Hormonal Regulation of Metabolism PDF

B. Degradation and inactivation  Degradation of peptide hormones often starts in the blood plasma or on the vascular walls; it is particularly intensive in the kidneys  All of the degradation reactions lead to amino acids, which become available to the metabolism again I. Extracellular...

B. Degradation and inactivation  Degradation of peptide hormones often starts in the blood plasma or on the vascular walls; it is particularly intensive in the kidneys  All of the degradation reactions lead to amino acids, which become available to the metabolism again I. Extracellular degradation Several peptides that contain disulfide bonds (e. g., insulin) can be inactivated by reductive cleavage of the disulfide bonds by reductase Peptides and proteins are cleaved by peptidases starting from one end of the peptide by exopeptidases Peptides and proteins are cleaved by proteinases (endopeptidases) in the middle II. Intracellular degradation Some peptide hormones and proteohormones are removed from the blood by binding to their receptors with subsequent endocytosis of the hormone– receptor complex; They are then broken down in the lysosomes Mechanisms of action of hydrophilic hormones  The messages transmitted by hydrophilic signaling substances to the interior of the cell by membrane receptors  These receptors bind the hormone on the outside of the cell “on the plasma membrane” and activate a new second signal on the inside  In the interior of the cell, this secondary signal influences the activity of enzymes or ion channels A. Mechanisms of action Receptors for hydrophilic hormones: - Receptors are classified into three different types according to their structure I. 1-Helix receptors Proteins that span the membrane with only one α-helix On their inner (cytoplasmic) side, they have domains with allosterically activatable enzyme activity. In most cases, these are tyrosine kinases 14  Hormones act via 1-helix receptors: Insulin, growth factors and cytokines o Binding of the signaling substance leads to activation of internal kinase activity. o The activated kinase phosphorylates itself using ATP (auto- phosphorylation), o Also phosphorylates tyrosine residues of other proteins (known as receptor substrates). o Adaptor proteins that recognize the phosphotyrosine residues bind to the phosphorylated proteins. o They pass the signal on to other protein kinases. II. Ion channels These receptors contain ligand-gated ion channels Binding of the signaling substance opens the channels for ions such as Na+, K+, Ca2+, and Cl– This mechanism is mainly used by neurotransmitters such as acetylcholine (nicotinic receptor) and GABA (A receptor) III. 7-Helix receptors (serpentine receptors) Represent a large group of membrane proteins that transfer the hormone or transmitter signal, with the help of G proteins to effector proteins 15 B. Signal transduction by G proteins  G proteins transfer signals from 7-helix receptors to effector proteins  G protein is heterotrimers consisting of three different types of subunit (α, β and γ)  The α-subunit can bind GDP or GTP (hence the name “G protein”) and has GTPase activity  G proteins are divided into several types, depending on their effects: 1) Stimulatory G proteins (Gs) are widespread. They activate adenylate cyclase 2) Inhibitory G proteins (Gi) inhibit adenylate cyclase 3) G proteins in the Gq family activate another effector enzyme phospholipase c  Steps:- 1. Binding of the signaling substance to a 7- helix receptor alters the receptor conformation in such a way that the corresponding G protein can attach on the inside of the cell. This causes the α-subunit of the G protein to exchange bound GDP for GTP 2. The G protein then separates from the receptor and dissociates into an α- subunit and a βγ-unit. Both of these components bind to other membrane proteins and alter their activity (ion channels are opened or closed, and enzymes are activated or inactivated) In the case of the β2-catecholamine receptor, the α-subunit of the Gs protein, by binding to adenylate cyclase, leads to the synthesis of the second messenger cAMP 3. The βγ-unit of the G protein stimulates a kinase, which phosphorylates the receptor. This reduces its affinity for the hormone and leads to binding of the blocking protein arrestin Second messengers  Second messengers are intracellular chemical signals, the concentration of which is regulated by hormones, neurotransmitters, and other extracellular signals  They arise from easily available substrates and only have a short half-life  The most important second messengers are cAMP, cGMP, Ca2+, inositol triphosphate (InsP3), diacylglycerol (DAG), and nitrogen monoxide (NO) 16 A. Cyclic AMP Metabolism The nucleotide cAMP (adenosine 3-, 5--cyclic monophosphate) is synthesized by membrane-bound adenylate cyclases on the inside of the plasma membrane The adenylate cyclases are a family of enzymes that cyclize ATP to cAMP by cleaving diphosphate (PPi) The degradation of cAMP to AMP is catalyzed by phosphodiesterases, which are inhibited by methylxanthines such as caffeine, and activated by insulin Adenylate cyclase activity is regulated by G proteins (Gs and Gi) Action cAMP is an allosteric activator of protein kinase A (PK-A) B. Cyclic GMP acts as a second messenger. It is involved in sight and in the signal transduction of nitrogen monoxide (NO) The effects of atrial natriuretic peptide (ANP) atrial natriuretic factor (ANF) in reducing blood pressure are also mediated by cGMP-induced vasodilation. In this case. cGMP is formed by the guanylate cyclase activity of the ANP receptor. C. Inositol 1,4,5-trisphosphate and Diacylglycerol Metabolism Type Gq of G proteins activate phospholipase C This enzyme creates two second messengers from the double-phosphorylated membrane Phosphatidylinositol bisphosphate (PInsP2), i. e., 1. inositol 1,4,5-trisphosphate (InsP3), which is soluble 2. Diacylglycerol (DAG) Action InsP3 migrates to the endoplasmic reticulum (ER), where it opens Ca2+ channels that allow Ca2+ to flow into the cytoplasm DAG which is lipophilic, remains in the membrane, where it activates type C protein kinases 17 D. Calcium ions Calcium effects The biochemical effects of Ca2+ in the cytoplasm are mediated by special Ca2+ binding proteins (“calcium sensors”) These include the annexins, calmodulin, and troponin C in muscle Calmodulin is a relatively small protein that occurs in all animal cells Binding of four Ca2+ ions converts calmodulin into a regulatory element. Via a dramatic conformational change Ca2+-calmodulin enters into interaction with other proteins and modulates their properties Using this mechanism, Ca2+ ions regulate the activity of enzymes, and ion pumps Signal cascades  The signal transduction pathways that mediate the effects of the metabolic hormone I. Insulin The diverse effects of insulin are mediated by protein kinases that mutually activate each other in the form of enzyme cascades. The insulin receptor is a dimer with subunits that have activatable tyrosine kinase domains in the interior of the cell. Binding of the hormone increases the tyrosine kinase activity of the receptor, which then phosphorylates itself and other proteins (receptor substrates) at various tyrosine residues. Adaptor proteins, which conduct the signal further, bind to the phosphotyrosine residues. II. The mediator nitrogen monoxide (NO) is also clinically important, as it regulates vascular caliber and thus the body’s perfusion with blood so they are short-lived substances, act as locally mediators in their site of synthesis cause relaxation of smooth muscle fibers and thus dilation of the vessels. (NO) diffuses from the endothelium into the underlying vascular muscle cells where it leads to activation of guanylate cyclase to the formation of the second messenger cGMP. which activating a special protein kinase G (PK-G), cGMP triggers relaxation of the smooth muscle  N.B ✓ The drug nitroglycerin (glyceryl trinitrate), which is used in the treatment of angina pectoris, releases NO in the bloodstream and leads to better perfusion of cardiac muscle 18  Eicosanoids  The eicosanoids are a group of signaling substances that arise from the unsaturated C-20 fatty acid arachidonic acid (Greek eicosa = 20)  As mediators, they influence a large number of physiological processes  Eicosanoid metabolism is therefore an important drug target  As short-lived substances, eicosanoids only act locally in their site of synthesis stimulate or inhibit smooth-muscle contraction A. Biosynthesis Almost all of the body’s cells form eicosanoids Membrane phospholipase A2 releases the arachidonate fatty acid from these phospholipids. Two different pathways occur on arachidonate one form prostaglandins, prostacyclin, and thromboxane. And on other hand form leukotrienes 1. The key enzyme for the first pathway is prostaglandin synthase (cyclo- oxygenase) for the prostaglandins, prostacyclin, and thromboxane. 2. As a result of the action of lipoxygenases on arachidonate, give rise to the leukotrienes. B. Effects Eicosanoids act via membrane receptors in their site of synthesis, both on the synthesizing cell itself (autocrine action) and on neighboring cells (paracrine action). Many of their effects are mediated by the second messengers cAMP and cGMP. As they can stimulate or inhibit smooth-muscle contraction, they affect blood pressure, respiration, and intestinal and uterine activity. In the stomach, prostaglandins inhibit HCI secretion via Gi-proteins. At the same time, they promote mucus secretion, which protects the gastric mucosa against the acid. Prostaglandins are involved in bone metabolism and in the activity of the sympathetic nervous system. In the immune system, prostaglandin are important in the inflammatory reaction, they attract leukocytes to the site of infection. Eicosanoids are also involved in the development of pain and fever. The thromboxane promote thrombocyte aggregation and other processes involved in hemostasis. C. Metabolism Eicosanoids are inactivated within a period of seconds to minutes This takes place by enzymatic reduction of double bonds and dehydrogenation of hydroxyl groups As a result of this rapid degradation, their range is very limited 19  Lipoxygenase Aspirin Leukotrienes Arachidonate inhibit 2O2 Cyclo-oxygenase PGG2 PGI2 prostacyclin Peroxidase PGH2 Thromboxane synthase PGE2 reductase TXA2 PGD2 thromboxane PGF2α TXB2 D. Further information Acetylsalicylic acid (Aspirin)and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase and consequently the synthesis of most eicosanoids This explains their analgesic, antipyretic, and antirheumatic effects Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis For example 1) They impair hemostasis because the synthesis of thromboxane by thrombocytes (platelets)is inhibited 2) In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus Long-term NSAID use can therefore damage the gastric mucosa 20  Cytokines  Cytokines are hormone-like peptides and proteins with signaling functions, which are synthesized and released by cells of the immune system and other cell types. Their numerous biological functions: 1. They regulate the development and homeostasis of the immune system. 2. They control the hematopoietic system. 3. They are involved in non-specific defense, influencing inflammatory processes, blood coagulation, and blood pressure. 4. They regulate the growth, differentiation, and survival of cells. 5. They are also involved in regulating apoptosis. The cytokines include: interleukins (IL), lymphokines, monokines, chemokines, interferons (IFN), and colony-stimulating factors (CSF). 21 Respiratory chain Electron transport chain (ETC) The respiratory chain is one of the pathways involved in oxidative phosphorylation It catalyzes the steps by which electrons are transported from reduced coenzyme (NADH+H+) or reduced ubiquinone (QH2) to molecular oxygen to form water The redox reactions “oxidation-reduction” are accompanied by release of free energy(this reaction is strongly exergonic) Most of the energy released is used to establish a proton gradient across the inner mitochondrial membrane which is then ultimately used to synthesize ATP with the help of ATP synthase (syntheses of high energy phosphate bond for conversion of ADP to ATP) Components of the respiratory chain ETC The electron transport chain ETC consists of: 1. Three protein complexes (complexes I, III, and IV) which are integrated into the inner mitochondrial membrane 2. Two mobile electrons carrier; ubiquinone (coenzyme Q ) and cytochrome C 3. Succinate dehydrogenase, of the tricarboxylic acid cycle TCA, is also assigned to the respiratory chain as complex II 4. ATP synthase is sometimes referred to as complex V, although it is not involved in electron transport All of the complexes in the respiratory chain are made up of numerous polypeptides and contain a series of different protein bound redox coenzymes; These include flavins (FMN or FAD in complexes I and II), iron–sulfur clusters (in I, II, and III), and heme groups (in II, III, and IV) Electrons enter the respiratory chain in various different ways A. Complex I: NADH dehydrogenase  Contains enzyme called NADH dehydrogenase  Its coenzyme is FMN and contains several Fe/S cluster  It oxidizes NADH+H+ into NAD, electrons pass via FMN and Fe/S clusters to ubiquinone CoQ to form CoQH2 B. Complex II: succinate dehydrogenase  Contains enzyme called flavoprotein dehydrogenase e.g. succinate dehydrogenase of TCA and acyl CoA dehydrogenase of fatty acid oxidation  Its coenzyme is FAD and contains Fe/S cluster and heme group  It catalyze transfer of electrons from FADH2 to CoQ to form CoQH2 C. Complex III: Ubiquinol-cytochrome c reductase  Ubiquinol (CoQ)passes electrons on to complex III, which transfers them via two heme b groups “cyt b”, one Fe/S cluster, and heme c1 “cyt c1” to the small heme protein cytochrome C. 1  D. Complex IV: Cytochrome C Oxidase  Cytochrome C then transports the electrons to complex IV  Cytochrome C oxidase contains redox-active components in the form of two copper centers (Cu A and Cu B) and hemes a and a3(Cyt a & Cyt a3), through which the electrons finally reach oxygen  As the result of the two-electron reduction of O2, the O2– anion is produced, and this is converted into water by binding of two protons 2H+ The electron transfer is coupled to the formation of a proton gradient by complexes I, III, and IV E. Complex V: H+ transporting ATP synthase ATP synthesis  Proton transport via complexes I, III, and IV takes place from the matrix into the inter membrane space  When electrons are being transported through the respiratory chain, the H+ concentration in this space increases i. e., the pH value there is reduced by about one pH unit  For each H2O molecule formed, around 10 H+ ions are pumped into the inter membrane space  If the inner membrane is intact, ATP synthase can allow protons to flow back into the matrix. This is the basis for the coupling of electron transport to ATP synthesis  The energy obtained in this process is used to establish a proton gradient across the inner mitochondrial membrane 2   ATP synthesis is ultimately coupled to the return of protons from the intermembrane space into the matrix.  O2 reduction and ATP formation also take place in the matrix. ATP synthase The ATP synthase (complex V) that transports H+ is a complex molecular machine The enzyme consists of two parts—a proton channel (Fo, for “oligomycin-sensitive”) that is integrated into the membrane; and a catalytic unit (F1) that protrudes into the matrix. The catalytic cycle can be divided into three phases, through each of which the three active sites pass in sequence 3 Regulation The need to coordinate the production and consumption of ATP is already evident from the fact that the total amounts of coenzymes in the organism are low A. Respiratory control  The simple regulatory mechanism which ensures that ATP synthesis is “automatically” coordinated with ATP consumption is known as respiratory control  It is based on the fact that the different parts of the oxidative phosphorylation process are coupled via shared coenzymes and other factors  If a cell is not using any ATP, there is no any ADP will be available in the mitochondria  Without ADP, ATP synthase is unable to break down the proton gradient across the inner mitochondrial membrane. This in turn inhibits electron transport in the respiratory chain, which means that NADH+H+ can no longer be reoxidized to NAD+ Finally, the resulting high NADH/NAD+ ratio inhibits the tricarboxylic acid cycle  Conversely, high rates of ATP utilization stimulate nutrient degradation and the respiratory chain via the same mechanism B. Uncouplers  Substances that functionally separate oxidation and phosphorylation from one another are referred to as uncouplers  They break down the proton gradient by allowing H+ ions to pass from the inter membrane space back into the mitochondrial matrix without the involvement of ATP synthase  Uncoupling effects are produced by mechanical damage to the inner membrane or by lipid-soluble substances that can transport protons through the membrane  Example: 1. 2,4-dinitrophenol (DNP) 2. Thermogenin (uncoupling protein-1, UCP-1) 3. Thyroxin 4. Bilirubin 5. Ca++ 6. Arsinate N.B Sites of inhibition of the respiratory chain by specific drugs, chemicals, and antibiotics.  Barbiturates such as amobarbital inhibit electron transport via Complex I by blocking the transfer from Fe-S to CoQ. At sufficient dosage, they are fatal.  Antimycin A and dimercaprol inhibit the respiratory chain at Complex III 4  The classic poisons H2S, carbon monoxide, and cyanide inhibit Complex IV and can therefore totally arrest respiration  Malonate is a competitive inhibitor of Complex II  The antibiotic oligomycin completely blocks oxidation and phosphorylation by blocking the flow of protons through ATP synthase C. Regulation of the tricarboxylic acid cycle(TCA)  The most important factor in the regulation of the cycle is the NADH/NAD+ ratio  In addition to pyruvate dehydrogenase (PDH) and α-keto glutarate dehydrogenase, citrate synthase and isocitrate dehydrogenase are also inhibited by NAD+ deficiency or an excess of NADH+H+ 5  Carbohydrate Metabolism  Normal requirement of carbohydrates / day (70 – 100 gm/day)  The word metabolism include:- 1) Digestion 2) Absorption 3) Utilization (anabolism or catabolism) 4) Excretion Digestion of Carbohydrates I. In the mouth: Digestion starts by the action of salivary amylase which hydrolyses the α 1-4 glycosidic linkage of starch to give maltose and dextrin II. In the stomach: Salivary amylase can’t act in the stomach due to high acidity (presence of HCl) III. In the small intestine: 1) Pancreatic amylase completes the digestion of starch to maltose and iso-maltose 2) Intestinal enzymes “of intestinal juice” ⋅ Lactose lactase α glucose + β galactose ⋅ Maltose maltase 2 α glucose ⋅ Isomaltose isomaltase 2 α glucose ⋅ Sucrose sucrase α glucose + β fructose ⋅ Digestion is completed when all carbohydrates are becoming monosaccharides Absorption of monosaccharides A. Site of absorption Mainly the upper part of the small intestine B. The mechanism of absorption 1. Simple diffusion which depends on the sugar concentration gradients between the intestinal lumen, mucosal cells and blood plasma 2. Facilitated transport:- Glucose, galactose and fructose carried by specific protein GLUT-5 3. Active transport:- Glucose and galactose are absorbed by a sodium-dependent process. They are carried by the same transport protein (SGLT1):- The more sodium concentration in the lumen, the more sugar transport SGLT1: Sodim glucose transport protein 1 C. Route of absorption At the basal border, all sugar are transported by GLUT-2 to portal vein to the liver 1  Metabolism of glycogen Glycogen is the storage form of carbohydrates in animals It is highly branched polysaccharide formed from α-D-glucose; united together by α 1-4 glycosidic bonds but at point of branch α 1-6 glycosidic bonds It occurs in liver and muscle Muscle glycogen is a source of glucose to supply energy within the muscle itself Liver glycogen is a source of glucose for extrahepatic tissue and to maintain blood glucose between meals After 12-18 hours of fasting; the liver glycogen is almost totally depleted but muscle glycogen is depleted after muscular exercise I. Glucose is changed to glycogen (Glycogenesis) Glycogen is synthesized from glucose A. Definition Synthesis of glycogen from α-D-glucose units B. Site Glycogen is formed in the liver and muscle C. Pathway primer Glycogen synthase UDP Formtion of straight chain of glycogen Glycogen "fully formed" Branching enzyme (1-4 & 1-6 glycosidic linkage) 2   Glucose is phosphorylated to glucose-6-phosphate by hexokinase in muscles or glucokinase in liver  Glucose-6-phosphate is isomerized to glucose-1-phosphate by phosphoglucomutase (mutase)  Glucose-1-phosphate reacts with uridine triphosphate (UTP) to form the active nucleotide uridine diphosphate glucose (UDPGlc) and pyrophosphate (PPi) catalyzed by UDPGlc pyro-phosphorylase  UDP glucose is the active unit for synthesis of glycogen  Glycogen primer must be present  Glycogen primer is a glycogen molecule already present in the cell  Primer may be formed of glycogenin “glycosylated protein”  Glycogen synthase is the key enzyme for controlling synthesis of glycogen by forming 1-4glycosidic bond between C1 of UDP-glucose and C4 of a terminal glucose residue of glycogen, liberating UDP to form straight chain of glycogen  When the chain becomes elongated to at least 11 glucose units; Branching enzyme transfers a part of the 1-4 chain to form 1-6 linkage at the branch point to form glycogen fully formed molecule D. Regulation of Glycogenesis Glycogen synthase is the key enzyme controlling glycogenesis. The enzyme is regulated by:- ⋅ Allosteric activation mechanisms (by glucose-6-Phosphate) ⋅ Covalent modification due to reversible phosphorylation and dephosphorylation of enzyme protein in response to hormone action There are two types of glycogen synthease enzyme:- 1) glycogen synthase I (a)"Independant" active enzyme (dephosphorylated) 2) glycogen synthase D (b)"Dependant" inactive enzyme (phosphorylated) Roule of insulin in glycogenesis:-(rgulation of glycogen synthase) 1. Insulin increase the activity of glycogen synthase by:- Activated synthase phosphatase to change glycogen synthase D to glycogen synthase I Chang cyclic-AMP to ordinary-AMP by activation of phosphodiesterase The net result will be stimulation of glycogenesis and increase in liver and muscle glycogen 2. Glucagon & Epinephrine inhibit glycogen synthase by stimulation of cyclic-AMP  cAMP is formed form ATP by adenyl cyclase at the inner surface of cell membrane which activated by epinephrine and glucagon  cAMP is nucleotide formed of adenine, ribose and phosphate which attached to carbon no. 3 and no. 5 of ribose in a cyclic form 3   cAMP acts as intracellular secondary messenger for epinephrine and nor- epinephrine and glucagon  cAMP is hydrolyzed to 5-AMP by phosphodiesterase which activated by insulin Insulin: Stimulates glycogenesis Epinephrine: Inhibits glycogenesis in liver and muscle, through stimulation of c-AMP Glucagon: inhibits glycogenesis in liver only, through stimulation of c-AMP 4  II. Glycogen is chaged to glucose(Glycogenolysis) Breakdown of glycogen to glucose in the liver A. Definition It is the breakdown of glycogen to yield α-D-glucose subunits B. Site Liver and muscle C. Pathway  Glycogen phosphorylase is the regulatory enzyme of glycogenolysis, it helps the hydrolysis of 1-4 glycosidic bond by inorganic phosphate to give glucose 1-P  This proceeds until approximately four glucose residues remain on either side of a 1→6 branch  Glucan transferase exposing the 1-6 branch unit by transfers a tri-saccharide point from one branch to the other  Debranching enzyme catalyzes the hydrolysis of the 1-6 glycosidic bond  Glucose -1-P is converted by phosphoglucomutase to Glucose-6-P  Glucose-6-phosphatase is present in the liver to release free glucose to blood and then to extra-hepatic tissues  In muscle Glucose-6-phosphatase is absent so no free glucose is released in blood; glucose-6-phosphate is utilized to give energy 5 D. Regulation of glycogenolysis Glycogen phosphorylase is the key enzyme controlling glycogenolysis The enzyme is regulated by:- ⋅ Covalent modification due to reversible phosphorylation and dephosphorylation of enzyme protein in response to hormone action There are two types of Glycogen phosphorylase enzyme:- 1) Glycogen phosphorylase (a) active enzyme (phosphorylated) 2) Glycogen phosphorylase (b) inactive enzyme (dephosphorylated) Convertion of (b) to (a) form is catalyzed by the active phosphorylase kinase Epinephrine: stimulates glycogenolysis in liver and muscle, through stimulation of c- AMP Glucagon: stimulates glycogenolysis in liver only, through stimulation of c-AMP Insulin: Inhibits glycogenolysis 6  Glycogen storage diseases A group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in the tissues Examples: 1) Type 0: is a deficiency of glycogen synthase Hypoglycemia, hyperketonemia and early death 2) Type I: Von Gierkes’s disease is a deficiency of glucose-6-phosphatase Liver cells and renal tubule cells are loaded with glycogen Hypoglycemia, lactic-acidemia, ketosis, hyperlipidemia and hyperuricemia are characteristic 3) Type II: Pompe's disease due to deficiency of lysosomal glucosidase enzyme It is a fatal disease, due to accumulation of glycogen in lysosomes juvenile onset:- muscle hypotonia, death from heart failure by age 2 adult onset:- muscle dystrophy 7  Oxidation of glucose and other carbohydrate Glycolysis (Anaerobic oxidation) Oxygen is present but not needed It can function under aerobic and anaerobic conditions Occurs in cytosol of all cells of the body Occurs in RBCs (no mitochondria) glucose is the main metabolic fuel and metabolized by anerobic glycolysis. The ability of glycolysis to provide ATP in the absence of oxygen is especially important because it allows skeletal muscle to act at very high levels when oxygen supply is not enough. Occurs on glucose, fructose, galactose & other monosaccharide Pyruvate is the end result in aerobic condition “aerobic glycolysis” Glucose 2 pyruvate + 8ATP + H2O Lactate is the end result in severe muscular exercise “in low oxygen or absent of oxygen” resulting in muscle fatigue “anaerobic glycolysis” Glucose lactate + 2ATP + H2O  Steps of glycolysis 1. Phosphorylation of glucose to glucose-6-(P), catalyzed by glucokinase in liver and hexokinase in muscle. ATP supplies phosphate 2. Glucose-6-(P) is changed to fructose-6-(P) by phosphor-hexose isomerase. 3. Phosphorylation of fructose-6-(P) to fructose-1,6 bisphosphate (diphosphate). The reaction is catalyzed by phospho-fructo-kinase-1(PFK1) in the presence of ATP resulting in phosphorylation of C1 of fructose-6- phosphate. This reaction is very important in regulating the rate of glycolysis. 4. Fructose 1,6 bisphosphate is cleaved (splitting) by Aldolase into two phosphorylated trioses: Glyceraldehydes-3-(P) and dihydroxy acetone-(P). 5. A phospho-triose isomerase converts dihydroxy-acetone-(P) to glyceraldehyde-3-(P). This reaction is reversible. 6. Now 2 molecules of glyceraldehyde-3-(P) are present. 7. Glyceraldehyde-3-(P) dehydrogenase catalyzes the oxidation of glyceraldehyde-3-(P) to 1,3 bisphosphoglycerate. The enzyme is NAD- dependent; NADH+H+ is produced. 8. Oxidation is accompanied with release of energy; which is captured by inorganic phosphorus, present in the cell and forms a high energy bond in position 1 of 1,3 bis-phosphoglycerate. 8  9. Formation of 2 molecules of ATP by substrate level phosphorylation catalyzed by phosphoglycerate kinase; phosphate is transferred from 1,3 bisphospho-glycerate to ADP, forming ATP and 3-phospho-glycerate. 10.3-phosphoglycerate is isomerized to 2-phosphoglycerate by phosphoglycerate mutase. 11.Dehydration of 2-phosphoglycerate to phosphoenolpyruvate; catalyzed by enolase; which is dependent on the presence of Mg++. 12.Formation of 2 molecules of ATP by substrate level phosphorylation catalyzed by pyruvate kinase; The transfer of high energy phosphate group of phosphoenolpyruvate (in position 2) to ADP is catalyzed by pyruvate kinase to form 2 molecules of ATP per molecule of glucose. 13.Pyruvate kinase reaction is irreversible. 14.Enol pyruvate is the product of reaction will be isomerized to pyruvate spontaneous (non enzymatically). 15.Under anerobic conditions, the re-oxidation of NADH through the respiratory chain is prevented. and Pyruvate is reduced by the NADH to lactate, the reaction is catalyzed by lactate dehydrogenase. 16.This allows glycolysis to proceed in the absence of oxygen by regenerating enough NAD for another cycle of the reaction catalyzed by glyceraldehyde- 3-phosphate dehydrogenase. 17.Under aerobic conditions pyruvate passes to mitochondria and changed to acetyl CoA to start oxidation in Kreb’s Cycle. and Two molecule of NADH are transported to mitochondria by malate shuttle, where they are oxidized by the ETC to form two molecules of water and 6 molecules of ATP N.B.  In RBC's; glycolysis always ends with lactate, even under aerobic conditions, as no mitochondria in RBCs.  In vigorous and severe muscular exercise, anerobic glycolysis proceeds with production of excess lactate resulting in muscle fatigue. 9  L.D.H (11) Lactic acid dehydrogenase 2 Lactate 10  Inhibition of glycolysis a) Iodoacetate inhibit glyceraldehyde-3-(p) dehydrogenase b) Fluoride inhibit enolase  Control (regulation) of glycolysis Glycolysis is regulated by 3 Irreversible reactions catalyzed: 1. Hexokinase or glucokinase Glucoe + ATP Hexokinase Glucose-6-(p) + ADP 2. Phospho-fructokinase1(PFK1) Fructose-6-(P) + ATP Phosphofructokinase1 fructose 1,6-di (P) + ADP 3. Pyruvate kinase Phosphoenol puruvic acid + ADP pyruvic kinase pyruvic acid + ATP The activity of these 3 enzymes are stimulated by carbohydrate feeding and inhibited during fasting 1. Phospho-fructokinase1(PFK1) ⋅ Inhibited by ATP and glucagon ⋅ Activated by AMP, insulin, Fructose-6-(P) and Fructose-2,6-(bi P) 2. Pyruvate kinase ⋅ Inhibited by ATP and glucagon ⋅ Activated by insulin and Fructose-1,6-(bi P) Insulin in general stimulate the oxidative pathways of glucose  Energy production from glycolysis Pathway Reaction catalyzed by Method of ATP Number of ATP production formed Glycolysis Glyceraldehydes-3- Respiratory chain 2x3= 6 ATP phosphate oxidation of dehydrogenase 2NADH Phosphoglycerate Phosphorylation at 2 ATP kinase substrate level Pyruvate kinase Phosphorylation at 2 ATP substrate level consumption of ATP by consumption -2 ATP reactions catalyzed by hexokinase and phosphofructokinase1 Net 8 ATP In presence of oxygen when the glycolysis is followed by aerobic oxidation, the (2NADH+H+) produced is oxidized in the respiratory chain give 6ATP + H2O so 11  the total gain of ATP is 8 ATP from oxidation of one molecule of glucose to pyruvate In abesnt of oxygen The gain (8 - 6) = 2 ATP from anaerobic oxidation of one molecule of glucose to lactate  Glycolysis in R.B.Cs In erythrocytes glycolysis; ATP formation may be bypassed The reaction catalyzed by phosphoglycerate kinase may be bybassed 2,3 biphosphoglycerate pathway in erythrocytes glucose glyceraldehydes-3-phosphate Pi NAD glyceraldehydes-3-phosphate dehydrogenase NADH+H+ 1,3 bisphosphoglycerate ADP bisphosphoglycerate mutase phosphoglycerate kinase 2,3 bisphosphoglycerate ATP 2,3 bisphosphoglycerate phosphatase 3 phosphoglycerate pyruvate This alternative pathway involves no net give of ATP from glycolysis Role of 2,3 bisphosphoglycerate in red blood cells: (BPG shunt) Regulator of O2 transports in red blood cells; 2,3 bisphosphoglycerate decreases the affinity of hemoglobin to O2 Good oxygenation of tissue  How fructose can join glycolysis to be oxidized 12  Aerobic oxidation O2 must be present & it is needed It occur in mitochondria of all body cell It started by pyruvate which is the end product of glycolysis under aerobic condition; It passes from cytosol to mitochondria to be converted to acetyl CoA (active acetate) by oxidative decarboxylation  Metabolism of Pyruvate Pyruvate passes from cytosol to mitochondria to convert to:- 1) Oxidative decarboxylation of pyruvate: pyruvate dehydrogenase is a multi-enzyme complex requires five coenzymes: NAD, CoA-SH, TPP, Lipoic acid and FAD Regulation of pyruvate dehydrogenase complex: 1. Activated by:- Pyruvate, NAD, CoA-SH, TPP, Lipoic acid, FAD, ADP, Insulin, Ca++ and Mg++ 2. Inhibited by:- Acetyl-CoA, NADH+H+ by end product inhibition and ATP is an allosteric inhibitor 2) Formation of oxaloacetate by carboxylation of pyruvate Regulation of pyruvate carboxylase: 1. Activated by:- Acetyl-CoA, glucagon, epinephrine and glucocorticoid 2. Inhibited by:- Insulin 13  Reactions of TCA cycle (kreb's cycle or citric acid cycle or tricarbxylic acid cycle TCA) TCA is the final pathway for the aerobic oxidation of carbohydrates, lipids and proteins; because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA which reacts with oxaloacetate to form citrate the cycle is the major route for production of ATP and occurs in the matrix of mitochondria near to the enzymes of the respiratory chain and oxidative phosphorylation The reduced coenzymes are oxidized by the respiratory chain linked to formation of ATP Steps of aerobic oxidation:  Role of Oxygen in Kreb's cycle Kreb's cycle need NAD and FAD as coenzymes for carriage of hydrogen So the reduced coenzymes NADH+H+ and FADH2 must be re-oxidized again to begin another cycle; this occur by the help of O2 NADH+H+ + O2 respiratory chain NAD + H2O + energy (3 ATP) FADH2+ O2 respiratory chain FAD + H2O + energy (2 ATP) 14  Energy production from aerobic oxidation Pathway Reaction catalyzed by Method of ATP Number of ATP production formed Glycolysis Glyceraldehydes-3- Respiratory chain 8 phosphate dehydrogenase oxidation of 2NADH Phosphoglycerate kinase Phosphorylation at Pyruvate kinase substrate level Oxidative pyruvate dehydrogenase Respiratory chain 6 decarboxylation oxidation of of pyruvate 2NADH TCA Isocitrate dehydrogenase Respiratory chain 6 oxidation of 2NADH α-ketoglutarate Respiratory chain 6 dehydrogenase oxidation of 2NADH Succinate thiokinase Phosphorylation at 2 substrate level Succinate dehydrogenase Respiratory chain 4 oxidation of 2FADH2 Malate dehydrogenase Respiratory chain 6 oxidation of 2NADH Net 38 ATP The energy is captured in the form of GTP, NADH and FADH2 The energy produced from TCA (oxidation of acetyl CoA) = 12 ATP The energy produced from oxidation of pyruvate Total 12 ATP from TCA + 3 ATP from formation of acetyl CoA = 15ATP 1molecule of glucose give 2 pyruvate The gain (15x2) = 30 molecule ATP In complete oxidation of 1molecule of glucose we will give 8 molecules ATP from anaerobic oxidation + 30 molecules from aerobic oxidation The gain (8+30) = 38 molecule ATP In oxidation of 1molecule of glucose under anaerobic conditions will give 2 molecules ATP 15  Control (regulation) of TCA cycle The cycle is regulated at the enzymatic level at the reactions catalyzed by: 1. Citrate synthtase ⋅ Activated by high concentrations of acetyl-CoA and oxaloacetate ⋅ Inhibited by ATP, NADH and high concentrations of succinyl-CoA 2. Isocitric dehydrogenase ⋅ Activated by ADP and NAD ⋅ Inhibited by ATP 3. α-ketoglutaric dehydrogenase ⋅ Activated by ADP ⋅ Inhibited by ATP, NADH and high concentrations of succinyl-CoA  Function of kreb's cycle Production of energy It provides the body with active succinate (succinyl CoA) which is used for: ⋅ Synthesis of hemoglobin It supplies the body with intermediate compounds which can give amino acids in the body e.g.: ⋅ Pyruvate can give alanine ⋅ α-ketoglutarate can give glutamic acid ⋅ Oxaloacetate can give aspartic acid Kreb's cycle is used for complete oxidation of carbohydrates, fats and Proteins  Source of succinyl CoA 1. Methionine 2. Valine 3. Isoleucine 4. α-ketoglutarate 5. Succinate  Fate (Function, importance & metabolism) of succinyl CoA 16  Source of oxaloacetate  Fat (Function, importance & metabolism) of oxaloacetate (role of oxaloacetate in gluconeogenesis) It is catalytic intermediate compound in kreb's cycle It is intermediate compound in gluconeogenesis  Source of acetyl CoA (active acetate) Carbohydrates pyruvic acid acetyl CoA Neutral fat glycerol glucose pyruvic acid acetyl CoA fatty acid acetyl CoA Amino acid glucogenic glucose pyruvic acid acetyl CoA ketogenic keton bodies acetyl CoA Oxidation of keton bodies acetyl CoA 17  Fate (Function, importance & metabolism) of acetyl CoA (active acetate) United with oxaloacetate to form kreb's cycle Used for synthesis of 1. Fatty acid 2. Cholesterol 3. Acetyl choline 4. Ketone bodies Used in detoxication of sulpha drugs Gluconeogenesis Definition It is the synthesis of glucose and/or glycogen from non-carbohydrate substances Sources 1. Glucogenic amino acids 2. Pyruvate and lactate 3. Glycerol 4. Propionate Site Mainly in the liver and the kidney 18 Importance 1. To supply body for glucose when sufficient carbohydrate is not available from the diet or glycogen reserves depleted e.g. fasting starvation. A supply of glucose is necessary especially for the nervous system and erythrocytes; so failure of gluconeogenesis is usually fatal because Hypoglycemia causes brain dysfunction, which can lead to coma and death 2. Glucose is also important in maintaining the level of intermediates of TCA cycle 3. Gluconeogenesis clear lactate produced by muscle & RBCs and glycerol produced by adipose tissue Pathways: 1) Conversion of pyruvate and lactate to glucose It is mainly the reversal of glycolysis, except for the three irreversible steps, they are circumvented as follow Glycolysis Gluconeogenesis Glucokinase or Hexokinase Glucose-6-phosphatase Phosphofructokinase-1 Fructose-1,6-bis-phosphatase Pyruvate kinase Pyruvate carboxylase Phosphoenolpyruvate carboxykinase All the enzymes of gluconeogenesis are present in the cytosol of liver and kidney cells except pyruvate carboxylase which is a mitochondrial enzyme Succinate thiokinase in the citric acid cycle produces GTP, and this GTP is used for the reaction of phosphoenolpyruvate carboxykinase Fructose 2,6-Bisphosphate plays a unique role in the regulation of glycolysis and gluconeogenesis in liver 1. The most potent positive allosteric activator of phosphos-fructokinase-1 and inhibitor of fructose 1,6-bisphosphatase in liver is fructose 2,6-bisphosphate. 2. It relieves inhibition of phosphofructokinase-1 by ATP and increases the affinity for fructose 6-phosphate. 3. It inhibits fructose 1,6-bisphosphatase by increasing the Km for fructose 1,6- bisphosphate. 4. Hence gluconeogenesis is stimulated by a decrease in the concentration of fructose 2,6-bisphosphate, which inactivates phospho-fructokinase-1 and relieves the inhibition of fructose 1,6-bisphosphatase. 19 2) Glycerol 3) Propionyl CoA converted to succinyl CoA then to glucose 20  Hormonal regulation of gluconeogenesis 1) Insulin: inhibits gluconeogenesis by decreasing the activity of gluconeogenic enzymes 2) Anti-insulin hormones; including: Glucocorticoids e.g. cortisone Epinephrine Glucagon Growth hormone All stimulate gluconeogenesis  How lactic acid is metabolized:-(Cori-cycle) Lactic acid is a dead end product of metabolism in muscle, so it cannot be utilized in muscle It must be go back to pyruvic acid, which not occur in the muscle because muscle has L.D.H specific for pyruvate not for lactate So lactic acid must be diffuse to blood then to liver, as liver has L.D.H specific for lactate not for pyruvate Clinical aspects in oxidation of glucose A. Genetic disease 1. Inherited pyruvate dehydrogenase deficiency: result in inhibition of pyruvate metabolism leads to lactic acidosis, these metabolic defects commonly cause neurologic disturbances 2. Inherited deficiency of aldolase A or pyruvate kinase in erythrocytes: result in hemolytic anemia 3. Muscle phosphofructokinase deficiency: result in low exercise capacity particularly in high carbohydrates diets; because using lipid as an alternative fuel B. Non genetic disease 1. Arsenite and mercuric ion poisoning: react with –SH group lipoic acid lead to inhibition of pyruvate dehydrogenase result in inhibition of pyruvate metabolism leads to lactic acidosis 2. Dietary deficiency of thiamin (TPP): lead to inhibition of pyruvate dehydrogenase result in inhibition of pyruvate metabolism leads to lactic acidosis 21  Alternative oxidative pathway of glucose I- Pentose Phosphate Pathway (PPP) Hexose Monophosphate Pathway (HMP) It is an alternative oxidative pathway of glucose by which glucose is changed to phosphorylated pentoses with the production of NADPH Reaction of Pentose Phosphate Pathway occur in cytosol Function of PPP: 1. Production of NADPH: for synthesis of Fatty acids and Cholesterol and steroid 2. Production of pentoses: e.g. ribose for synthesis of Nucleotides and Nucleic acid Glucose 6-phosphate CO 2 Ribulose 5-phosphate + NADP NADPH+H Genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD): The first enzyme of Pentose Phosphate Pathway It is a major cause of hemolysis of red blood cells, resulting in hemolytic anemia or Favism The defect appears when those individuals are subjected to oxidants such as; antimalarial drug, aspirin & sulfonamides and Ingestion of fava beans Role of Pentose Phosphate Pathway in glutathione peroxidase reaction in RBCs The pentose phosphate pathway and glutathione peroxidase protect erythrocytes against hemolysis: In red blood cells the pentose phosphate pathway provides NADPH for the reduction of oxidized glutathione catalyzed by glutathione reductase Reduced glutathione removes H2O2 in a reaction catalyzed by glutathione peroxidase, an enzyme that contains the selenium analogue of cysteine (selenocysteine) at the active site. The reaction is important, since accumulation of H2O2 may decrease the life span of the erythrocyte by causing oxidative damage to the cell membrane, leading to hemolysis 22 II- Uronic acid pathway Glucose is changed to glucuronic acid Function of glucuronate:- A precurser of proteoglycans Enter in the formation of heparin, healouronic acid, chondrotin sulfat major significance for the excretion of metabolites and foreign chemicals (xenobiotics) as glucuronides The lack of enzyme gulonolactone oxidase explains why ascorbic acid (vitamin C) is a dietary requirement for humans but not most other mammals deficiency in the pathway leads to the condition of essential pentosuria III- Synthesis of lactose in mammary gland UDP Gal condenses with glucose to yield lactose; catalyzed by lactose synthase IV- Glucose is the precursor of all Amino sugars (hexosamines) Amino sugars are important components of glycoproteins of certain glycosphingolipids and of glycosaminoglycans. The major amino sugar are the hexosamines glucosamine, and mannosamine, and the nine-carbon compound sialic acid. sialic acid found in human tissues is N-acetylneuraminic acid (NeuAc). Clinical aspects in alternative oxidative pathway 1. Impaired of Pentose Phosphate Pathway Genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD) with impairment of the generation of NADPH: cause of hemolysis of red blood cells, resulting in hemolytic anemia or Favism The defect appears when those individuals are subjected to oxidants such as; antimalarial drug, aspirin & sulfonamides and Ingestion of fava beans Glutathione peroxidase is dependent upon a supply of NADPH, which in erythrocytes can be formed only via the pentose phosphate pathway 2. Disruption of the uronic acid pathway is caused by enzyme defects and some drugs 1. Essential pentosuria Rare hereditary condition essential pentosuria, considerable quantities of L- xylulose appear in the urine, because of absence of the enzyme necessary to reduce L- xylulose to xylitol. 23  2. Various drugs Increase the rate at which glucose enters the uronic acid pathway. For example, administration of barbital or chlorobutanol to rats results in a significant increase in the conversion of glucose to glucuronate, L- gulonate, and ascorbate. Aminopyrine and antipyrine increase the excretion of L- xylulose in pentosuric subjects. 3. Defects in fructose metabolism cause disease 1. Essential fructosuria and fructose intolerance A lack of hepatic fructokinase causes essential fructosuria. Absence of aldolase B, which cleaves fructose 1-phosphate, leads to hereditary fructose intolerance. Diets low in fructose, sorbitol, and sucrose are beneficial for both conditions. One consequence of hereditary fructose intolerance and of a related condition as a result of fructose 1,6- bisphosphates deficiency is fructose-induced hypoglycemia despite the presence of high glycogen reserves, because of fructose 1-phosphate and 1,6- bisphosphate allosterically inhibit liver glycogen phosphorylase. The sequestration of inorganic phosphate also leads to depletion of ATP and hyperuricemia. 2. Fructose and sorbitol in the lens are associated with diabetic cataract Both fructose and sorbitol are found in the lens of the eye in increased concentrations in diabetes mellitus, and may be involved in the pathogenesis of diabetic cataract. Glucose is reduced to sorbitol by aldose reductase, Sorbitol does not diffuse through cell membranes, but accumulates, causing osmotic damage. Diabetic cataract, can be prevented by aldose reductase inhibitors in experimental animals, but to date there is no evidence that inhibitors are effective in preventing cataract or diabetic neuropathy in humans. 4. Galactosemia Elevated blood level of galactose caused by inherited defects in galactokinase, uridyl transferase or 4-epimerase “most common is deficiency of uridyl transferase” Galactose increase in blood and reduced in the eye by aldose reductase to form galactitol “dulicitol” causing cataract Accumulation of galactose 1-phosphate and depletion of liver phosphate result in liver failure and mental deterioration These complications can be avoided by giving a galactose free diet, as the galagtosemic individual can still form UDP Gal from UDP Glc by epimease 24 Blood sugar Normal level of blood glucose  Normal fasting level: (6-8 hours fasting)It ranges from 70-110 mg%  Normal level after carbohydrate meal(post prandial): It doesn’t exceed 180 mg%  Hypoglycemia: It is the decrease of blood sugar level below 60 mg%. It may lead to coma and death if not treated  Hyperglycemia: It is the increase of blood sugar leve1 above 180 mg% which is the normal renal threshold for glucose  Renal threshold: the capacity of the kidney to reabsorb plasma glucose Sources of Blood Glucose 1) Carbohydrates of diet 2) 10% of fat of diet 3) 58% of proteins of diet 4) Liver glycogen by glycogenolysis Factors Regulating Glucose Level in Blood Role of the kidney:- When blood glucose levels exceeds 180 mg% (renal threshold), glucose will pass in urine resulting in glucosuria Hormonal regulation:- I. Hypoglycemic hormones Insulin  From: β-cells of pancreas  Action: 1. It is the only hypoglycemic hormone (decrease blood glucose level) 2. It is secreted in response to hyperglycemia 3. Glucose stimulates secretion of insulin from pancreas in 30-60 sec. 4. Insulin stimulate all oxidative pathways of glucose 5. Insulin stimulates the liver and muscle to store glucose as glycogen (glycogenesis) 25  6. Insulin helps uptake of glucose into extra-hepatic tissues (muscle & adipose tissue) 7. Insulin inhibits glycogenolysis and gluconeogenesis 8. Insulin stimulates lipogenesis 9. Insulin stimulates protein synthesis (anabolic hormone)  Mode of Action : Insulin receptors are present on the plasma membrane of target organs of insulin (muscle cells, adipose tissue and liver cells) II. Hyperglycemic hormones (Anti-insulin hormones) 1. Epinephrine (adrenaline)  From: Adrenal medulla  Action: 1. Secreted in response to hypoglycemia 2. It is the hormone of rapid physiologic response (e.g. fear, hypoglycemia and hypotension) 3. It stimulate glycogenolysis in liver and muscle through activation of phosphorylase enzyme by c-AMP 4. It inhibits glycogenesis in liver and muscle 5. It inhibits insulin secretion 6. It stimulates anterior lobe to secret ACTH 2. Glucagon  From: α-cells of pancreas  Action: 1. It is secreted in response to hypoglycemia 2. It stimulate glycogenolysis in liver only through activation of phosphorylase enzyme by c-AMP 3. It inhibits glycogenesis in liver only 4. It stimulates gluconeogenesis 3. Anterior pituitary hormones (i) Growth hormone 1. It inhibits glucokinase enzyme so inhibits glycolysis 2. It stimulates gluconeogenesis 3. It stimulates lipolysis in adipose tissues (ii) ACTH Stimulates adrenal cortex for secretion of glucocorticoids 26  4. Glucocorticoids  From: adrenal cortex e.g. cortisone  Action: 1. It stimulates gluconeogenesis from amino acids by activation of transaminase enzymes 2. Prolonged treatment with cortisone leads to persistent hyperglycemia and diabetes mellitus 5. Thyroxin  From: thyroid gland  Action: 1. It is a mild hyperglycemic hormone 2. It increase absorption of glucose from intestine 3. It accelerates insulin catabolism 4. It stimulates glucose oxidation 5. It stimulates lipolysis in adipose tissues Glucosuria Definition: Appearance of glucose in urine Causes and Types: I. Normoglycemic glucosuria Presence of glucose in urine while blood glucose level is normal Causes:- 1. Physiological as in pregnancy due to decreased carbohydrate tolerance in late months 2. Renal diabetes due to congenital low renal threshold 3. Injection of phlorhizin which causes inhibition of reabsorption of glucose in renal tubules II. Hyper glycemic glucosuria It occurs when blood glucose level is above the renal threshold (180 mg %) Causes:- 1. Diabetes mellitus (due to insulin deficiency) 2. Emotional: due to over secretion of epinephrine 3. Alimentary: increase carbohydrates feeding 4. Experimental pancreatectomy 27  Diabetes mellitus Diabetes mellitus is a medical disorder characterized by persistent hyperglycemia especially after eating All types of diabetes mellitus have similar symptoms and complications It may lead to dehydration and ketoacidosis Symptoms of diabetes mellitus: 1. Polyuria 2. Increased thirst sensation 3. Weight loss 4. Fatigue, nausea and vomiting 5. Infections 6. Blurred vision 7. Diabetic coma Complications: 1. Cardiovascular disease 2. Chronic renal failure 3. Retinal damage with eventual blindness 4. Nerve damage with risk of amputation of toes, feet and even legs Causes and types: I. Type1 Diabetes Mellitus "Insulin Dependent Diabetes Mellitus" (IDDM) It is an autoimmune disease It is also called “childhood” or “juvenile” diabetes It is treated by insulin injection II. Type 2 Diabetes Mellitus "Non Insulin Dependent Diabetes Mellitus" (NIDDM) Characterized by “insulin resistance” It is also called “adult onset diabetes”, “insulin resistance diabetes” The majority of patients is suffer from obesity or may be on long-term steroid Treated by: a) Change in diet and weight loss b) Next step:- oral anti-diabetic c) If these failed insulin therapy is necessary Criteria for diagnosis of diabetes mellitus: Diabetes mellitus is diagnosed by demonstrating any one of 1. Two fasting plasma glucose levels above (126 mg %) on different days 2. Plasma glucose above (200 mg %) two hours after drinking 75gm glucose 3. Symptoms of diabetes and a random glucose above 200 mg% 4. Elevated glucose bound to hemoglobin HbA1c "glycosylated hemoglobin" this is a screening and follow up test showing average blood glucose level 28  Hypoglycemia Hypoglycemia is the decrease of blood glucose level below its normal fasting level During pregnancy, fetal glucose consumption increases and there is a risk of maternal and possibly fetal hypoglycemia Premature babies are more susceptible to hypoglycemia Hypoglycemic coma occurs when blood sugar is less than 40mg% due to over dosage of insulin Diabetic patients on insulin or oral anti-diabetic medication are liable to drug- induced hypoglycemia Glucose tolerance curve This test is used to diagnose diabetes mellitus How the curve is produced? 1. Fasting patient (8 hours after the last meal) and take blood and urine sample (zero time of test) 2. Give to the patient 70 gm of glucose by mouth in a cup of water (1gm/ kg body weight) 3. Samples of blood are taken every 1/2 hour and estimate the amount of glucose in blood in every sample 4. Samples of urine are taken every 1/2 hour and detect the presence or absence of glucose in every sample 300 250 Diabetic curve Blood Glucose (mg%) 200 Renal threshold 150 Normal curve 100 Insulin over shooting 50 0 0 1 2 3 29 Time (hours) Terms Used  Hypoglycaemia: It is the decrease of blood sugar level below 60 mg%  Hyperglycaemia: It is the increase of blood sugar leve1 above 180 mg% which is the normal renal threshold for glucose  Glycogenesis: It is the formation of glycogen from glucose or other carbohydrate sources  Glycogenolysis: It is the breakdown of glycogen to glucose  Gluconeogenesis: It is the formation of glucose from non carbohydrate sources e.g. fats and proteins  Glycolysis: It is the formation of pyruvic acid or lactic acid from glucose or glycogen (It is the breakdown of glucose) 30