicke- Korsakoff syndrome. The symptoms of Wernicke-Korsakoff syndrome include weakness, mental disorder, loss of memory, partial paralysis, etc. Uronic Acid Pathway (Glucuronic Acid Cycle) Definition A pathway in liver for the conversion of glucose to glucuronic acid, ascorbic acid (except in humans) and pentoses An alternative oxidative pathway for glucose but does not generate ATP Significance of Uronic Acid Pathway Uronic acid pathway is a source of UDP -glucuronate. UDP-glucuronate is a precursor in synthesis of proteoglycans (glycosaminoglycans) and glycoproteins. UDP-glucuronate is involved in detoxification reactions that occur in liver e.g.bilirubin,steroid hormones Metabolic role of UDP-glucuronate. The uronic acid pathway is a source of UDP-glucose, which is used for glycogen formation. The uronic acid pathway provides a mechanism by which dietary D-xylulose can enter the central metabolic pathway Galactose Metabolism And Galactosemia Galactose is derived from disaccharide, lactose (the milk sugar) of the diet. It is important for the formation of: Glycolipids Glycoproteins Proteoglycans Lactose during lactation. Galactose is readily converted in the liver to glucose. Galactosemia It is an inborn error of galactose metabolism. Caused by deficiency of enzyme galactose-1phosphate uridyl transferase The inherited deficiencies of galactokinase and UDPgalactose-4-epimerase also lead to minor types of galactosemia. It causes a rise in galactose in blood and urine and leads to accumulation of galactose and galactose-1-phosphate in blood, liver, brain , kidney and eye lenses. In these organs, the galactose is reduced to galactitol by the enzyme aldose reductase. Clinical findings The accumulation of galactitol and galactose-1phosphate in liver, brain and eye lenses causes: - Liver failure (hepatomegaly followed by cirrhosis) - Mental retardation and - Cataract formation Treatment: Galactose in milk and milk products should be eliminated from the diet. Sufficient galactose for the body’s need can be synthesized endogenously as UDP-galactose. A 6-month-old infant was presented with elevated blood and urine galactose. Questions a. Name the disease. b. Give the biochemical steps related to the disease and point out the metabolic defect. c. What are the clinical manifestation of the disease BLOOD GLUCOSE LEVEL AND ITS REGULATION Blood glucose level maintained within 70-100 mg/dl. Levels above normal range : Hyperglycemia, Levels below normal range : Hypoglycemia. After the intake of a carbohydrate meal, blood glucose level rises to 120-140 mg/dl. Factors involved in the regulation of blood glucose are: 1. Hormones 2. Metabolic processes 3. Renal mechanism Two major hormones controlling blood glucose levels are: 1. Insulin (hypoglycemic hormone) 2. Glucagon (hyperglycemic hormone). Reciprocal control of insulin and glucagon on the homeostasis. Maintenance of Glucose in Fed State (Hyperglycemic condition) Increased blood glucose level ,hyperglycemia occur after each meal Increased level of blood glucose releases insulin Insulin reduces the blood glucose level in a number of ways Various metabolic systems affected by insulin. Effect of glucagon on blood glucose. Maintenance of Blood Glucose in Fasting State (Hypoglycemic Condition) . Decreased level of blood glucose (hypoglycemia) causes release of hyperglycemic hormones, e.g.  Glucagon  Epinephrine or adrenaline  Glucocorticoids  Growth hormone  ACTH  Thyroxin. Glucagon Glucagon opposes the action of insulin. It acts primarily in the liver as follows: In the liver, it stimulates glycogenolysis & inhibits glycogen synthesis Enhances gluconeogenesis from amino acids and lactic acids Epinephrine or Adrenaline Stimulates glycogenolysis in the liver and the muscle by stimulating glycogen phosphorylase In muscle due to absence of glucose-6phosphatase, glycogenolysis results with the formation of lactate, whereas in the liver, glucose is the main product, leading to increase in blood glucose. Glucocorticoids Increases Gluconeogenesis by increasing the: activity of enzymes of gluconeogenesis. protein catabolism to provide glucogenic amino acid hepatic uptake of amino acids. Inhibit utilization of glucose in extra-hepatic tissues. Growth hormone and anterior pituitary hormones Growth hormone and ACTH antagonise the action of insulin. Growth hormone decreases glucose uptake in the muscle and ACTH decreases glucose utilization by the tissue. Thyroxine Accelerates hepatic glycogenolysis with consequent rise in blood glucose. It may also increase the rate of absorption of hexoses from the intestine Renal Control Mechanism If the blood glucose level is raised above 180 mg/100 ml, complete tubular reabsorption of glucose does not occur and the extra amount appears in the urine causing glycosuria. GLYCOSURIA Excretion of detectable amount of sugar in urine is known as glycosuria. Glycosuria results from the rise of blood glucose above its renal threshold level (180 mg%) Glycosuria may be due to various reasons on the basis of which is classified into following groups: 1. Alimentary glycosuria 2. Renal glycosuria 3. Diabetic glycosuria. DIABETES MELLITUS Definition Syndrome of impaired carbohydrate,fat and protein metabolism, caused by either: Lack of insulin secretion or Decreased sensitivity of tissues to insulin. Classification of Diabetes Mellitus 1. Type I diabetes mellitus or insulin dependent diabetes mellitus (IDDM) or juvenile diabetes. 2. Type II diabètes mellites or non insulin dépendent diabetes mellitus (NIDDM) or adult diabetes mellitus. Type l diabetes mellitus Cause Lack of insulin secretion due to destruction of pancreatic beta cells. The destructions of beta cells may be due to: 1. Viral infection 2. Autoimmune disorder 3. Hereditary tendency of beta cell degeneration. Onset At about 14 years of age and for this reason it is called juvenile diabetes mellitus. Juvenile’ means teenage in Latin. Symptoms It develops symptoms very abruptly with: – Polyuria (frequent urination) – Polydypsia (excessive thirst) – Polyphagia (excessive hunger). Loss of body weight, weakness, and tiredness. Hyperglycemia with glycosuria and ketoacidosis The patients of type-I diabetes mellitus are not obese. Treatment Since patients of IDDM (type-I) fail to secrete insulin, administration of exogenous insulin is required. Type II diabetes mellitus Cause Decreased sensitivity of target tissues to insulin. (insulin resistance). Inadequate insulin receptors on cell surfaces of target tissues. This syndrome is often found in an obese person. Onset After age 40 and the disorder develops gradually. Therefore, this syndrome is referred to as adult onset diabetes. Symptoms The symptoms are developed gradually Similar to that of type-I Except Ketoacidosis is usually not present in type II diabetes mellitus Treatment NIDDM (type-II) can be treated in early stages by diet control, exercise and weight reduction No exogenous insulin administration is required.. Drugs that increase insulin sensitivity or drugs that cause additional release of insulin by the pancreas may be used. In the later stages insulin administration is required. Metabolic changes occur in diabetes mellitus Changes in levels of insulin and glucagon affect metabolism in three tissues; liver, muscle and adipose tissue. The lack of insulin activity results in failure of transfer of glucose from the blood into cells and leads to hyperglycemia. Elevated levels of blood glucose and ketone bodies are the characteristic feature of untreated diabetes mellitus. The body responds as it were in the fasting state with stimulation of: – Glycogenolysis – Gluconeogenesis – Lipolysis – Proteolysis. Increased lipolysis leads to increased formation of ketone bodies causing ketoacidosis. Due to increased rate of proteolysis the amino acids released from muscle are converted to glucose by gluconeogenesis. GLUCOSE TOLERANCE TEST (GTT) Glucose tolerance test (GTT) is a test to assess the ability of the body to utilize glucose. GTT can be performed by two ways: 1. Oral GTT 2. Intravenous GTT Types of Glucose Tolerance Curves 1. Normal glucose tolerance curve 2. Decreased glucose tolerance 3. Increased glucose tolerance. Decreased glucose tolerance occurs in: Diabetes mellitus Certain endocrine disorders like: – Hyperthyroidism – Hyperpituitarism – Hyperadrenalism (Cushing’s syndrome). Increased glucose tolerance occurs in : – Hypothyroidism (myxedema, cretinism) – Hypoadrenalism (Addison’s disease) – Hypopituitarism. The glucose tolerance curves Significance of GTT GTT is not necessary in symptomatic or in known cases of diabetic patients GTT is most important in the investigation of asymptomatic hyperglycemia or glycosuria such as renal glycosuria & alimentary glycosuria. Give useful information of endocrine dysfunctions. It is also helpful in recognizing milder cases of diabetes.

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