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Prepared by MD, Marta R. Gerasymchuk, …

Prepared by MD, Marta R. Gerasymchuk,
pathophysiology department of IFNMU

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  • Where does the sugar in our body go? It's well and good that sugar from fruit and grain gets into our bodies, but what happens to it thereafter?  Let's look at a model of our "Sugar Central" or, more correctly, blood sugar.  The barrel represents the storeroom of sugar in the body.  Food provides input in good times (read "after a meal").  There are three major routes out of that storeroom:
  • Major index which describes metabolism of carbohydrates, is a sugar level in blood. In healthy peoples it is (3,5) 4,4-6,6 mmol/l.   This value is summary result of complicated interaction of many exogenous and endogenous influences. The first it reflects a balance between amount of glucose which entrance in blood and by amount of glucose which is utilized by cells.  The second , glucose level in blood reflects an effect of simultaneous regulatory influence on carbohydrates metabolism of the nervous system and endocrine glands: front pituitary gland (somatotropic, thyreotropic, adrenocorticotropic hormones), adrenal cortex (adrenalin ,noradrenalin) layer, pancreas (insulin, glucagone, somatostatin), thyroid (thyroxin, triiodthyronine). Among enumerated hormones only insulin lowers glucose concentration in blood the rest of hormones increase it.
  • Pathogenesis of insulin-dependent diabetes mellitus Insulin-dependent diabetes mellitus has genetic base. Inclination to diabetes of this type is conditioned by some genes of major histocompatibility complex (MHC). The system of HLA genes is situated on small extent of short shoulder of 6 chromosome . Here are identified several locuses – A, B, C and area D which includes three locuses – DP ,  DQ and DR . High probability of insulin-depending diabetes mellitus is to area D and nominally  with locuses DR . Genes DR3 and DR4 are diabetogenic . The very high risk of illness is created in those person who have both gene – DR3 and DR4 . Inclination to insulin-depending diabetes is associated also with locus DQ (genes DQ2 and DQ8 ). Diabetes arises only in part of person with diabetogenic genes. For example, alleles DR3 and DR4 occur in 50-60 % healthy person of european race, and illness develops only in 0,25 %. Inheritance of insulin-depending diabetes is conditioned, presumably, by not one gene, but by group of kindred genes. Where in essence of genetic defect in peoples with genes DR3, DR4, DQ2, DQ8? Exact answer on these questions while is not found. Think, that the enumerated genes in lone or in combinations form a low resistibility of β -cells of pancreas to external actions. β -Cells of such persons lightly collapse and very difficult restore. High readiness to destruction combines in them by limited capacity for regeneration. The system of HLA genes are inherited from generation to generation, therefore inclination of β -cells to destruction also is inherited from generation to generation. However general amount of β -cells is attached to birth identically in patients and healthy. Typical affection of Langergans islets attached to insulin-depending diabetes is infiltration of them by lymphocytes and selective destruction of β -cells . Clinical illness picture develops when 80-95% of β -cells are already destroyed. In such patients mass of pancreas is less, than in healthy people. Amount and volume of Langergans islets also is less. Thus insulin-depending diabetes is result of equilibrium violation between destruction of β -cells and their regeneration . Both process – increase of destruction and limitation of regeneration – are genetically conditioned. Depending upon affection mechanism of β-cells there are two forms of insulin-dependent diabetes mellitus – autoimmune and virus-inductive .
  • http://bjo.bmj.com/content/89/6/730.full

Transcript

  • 1. Disorders of metabolism of carbohydrates and lipids By M.D. Marta R. Gerasymchuk Pathophysiology department 15.11.2012
  • 2. General etiopathogenesis of metabolic disorders1. Genetic disorders (enzymopathy)→ impairment of intracellular regulation2. Damage to membrane and intracellular receptors→ signal pathology3. Impairment in endocrine regulation→ impairment in enzyme synthesis and activation
  • 3. General etiopathogenesis of metabolic disorders4. Impairm of neural control enta) Impairment of trophic function (via axoplasmic influence)b) emotional stress → impairment of cortical regulationc) impairment in secretion of hypothalamic releasing hormonesd) disorders of vegetative nervous system5. Dietary and digestive disorders6. Other organ disorders
  • 4. • 1.  To the liver.  Here excess sugar  from meals is stored to cover sugar  shortages between meals and to  make fat from excess  sugar.  • Transport of sugar goes both to and  from the liver.  The liver fills the  "Sugar Central" between meals. • 2.  To the brain.  The brain is  completely dependent upon sugar  combustion for its supply of energy,  in any case under normal  conditions.  It uses really huge  amounts of sugar.•    3.  To muscles and fat tissue.  At  To muscles and fat tissue.least 40% of the body is comprised of skeletal muscles.  These can use both fats and sugar to supply energy.  The rate of sugar uptake and burning follows physical activity; more work; more sugar burned.  Muscles do take up and store glucose to cover future activity but they cannot release sugar back to the blood stream or "Sugar Central".  Fat tissue stores surplus sugar as fat.  About half of this comes sugar as fatfrom the liver, the rest is made by fat itself.
  • 5. Regulation of glucose metabolism The glucose concentration in blood describes carbohydrates metabolism both of healthy man and sick. Illnesses base of which is disorder of carbohydrates metabolism can flow with rise of glucose concentration in blood and with lowering of it. Rise of glucose concentration is named hyperglicemia lowering hypoglicemia . For example, hyperglicemia is very typical for diabetes mellitus, hypoglycemia – for glycogenosis. 
  • 6. Impairments of glucose balanceNormal glucose level in the blood 65 -110 mg/ % 3.50 - 6.05 mmol/L (5.5 mmol/ L)• Hypoglycemia (less than 2.5 mmol/L results in coma)• Hyperglycemia 3.50 6.05 Hypoglycemia NORM Hyperglycemia GLUCOSE
  • 7. Blood Glucose & HormonesHormone Action Insulin  ↓  Glucose Glucortocoids  ↑  Glucose Glucagon  ↑  Glucose Growth Hormone  ↑  Glucose Epinephrine  ↑  Glucose
  • 8. Regulation of carbohydrate metabolism Counter-insulin hormonesACTH, growth hormone, cortisol, thyroid hormone, glucagon, adrenaline1.Stimulate absorption of carbohydrates (cortisol, thyroid hormone)2. Increase glycogenolysis in liver and muscles, inhibit glycogenesis (adrenaline, cortisol, thyroid)3. Inhibit hexokinase activity and therefore its utilization (cortisol, growth hormone)4. Stimulate gluconeogenesis (cortisol, thyroid, glucagon)5. Activate insulinase (growth hormone, thyroid)
  • 9. Blood glucose balance regulation inhibition Counter- • Permeability of insulinactivation cellular hormones membranes (glucagon, adrenaline, • glucokinase thyroids, Insulin glucocorticoids reaction rate sgrowth • synthesis of hormone, ACTH) glycolytic enzymes • gluconeogenesis • glucose-6-phosphate production
  • 10. Below is a summary of the way insulin influences the physiological processes within the cells of each of these tissues. Liver Muscle Adipose Stimulation of glucose uptake Stimulation of cellular respiration Stimulation of glycogenesis Inhibition of glycogenolysis Stimulation of amino acid uptake Stimulation of protein synthesis Inhibition of protein degradation Stimulation of fatty acid and triglyceride synthesis Inhibition of lipolysis Stimulation of lipoproteins uptakeThe most important ones are emphasised by the pointing fingers.A indicates that the process stated is stimulated within the cells of that tissue by the hormone.
  • 11. The Metabolic Effects of Glucagon The Liver Muscle Adipose Stimulation of glycogenolysis Inhibition of glycogenesis Stimulation of gluconeogenesis Stimulation of lipolysis Stimulation of ketone formation Stimulation of amino acid uptakeLike insulin, glucagon is a polypeptide hormone. However, in contrast to insulin, receptors for glucagon are not as abundant in cells throughout the body. Theaction of glucagon to increase blood glucose concentrations is largely as a result of the effects it has on cells of the liver after binding to membrane receptors.
  • 12. HypoglycemiaExogenous Functional Endogenous
  • 13. Exogenous hypoglycemia• Insulin injection• Alcohol (develops 6-36 hours after heavy consumption)• Some drugs (e.g. salicylates)• Long term physical exercise
  • 14. Endogenous hypoglycemia insulinoma (hyperplasia of β-cells) glycogenosis hereditary fructose intolerance insufficiency in phosphoenolpyruvate carboxykinase Hepatocellular insufficiency Impaired absorption
  • 15. Functional Hypoglycemia1. Alimentary (after gastrectomy, demping syndrome)2. Spontaneous reactive (cause is not known → diarrhea, tachycardy, tremor, headache, weakness)3. Alcohol (consumption in hungry state)4. Endocrine insufficiency (decrease in counter-insulin hormone ↓)5. Hepatic failure6. Malnutrition7. Heavy physical load (without carbohydrate uptake)8. Transient functional hypoglycemia of children• Neonatal (10%)• Maternal diabetes• Erythroblastosis• Ketogenic
  • 16. Manifestations of hyperglycemia  Glucosuria  Polyuria  Polydypsia  Hypohydration of the organism  Arterial hypotensionManifestations of hypoglycemia  Starvation  Tremor  Excessive sweating  Tachycardia  Headache, dizziness  Impaired vision  Anxiety, fear  Impaired cognition
  • 17. Diabetes mellitus• Diabetes mellitus is heterogenic diseases  group which arise on base of absolute or  relative insulin insufficiency and have  hyperglycemia as general symptom. • Impairment in carbohydrate, lipid, protein metabolism• Hyperglycemia• Non-enzymatic glycosylation
  • 18. Classification Primary DM – (primary - no other disease)  Type I – IDDM / Juvenile – 10%.  Type II – NIDDM /Adult onset – 80%.  MODY – 5% maturity onset - Genetic  Gestational Diabetes Secondary DM – (secondary to other dis.)  Pancreatitis, tumors, hemochromatosis.  Infectious – congenital rubella, CMV.  Endocrinopathy.  Drugs – Corticosteroids.
  • 19. There are counts six  millions of patient with  insulin-dependent  diabetes mellitus in the world. This is mainly illness of white race. It occur more frequent in highly developed countries (Finland, Italy, Sweden, Denmark, Canada, Norway, USA, England).There are about 100  millions of patient with  insulin-dependent  diabetes mellitus. They consist 85 % of all diabetics. They belong to mainly native population of USA (american indians), Fiji, South Africa, India, Polynesia.
  • 20. Normal Pancreatic Islet:ß α ß cells (Insulin) α cells (Glucagon) δ cells (Somatostatin) pp Cells (pan prot)
  • 21. Type-I Type-II Less common  More common Age < 25 Years  Adult >25 Years Insulin- Dependent  Insulin Independent * Onset: Weeks  Months to years Acute Metabolic  Chronic Vascular complications. complications  No Autoantibody: Yes  Yes Family History: No  Normal or high * Insulin levels: very low  Normal / Exhaustion Islets: Insulitis  60-80% in twins 50% in twins
  • 22. Insulin-dependent diabetes mellitus  Insulin-dependent diabetes mellitus arises as result of absolute insulin insufficiency. It is described by insulinopenia  and by inclination to ketoacidosis. This diabetes occur more frequently is in children and young peoples (till 30 years). Insulin is needed for sustentation of patient life. Attached to it’s absence ketoacidic coma develops.
  • 23. Carbohydrate metabolism in normal conditions and diabetes mellitus INSULIN1. Increase in permeability of myocyte and adipocyte membranesfor glucose (Glut-4)2. Increase in activity of glucokinase, glycogen-sythetase, aerobic IMPAIRMENTglycolysis, pentose-phosphate shunt and Krebs cycle enzymes3. Increased rate of glycogen synthesis in liver4. Increase in synthesis of lipids from glucose5. Inhibition of gluconeogenesis HYPERGLYCEMIA
  • 24. Forms of insulin-dependent diabetes mellitus Autoimmune – DR3 Virus-induced – DR4
  • 25. β -cell genetic defects in diabetes mellitus Maturity-onset diabetes of the young• Chr. – 2 HNF4a (MODY I )-Hepatic Nuclear factor 4 α gene• Chr.-7 glucokinase (MODY I I )• Chr.-11, 12 HNF1a (MODY I I I )- Hepatic Nuclear factor mutation• Mitochondrial DNA mutations, other genetic defects
  • 26. Pathogenesis of Type I DM Genetic HLA-DR3/4 Environment Viral infe..? Autoimmune Insulitis1. drugs, chemicals Ab to ß cells/insulin (streptozotocin, alloxane, pentamidine)2. Dietary (cow milk, high nitrosamine levels) ß cell3. Viruses (Coxsackie, measles) Destruction(molecular m icry) ym Type I / IDDM Insulin deficiency
  • 27. PATHOGENESIS OF DIABETES MELLITUS Insulin insufficiency Fatty acids ↑ Ketone bodies ↑ Blood glucose level ↑β - hydroxybutirate, acetoacetate accumulation in blood glucosuriaMetabolic polyuria Ketonuriaacidosis dehydration→ Poly-Kussmauls CNS depression thirst ↑ dipsiarespiration SHOCK Hypovolemia
  • 28.  Autoimmune insulin-dependent diabetes arises in persons with genome  DR3. It is associated with other autoimmune endocrinopathies, for example, with illnesses of thyroid gland (autoimmune thyreoiditis, diffuse toxic goiter), adrenal gland (Addison’s disease). This diabetes type develops in any age more frequent in women. Autoimmune is diabetes described by presence in blood of patient autoantibodies against of Langergans islets.
  • 29. • Virus-induced insulin-dependent diabetes mellitus binded with genome DR4 and different from autoimmune on mechanisms of development. In this case there are no autoantibodies against islets of pancreas. Its certainly can appear in blood but rapidly (pending of year) disappear. They do not perform essential role in pathogenesis of illness. Development of this diabetes type frequently preceede from viral infectious epidemic parotitis,  german measles, measles, viral hepatitis.• Pathogenic viruses action is not specific. It consists in development of inflammatory process in Langergans islets. Insulitis arises. Lymptoid infiltration of damaged islets develops at first after then destruction. Sometimes the specific (immune) destruction mechanisms of β-cells are linked. The viruses pervert antigen membranes properties of affected β-cells and are followed with attack of autoimmune mechanisms.• There is one more possibility. Membrane β-cells is lightly damaged by much chemical substances even in insignificant concentrations. Such substances are called β-cytotoxic. They are, for example, alloxane and streptosocine. They create a favourable background for immediate viruses action on membrane of β-cells.• Virus-induced diabetes arises early before 30 years of life. It is identically widespread and among males, both among women.
  • 30. Insulin-independent diabetes mellitus This diabetes type principle differs from the first. Patients, as a rule don’t need to exogenic insulin. Metabolic disorders attached to this diabetes are minimal. Diet therapy and per oral glucose decreasing medicines are sufficiently for their compensation. Only in stress (trauma action, sharp infection) conditions patient use insulin. Illness can course for years without hyperglycemia. Sometimes it is disclosed in age more 40 years. There are three factors group, which play a decisive role in forming of this diabetes type. Here are the genetic factors, functional disturbance of β-cells and insulin resistance.
  • 31. Pathogenesis of insulin- independent diabetes mellit us Diabetogenic action has diet is result of diet, which contains a surplus of high-calorie products. They are fats and purified simple carbohydrates. Such action is result of diet, which contains a small amount of complex carbohydrates (food fibres). Inhibiting influence of obesity on insulin receptors very clearly displays in conditions of low physical activity. Regular physical exercises on the contrary raise receptor affinity to insulin and raise tolerance to glucose.
  • 32.  Genetic factors determine hereditary liability to disease. Specific genetic marker (special diabetogenic gene) is not found. It is known only, that inclination to insulin-independent diabetes is not coupled with major complex of histocompatibility. Function of β-cells of patient with insulin-independent diabetes is violated. Amount of them is diminished. Attached to loading by glucose they do not multiply insulin secretion in necessary amount. Diabetologist connects these violations with amyloidosis of Langergans islets.
  • 33. Pathogenesis of Type II DM Genetic / Obesity /ß cell defect Life style ? Abnor. Secretion Insulin Resistance RelativeIDDM Insulin Def. ß cell exhaustion Type II NIDDM
  • 34. Insulin-resistance• Insulin-resistance arises or on genetic base or as result of influence of external factors (risk factors). Biological insulin action is mediated over receptors. They are localized on cells-targets membranes (myocytes, lypocytes). Interaction of insulin and receptor is followed with changes of physical state of cells-targets membrane. As result of this transport system is activated, which carries glucose over cellular membrane. Transmembrane moving of glucose is provided by proteins- transmitters.• Amount of glucose carried in cell depends on closeness of insulin receptors on membrane and on receptor affinity to insulin. These parameters depend on insulin level in blood. Hyperinsulinemia diminishes amount of receptors and their  affinity to insulin. Hypoinsulinemia on the contrary multiplies amount of  receptors and their affinity to insulin.• Some external factors provoke insulin-resistance and development of insulin- independent diabetes. Among these factors in first place belongs to surfeiting and  obesity. Mechanisms of insulin-resistance attached to obesity following: diminution of amount of insulin receptors on cells-targets, slowing down of glucose transport over membrane, disorder of intracellular metabolism of glucose. •  Chronic resistance of insulin receptors causes a chronic hyperfunction of β-cells and surplus production of insulin. This in turn raises receptor resistance.  Thus arises a vicious circle. Protracted loading of β-cells conduces to exhaustion of their functions.
  • 35. The other types of diabetes mellitus• This is large geterogeneous group of illnesses with hyperglycemia. Mains it’s causes following:• а) illnesses of pancreas innate lack of Langergans  islets, trauma and infections, tumor, kystose fibrosis;• b) illnesses of hormonal nature pheochromocytoma, glucagonoma, acromegaly, Itsenko-Cushing illness, thyreotoxicosis;• c) medicines and chemical agents – glucocorticoids, thyreoid hormones, diuretics, analgetics and other remedies;• d) change of insulin receptors diminution or lack of  them (gene mutation in 19 chromosome), antibodies to receptors (mutations of 2 and 14 chromosomes);• e) hereditary syndromes Down’s, Turner’s, Klinefelter’s.
  • 36. IMPAIRMENT OF LIPID METABOLISM IN DIABETES MELLITUS Insulin deficiency Decreased glucose utilization Decreased lipogenesis Mobilization of fats to depoes Hyperlipidemia Metabolic acidosis Increased ketogenesis and cholesterol productoin Ketonemia and Ketonuriahypercholesterolemia Loss of Na+ Keto-acidotic coma
  • 37. IMPAIRMENT OF PROTEIN METABOLISM IN DIABETES MELLITUS Insulin deficiency Decreased glucose utilization Increase in proteolysis Aminacidemia, increased uptake of aminoacids by the liver 1. Activation of gluconeogenesis 2. Increased removal of nitrogen via urea Loss of potassium and other ions by the cells Dehydration of the Potassium loss by the cells organism
  • 38. Symptoms of diabetes mellitusMajor symptoms are:• hyperglycemia,• glucosuria and• polyuria.
  • 39. Pathogenesis of diabetes mellitus symptoms
  • 40. Hyperglycemia Hyperglycemia is connected, foremost with lowering of glucose utilization by muscular and fatty tissues. Lowering of glucose utilization has membranogenic nature. In case of insulinopenia and in case of insulin- resistance nteraction of insulin and receptor is damaged. Therefore protein-transporters of glucose are not included in membranes of cells-targets. This limits glucose penetration in cells. It is use on power needs (in myocytes) diminishes. Lypogenesis is slowed-glucose deposit in fats form (in lypocytes). Glycogenesis slows- synthesis of glycogene (in hepatocytes and myocytes). On other hand, attached to diabetes a supplementary amount of glucose is secreted in blood. In liver and muscles of diabetics glycogenolysis is a very active. Definite endowment in hyperglycemia belongs to gluconeogenesis. Here with glucose will is derivated in liver from amino acids (mainly from alanine).
  • 41. Glucosuria In healthy man practically has not glucose in urine. It is excreated in amount not more 1 g. Attached to sugar diabetes amount of exreted glucose increases repeatedly. It is explainet by next way. If glucose concentration in blood and primary urine does not exceed 9 mmol/l, epithelium of canaliculi reabsorbed it. This maximum concentration is called nephritic threshold. If a glucose concentration exceeds a nephritic threshold (9 mmol/l), part of glucose goes in secondary urine (glucosuria).
  • 42. Polyuria• Glucose is osmotic active substance. Increasing of it’s concentration in primary urine raises osmotic pressure. Water is exuded from organism together with glucose (osmotic diuresis). Patient excretes 3-4 l of urine per day, sometimes till 10 l.
  • 43. PATHOGENESIS OF HYPERGLYCEMIC COMA Insulin deficiency Decreased glucose utilization Increased glucose production Hyperglycemia Glucosuria Osmotic diuresis Hyperosmolarity and dehydration DIC syndromeCOMA DEATH SHOCK
  • 44.  Complication of diabetes mellitusThe very frequent diabetes complications are following:♦ ketoacidosis, ♦ macroangiopathy, ♦ microangiopathy,  angiopathy♦ neuropathy.
  • 45.  Ketoacidosis. In healthy peoples  synthesis of ketone bodies in liver is strictly controled. Main regulatory mechanism is access limitation of fat acids in mytochondries of hepatocytes. Over head permissible concentration limit of ketone bodies in blood is approximately 0,1 mmol/l. In case of exceeding this level regulatory mechanisms are stated. Foremost ketone bodies put specific receptors back up on membrane β-cells of Langergan’s islets. Insulin excretion in blood increases. Insulin stimulates resynthesis of fat acids. First stage of resynthesis is derivation if malonil-КоА. Surplus amount of malonil- КоА oppresses penetration of fat acids in mytochondries.  Synthesis of ketone bodies slows. Attached to diabetes mellitus disturb mechanism of both synthesis regulation of ketone bodies – both on level of β-cells, and on level of hepatocytes. Receptor stimulation of β-cells by ketone bodies does not cause increased excretion insulin in blood. In conditions of insulinopenia fat acids penetrate in hepatocytes in unrestricted amount. Liver synthesizes many ketone bodies. Extrahepatic tissues can not utilize them. Amount of ketone bodies in blood increases. Metabolic acidosis occur. It can complete by ketoacid  coma. Seldom attached to  diabetes mellitus lactoacidosis occur. It is attached to insulin-independent diabetes mellitus, attached to combination of diabetes with hypoxia,  sepsis, shock.
  • 46. MacroangiopathyMacroangiopathy is vessels atherosclerosis ofcerebrum, heart, kidneys, legs. Diabetes lead toatherosclerosis development. There are threeacceleration way of atherogenesis in patients withdiabetes. In conditions of insulin insufficiency growthhormone synthesis increases. Here upon proliferation ofsmooth myocites accelerates key stage ofatherogenesis. Attached to diabetes vessels endotheliumdamages. Synthesis of thromboxane increase, and thishelps to adhesion of thrombocytes. Thrombocytes excretmitogene (thrombocytic growth factor). It also stimulatesproliferation of smooth myocytes.Attached to diabetes concentration of lipoproteids lowdensity, increase concentration of lipoproteids of highdensity.
  • 47. Microangiopathy• Microangiopathy develop in shallow vessels – arterials, venues, capillaries. Two process form their pathogenic base – thicking of basal membrane and reproduction endothelium. Direct cause of microangiopathy is hyperglycemia and synthesis of glycoproteids in basal membrane.• There are two main clinical forms microangiopathy: diabetic retinopathy and diabetic nephropathy.
  • 48. A composite photograph showing a pretreatment fundus photograph (A), and aphotograph demonstrating radiation retinopathy at 24 months (B). A fluoresceinangiogram demonstrates intraretinal microangiopathy next to the tumour (C), andregression to chorioretinal scar after laser photocoagulation (D).
  • 49. Neuropathy• Neuropathy manifest by violation of nerves function sensible, motor, vegetative. Essence of these decreases is demyelinisation of nervous fibres, decrease of axoplasmatic flow.
  • 50. Galactosemia• This is hereditary illness. In it’s base lies an blockade of  galactose metabolism. In organism intermediate metabolits accumulate. There are two the main forms of galactosemia on base of transferase insufficiency and on base of galactokinase insufficiency.
  • 51. Deficit of glucose-1- phosphaturidyltransferase.• This enzyme converts galactose-1-phosphate in glucose-1-phosphate. Attached to it’s insufficiency galactose-1-phosphate and sugar alcohol of galactose (galactit) accumulates in tissues lens of the eye, liver,  brain, kidneys. Mammal and cow milk contains lactose.• Therefore the illness symptoms appear with first days of child life.• Diarrhea, vomiting, dehydrotation occur.• Liver increases (splenomegalia). Hepatocytes lose ability to conjugate bilirubine. Children become yellowish.• Affection of kidneys displays in proteinuria, aminoaciduria and acidosis.• For galactosemia cataract is very typical. Their beginnings related to accumulation of osmotic active galactite in vitreous bodies of eyes. Galactite absorb in water, and water breaks tissues.• Dangerous consequences arise in the brain. This foremost is delay of mental development.• Mortal end is possible.• Cure method is diet without galactose.
  • 52. Deficit of galactokinase. Attached to this illness variant a process of phosphorilation of galactose is blocked, that is transformation of galactose in galactose-1-phosphat. Illness displays in cataracts. Other symptoms are absent or minor. Cure is diet without galactose.
  • 53. GLYCOGENOSIS Type І – Girke disease . Deficit of glucoso-6- phosphatase Type ІІ – Pompe disease . Deficit of acidic maltase (α-1,4-glucosidase) Type ІІІ – Cori disease , Forbs disease . Deficit of amylo-1,6- glucosidase Type ІV – Anderson disease . Deficit of amylo- 1,4,1,6-transglucosidase Type V – McArdel disease Deficit of phosphorilase of myocytes Т ype VІ – Hers disease . Deficit of phosphorilasic complex in liver Т ype VІІ. Deficit of muscle phosphofrutкinase
  • 54. Glycogenoses• Simple carbohydrates deposit in organism as polysaccharides. In muscles and liver accumulates glycogen. It consist of 4 % of liver weight and 2 % of muscles weight. Muscles glycogen is used as of ready fuel source for immediate guaranteeing by energy. Liver without interruption provides cerebrum and erythrocytes with glucose .• Synthesis and splitting of glycogen are exactly adjusted and coordinated processes. Attached to immediate need in glucose α–cells of pancreas secret glucagone. It activates adenylatcyclase of hepatic cells. Adenilatcyclase stimulates derivation of cAMP. Under action of cAMP takes place activation of proteinkinase and this enzyme raises activity glycogenphosphorilase and oppresses activity of glucogensynthase. Here upon starts intensive glycogenolysis. Supplementary amount of glucose is secreted in blood.• In other situation after consuming of carbohydrates in blood accumulates surplus of glucose. β-cells of pancreas multiply insulin synthesis. Insulin raises activity of glycogensyntase. Active glucogenesis starts too. Surplus of glucose reserves in appearance of glucogen in liver and muscles.• There are illnesses in base of which is accumulation of glycogen in organs. They are called glycogenoses. All of them are hereditary enzymopathy. There are seven main types of glycogenoses.
  • 55. Glycogenosis type I – Girke’s disease.• Girke’s disease cause deficit of glucose-6-phosphatase. This enzyme provides 90 % of glucose which disengages in liver from glycogen. It play central role in normal glucose homeostasis. Glucose which disengages attached to disintegration of glycogen or is derivated in process of gluconeogenesis obligatory goes over stage of glucose-6-phosphate. Enzyme glucose-6-phosphatase tears away a phosphate group from glucose. There free glucose is formed it goes out in blood. Attached to Girke’s disease stage of tearing phosphate group is blocked. There are no free glucose hypoglycemia occur. Hypoglycemia arises. Attached to Girke’s disease glycogen is deponed  in liver and kidneys.
  • 56. Glycogen Storage Disorders:• Type 1= Von Gierke’s: – Shortly after birth: Severe lifethreatening Hypoglycemia – Lactic acidosis –due to isolated glycolysis of G6Po – Hyper-uricemia, hyper lipidemia – Increased association with epistaxis – *Hepatomegaly – **Adverse response to Glucagon with worsening Lactic acidosis• Management requires IV glucose, and then as outpt, close NG corn-starch or glucose solution administration to achieve close to nl glucose homeostasis.• Frequent snacks and meals. Continuous nighttime glucose infusions up to the age of 2.
  • 57. Type ІІ glycogenosis – Pompe’s disease.• Illness is related to deficit of lysosomal enzyme – sour maltase, or α-1,4- glucosidase. This enzyme slits glycogene to glucose in digestive vacuoles. Attached to it’s deficit glycogen accumulates at first in lysosomes and then in cytosole of hepatocytes and myocytes.
  • 58. Glycogen Storage Disorders:• Type 2- Pompe’s disease:• Normal Glucose• Do to an accumulation of glycogen in lysosomes.• **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD**• Manifested by massive Cardiomegaly, Hepatomegaly, Macroglossia.• Fatal If results in CHF.• Limited therapies in Neonatal Variant. – Attempts at enzyme replacement ongoing.
  • 59. Type ІІІ glycogenosis – Cori’s disease, Forbs’ diseaseThis illness is namedlimited ecstrinosis. Init’s base lies a deficit of Glycogenglycogen, right normal) to show in the Liver (left stainedamylo-1,6-glucosidase.Degradation ofglycogen pauses insites of branching.Glycogen accumulates Glycogen in Muscle Cellsin liver and muscles.Cure is diet with bigproteins maintenance.
  • 60. Type ІV glycogenosis – Anderson’s disease.• It is called by deficit of amilo- 1,4,1,6-transglucosidase (branching enzyme). As result of this there is derivated anomalous glycogen with very long branches and rare points of branching. It is not exposed to degradation and accumulates in liver, heart, kidneys, spleen, lymphatic nods, skeletal muscles.
  • 61. Type V glycogenosis – McArdel’s disease.• It’s cause is deficit of phosphorilase of myocytes. Typical pain displays in muscles after physical loading. Glycogene does not slit only in muscles. Here it accumulates. In liver mobilization of glycogen comes normal.
  • 62. Type VІ  glycogenosis – Hers’ disease.• Illness arises as result of insufficiency of hepatic phosphorilase complex. Glycogen accumulates in liver. Typical sign is hepatomegalia.
  • 63.  Type VІІ glycogenosis. Illness essence is in oppression of muscle phosphofrutkinase. Symptoms are similar to McArdles disease.
  • 64. Four main types of lipoproteins• Chylomicrons- carry triglyceride from intestine to liver, skeletal muscle and adipose tissue. Chylomicrons are triglyceride rich lipoproteins appear in the blood after fat containing meal.• Very low density lipoproteins (VLDL) - carry synthesized triglycerides from liver to adipose tissue. VLDL is triglyceride rich lipoprotein contains 10-15% of total serum cholesterol.
  • 65. Four main types of lipoproteins• Low density lipoproteins (LDL) - carry cholesterol from liver to cells. It is referred to as the “bad cholesterol” lipoproteins. 60-70% of total serum cholesterol contains in LDL.• High density lipoproteins (HDL) – collect cholesterol from the tissue back to the liver (RCT). It is referred to as the “good cholesterol” lipoproteins. HDL carry 20-30% of total serum cholesterol
  • 66. Endothelial Dysfunction in AtherosclerosisMacrophages play main  role:1. They have  “scavenger”-receptors so Cholesterol comes in macrophage  only due to  concentration difference 2. They can accumulate a  lot of Ch inside (this  process is controlled by HDLP only)3. Changed LDLP  stimulate  Ross R. N Engl J Med 1999; 340:115–126.macrophages activity
  • 67. Fatty-Streak Formation inAtherosclerosisRoss R. N Engl J Med 1999; 340:115–126.
  • 68. Formation of an Advanced, Complicated Lesion in AtherosclerosisRoss R. N Engl J Med 1999; 340:115–126.
  • 69. 3 stage – FIBROUS PLAQUE Cholesterol and  lisosomal enzymes  irritates intimae  (because they are  the alien bodies)Excreation of  proliferation factors  by macrophages,  еndotheliocytes,  lymphocytes,  thrombocytesSMC migration in intimae  and active  proliferation collagen  and elastin (capsule  for Cholesterol and  injured vessel wall  isolation)
  • 70. 4 stage -  COMPLICATIONS1. THROMBOSIS (due to endotheluum  damage)2. Ulceration(necrosis of and  releasing of  lisosomal  enzymes  causes damage  of plaque wall)3. Calcinations(deposit of insoluble  calcium salts)
  • 71. LDL Particles Promote Atherogenesis Particle Movement into Intima Particle Movement into Intima – – Gradient driven Gradient driven “The rate of passive diffusion is  “The rate of passive diffusion is  Enhanced Enhanced increased when the circulating          increased when the circulating          Endothelial Endothelial levels of LDL are elevated.” 1 levels of LDL are elevated.” 1 Dysfunction Dysfunction Monocyte Colony- Adhesion Tissue stimulating molecules PAI-1 MCP-1 factor factors Lumen Endothelial cells Mildly modified LDL Intima Extensively modified LDL Particle Uptake by Particle Uptake by Particle Retention Particle Retention Particle Oxidation Particle Oxidation Macrophage Macrophage – – Lipoprotein particle Lipoprotein particle binding to proteoglycans binding to proteoglycans Cholesterol Deposition; Cholesterol Deposition; Increased Plaque Burden Increased Plaque Burden1 Weissberg PL, Rudd JH. Textbook of Cardiovascular Medicine. 2002. p. 6.
  • 72. OBESITY