Carbohydrate Metabolism PDF

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...

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. Figure 10.2: 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 brush border membrane enzymes The end products of carbohydrate digestion are: Glucose Fructose Galactose  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 Figure 10.3: 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.  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, CO2 and methane 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.  Metabolic Fate of Carbohydrates  After absorption from the intestine, the monosaccharides are carried by the portal circulation to the liver.  In the liver, most of the entering free D-glucose is phosphorylated to glucose-6-phosphate and sugar is trapped within the cell and it cannot diffuse back out of the cell because its plasma membrane is impermeable to the glucose-6-phosphate.  Rest of the glucose passes into the systemic blood supply.  Other dietary monosaccharides D-fructose and D- galactose are phosphorylated and may be converted into glucose in the liver.  Glucose-6-phosphate is an intermediate in several metabolic pathways: ‾ Glycolysis ‾ Pentose phosphate pathway ‾ Glycogenesis, and ‾ Glycogenolysis.  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. Figure 10.5: 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. 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.  Significance of Glycolysis  Glycolysis is the principal route for glucose meta­bolism for the production of ATP molecules.  It also provide pathway for the metabolism of fructose and galactose derived from diet.  Glycolysis has the ability to provide ATP in the absence of oxygen and allows tissues to survive anoxic episodes. Anaerobic glycolysis is an emergency source of ATP.  It provides precursors for biosynthetic pathway, e.g. − Pyruvate to alanine − acetyl CoA to fatty acids biosynthesis. − Glycerol-3-phosphate to triacylglycerol  In erythrocytes glycolysis supplies 2,3-BPG which is required for the transport of oxygen.  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. Regulation of Glycolysis  The glycolytic pathway has dual role. It degrades glucose to generate ATP and it provides building blocks (precursors) for synthesis of fatty acids , cholesterol etc.  The rate of conversion of glucose into pyruvate is regulated to meet these two major cellular needs. Glycolysis is regulated at 3 irreversible steps. These reactions are catalysed by: 1. Hexokinase and glucokinase 2. Phosphofructokinase-I 3. Pyruvate kinase Regulation of Glycolysis in Muscle Glycolysis in muscle is regulated to meet the need of ATP. Control of glycolysis in muscle depends on ratio of ATP to AMP Regulation of Glycolysis in Liver  The liver maintains blood glucose levels: it stores glucose as glycogen when glucose is plentiful and it releases glucose when it is low. Figure 10.9: Regulation of phosphofructokinase by fructose-2,6-bisphosphate Energetics of Glycolysis  The net reaction of aerobic glycolysis of glucose into two molecules pyruvate generates: – 2 molecules of NADH (2.5 x 2 = 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. Disorders of Glycolysis Pyruvate Kinase Deficiency  Genetic deficiency of pyruvate kinase in the erythrocyte leads to hemolytic anemia due to excessive erythrocyte destruction.  Deficiency of pyruvate kinase leads to reduced rate of glycolysis and inadequate supply of ATP impairs the structural integrity of the erythrocyte membrane.  Lysis of the red blood cells result in hemolytic anemia. Lactic Acidosis  Lactic acidosis is the accumulation of lactic acid in the blood to levels that significantly affect the blood pH.  The high concentration of lactate results in lowered blood pH (7.2).  The high blood lactate levels can result from increased formation or decreased utilization of lactate. Hexokinase Deficiency  Genetic defect in the hexokinase of erythrocyte reduces levels of 2, 3-BPG.  Low levels of 2,3-BPG leads to inadequate supply of oxygen to the tissue and results in anemia. Figure 10.14: 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+. Figure 10.15: 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 Figure 10.17: The link between glycolysis and final common pathway citric acid. 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 protein.  Amphibolic (catabolic and anabolic) process , has a dual function.  Pathways originate from the TCA cycle: – Gluconeogenesis – Transamination – Fatty acid synthesis – Heme synthesis. Figure 10.21: Anabolic role of the citric acid cycle.  Regulation of Citric Acid Cycle The rate of citric acid cycle is specifically regulated to meet cell’s needs for ATP. The cycle is regulated primarily by the concentration of ATP and NADH.  An excess of ATP, NADH, and acetyl-CoA occurs when energy supply is sufficient for the cell.  As energy is used, the ratio of ATP/ADP declines and the inhibition of the cycle is relieved.  The primary regulatory enzymes are isocitrate dehydrogenase and α-Ketoglutarate dehydrogenase  In brain tissue control of the citric acid cycle may occur at pyruvate dehydrogenase. Figure 10.20: Regulation of citric acid cycle.  GLUCONEOGENESIS Describe the pathway of Gluconeogenesis, its regulation and significance  Synthesis of glucose from non-carbohydrate precursors.  Liver is the major tissue  During starvation, the kidney is also capable of making glucose by gluconeogenesis.  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.Three reactions of glycolysis are irreversible and cannot be used in gluconeogenesis 4.Involves glycolysis plus some special reactions. Non-carbohydrate Precursors of gluconeogenesis  Lactate  Glycerol  Glucogenic amino acids  Propionic acid  Intermediates of TCA Figure 10.24: Pathway of Cori cycle or lactic acid cycle. Figure 10.25: Conversion of glycerol to dihydroxyacetone phosphate. Figure 10.27: Conversion of propionate to succinyl-CoA. Figure 10.26: Glucose alanine cycle or Cahill cycle. Figure 10.23: Major non-carbohydrate substrates and their entry points into gluconeogenesis. Energetics of Gluconeogenesis Gluconeogenesis is energetically expensive process. For each molecule of glucose formed from pyruvate, six high energy phosphate groups are required. - Four from ATP - Two from GTP - Two molecules of NADH are required for reduction of two molecules of 1,3-bisphosphoglycerate. Conversion glucose to pyruvate by glycolysis would require only two molecules of ATP.  Significance of Gluconeogenesis  Maintains blood glucose level when carbohydrate is not available in sufficient amounts from the diet.  During starvation glucose is provided to the brain and other tissues like erythrocytes, lens, cornea of the eye and kidney  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  Glucagon and epinephrine stimulate gluconeogenesis by inducing 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)  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 byglycogenesis.  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  These enzymes are regulated reciprocally by Allosteric and Hormonal mechanism Allosteric regulation of glycogenesis and glycogenolysis Hormonal regulation Figure 10.37: Regulation of glycogen synthesis by action of protein phosphatase-1. Figure 10.38: 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.  Major purpose of this pathway is generation of NADPH and pentose phosphates  It does not generate ATP.  The pentose phosphate pathway is also called the phosphogluconate pathway or the hexose monophosphate pathway.  Location  The enzymes of pentose phosphate pathway are present in cytosol of all cells.  The pathway is found in all cells.  Tissues most enriched in enzymes of the pentose phosphate pathway are those that have the greater demand for NADPH  Reactions Of The Pathway The reactions of the pathway are divided into two phases: 1.Phase I : Oxidative 2.Phase II : Non-oxidative Oxidative generates pentose phosphates and NADPH Non-oxidative recycles excess pentose phosphates to glucose-6-phosphate Figure 10.39: Outline of pentose phosphate pathway. Phase I: Oxidative Phase II  Significance of Pentose Phosphate Pathway  Pentose phosphate pathway is an alternative route for metabolism of glucose.  Pentose phosphate pathway is a source of: − Ribose-5-phosphate: for synthesis of RNA, DNA and coenzymes as ATP, NAD, FAD and coenzyme A. − NADPH needed for reductive biosynthesis as well as for protection against oxidative stress due to oxygen radicals. NADPH is required in  Biosynthesis of − Fatty acids − Cholesterol − Steroid hormones − Neurotransmitters.  Detoxification reactions  In RBC and cells of cornea and lens, 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. Figure 10:41: Role of NADPH and glutathione  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 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 confusion , 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, and ascorbic acid (except in humans).  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 Figure 10.43: 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-1- phosphate uridyl transferase  The inherited deficiencies of galactokinase and UDP galactose-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-1- phosphate 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. FRUCTOSE METABOLISM  There is no catabolic pathway for metabolising fructose, so it is converted into a metabolite of glucose.  Fructose is channelled into the glycolytic pathway. Entry points of fructose in glycolysis. Fructose metabolism in liver. Fructose-1-phosphate pathway Sorbitol or Polyol Pathway for Formation of Fructose  Because insulin is not required for entry of glucose into the cells (such as lens, retina and nerve) large amounts of glucose may enter these cells during hyperglycemia, e.g., in uncontrolled diabetes.  Elevated intracellular glucose concentrations cause increase in the amount of sorbitol, which accumulated inside the cell causing osmotic damage, leading to cataract formation, peripheral neuropathy, retinopathy and nephropathy. Disorders of Fructose Metabolism Essential Fructosuria  Essential fructosuria is a rare and benign genetic disorder caused by a deficiency of the enzyme fructokinase.  In this disorder fructose cannot be converted to fructose-1-phosphate.  It is asymptomatic with excretion of fructose in urine. Hereditary Fructose Intolerance  It is due to deficiency of the enzyme Aldolase-B. Fructose-1-phosphate cannot be converted to dihydroxyacetone phosphate and glyceraldehyde and therefore fructose-1-phosphate accumulates.  This results in the inhibition of fructokinase and an impaired clearance of fructose from the blood.  Accumulation of fructose-1-phosphate leads to liver and kidney damage. Hypoglycemia occurs due to inhibition of glycogenolysis (because fructose-1-phosphate allosterically inhibits liver glycogen phosphorylase) and gluconeogenesis. Treatment Elimination of foods containing fructose from the diet 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  The liver is the organ responsible for control­ling the concentration of glucose in the blood.  It can rapidly take up and release glucose in response to the concentration of blood glucose.  Two major hormones controlling blood glucose levels are: 1. Insulin (hypoglycemic hormone) 2. Glucagon (hyperglycemic hormone). Figure 10.48: 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 known as postprandial hyperglycemia  Increased level of blood glucose releases insulin  Insulin reduces the blood glucose level in a number of ways Figure 10.49: Various metabolic systems affected by insulin.  Insulin stimulate active transport of glucose across cell membranes of muscle and adipose tissue by stimulating GLUT-4 transporter but not the liver.  Glucose is rapidly taken up into liver as it is freely permeable to glucose via GLUT-2 transporter  In the liver insulin increases the use of glucose by glycolysis by inducing the synthesis of key glycolytic enzymes: − Glucokinase − Phosphofructokinase − Pyruvate kinase  In the muscle and the liver insulin stimulates glycogenesis by stimulating glycogen synthase  Insulin inhibits gluconeogenesis by suppressing the action of key enzymes of gluconeogenesis, e.g. − Pyruvate carboxylase − Phosphoenolpyruvate carboxykinase − Fructose 1,6-bisphosphatase − Glucose-6-phosphatase  In adipose tissue, glucose is converted to the glycerol- 3-phosphate, needed for the formation of triacylglyce­rol (lipogenesis) and inhibits the lipolysis by inhibiting hormone sensitive lipase.  Insulin increases protein synthesis and decreases protein catabolism, thereby decreases release of amino acids.  Insulin inhibits gluconeogenesis by suppressing the action of key enzymes of gluconeogenesis, e.g. − Pyruvate carboxylase − Phosphoenolpyruvate carboxykinase − Fructose 1,6-bisphosphatase − Glucose-6-phosphatase 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. Figure 10.50: Effect of glucagon on blood glucose. 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  Alanine is the predominant amino acid released from muscle to liver by glucose alanine cycle  Lactate formed by oxidation of glucose in skeletal muscle is transported to the liver by lactic acid (Cori) cycle Glucose alanine cycle Figure 10.24: Pathway of Cori cycle or lactic acid cycle. Epinephrine or Adrenaline  Stimulates glycogenolysis in the liver and the muscle by stimulating glycogen phosphorylase  In muscle due to absence of glucose-6-phosphatase, 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 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  Glucose is continuously filtered by the glomeruli but is normally reabsorbed completely in renal tubules.  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.  The 180 mg/100 mL is the limiting level of glucose in the blood, above which tubular reabsorption does not occur which is known as renal threshold value for glucose.  Thus, by excreting extra amount of sugar in the urine during hyperglycemic state and reabsorbing sugar during the hypoglycemic state, the kidney helps in regulating the level of glucose in blood.  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. Alimentary (Lag Storage) glucosuria  The blood sugar level of some individuals after meal rises rapidly above the normal renal threshold (180 mg/dL) and results in glucosuria and known as alimentary glucosuria.  This is due to an increased rate of absorption of glucose from the intestine.  This is called alimentary glucosuria since alimentary canal (GI-tract) is involved.  Characteristic feature of this glucosuria is that usually high blood glucose level returns to normal at 2 hours after a meal. This type of glucosuria is benign (harmless). Renal glucosuria  This is observed due to impaired tubular reabsorption of glucose and have lowered renal threshold (may be 130 to 150 mg %) for glucose.  In such cases, the blood glucose level is below 180 mg %, i.e. below normal renal threshold for glucose, but glucose appears in the urine due to lowered renal threshold.  Renal glucosuria is a benign condition, unrelated to diabetes and it may occur temporarily in pregnancy without symptoms of diabetes. Renal glucosuria may result from inherited defects in the kidney or it may be acquired as a result of kidney disease. Diabetic Glucosuria  Diabetic glucosuria is a pathological condition and is due to deficiency or lack of insulin which causes diabetes mellitus.  Although the renal threshold is normal, as blood glucose level exceeds the renal threshold, the excess glucose passes into the urine to produce glucosuria. 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 insuline 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).  The resultant hyperglycemia exceeds the glucose renal threshold for reabsorption, and glycosuria results.  Glycosuria induces an osmotic diuresis and, consequently resulting in, polyuria, dehydration and thirst due to profound loss of water and electrolytes.  The catabolism of proteins and fats induces a negative energy balance which in turn leads to increasing appetite polyphagia.  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 lack of insulin decreased synthesis of lipoprotein lipase leads to elevated levels of plasma VLDL, resulting in hypertriglyceridemia  Due to increased rate of proteolysis the amino acids released from muscle are converted to glucose by gluconeogenesis. Secondary effects: Heart attack Stroke Nephropathy Retinopathy and blindness, Cataract. Hypertension Atherosclerosis  Gestational Diabetes Mellitus (GDM)  Gestational diabetes mellitus is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy which resolve after pregnancy  Undiagnosed or inadequately treated GDM can lead to maternal & fetal complications.  Gestational diabetes mellitus should be diagnosed at any time in pregnancy if one or more of the following criteria are met: - Fasting plasma glucose 92 -125 mg/dl - 2-hour plasma glucose 153 -199 mg/dl following a 75g oral glucose load  Women with GDM and their offspring are at increased risk of developing type -II diabetes later in life.  Maternal risks of GDM include pre-eclampsia  Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine.  Fetal risks include spontaneous abortion, intra-uterine death, stillbirth, congenital malformation etc 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. Thank you