1. Disorders of Carbohydrate Metabolism

2. 65 -110 mg/% Normal glucose level in the blood 65 -110 mg/% 3.50 - 6.05 mmol/L 3.50 - 6.05 mmol/L (5.5 mmol/L) (5.5 mmol/L) Impairments of glucose balance Hypoglycemia (less than 2.5 mmol/L results in coma) Hypoglycemia (less than 2.5 mmol/L results in coma) Hyperglycemia Hyperglycemia GLUCOSE 3.50 6.05 NORMHyperglycemiaHypoglycemia

3. Blood Glucose & Hormones Hormone  Insulin  Glucortocoids  Glucagon  Growth Hormone  Epinephrine Action   Glucose   Glucose

4. 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. 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. Rise of glucose concentration is named hyperglicemia lowering hypoglicemia. For example, hyperglicemia is very typical for diabetes mellitus, hypoglycemia – for glycogenosis. For example, hyperglicemia is very typical for diabetes mellitus, hypoglycemia – for glycogenosis.

5. Regulation of carbohydrate metabolism Counter-insulin hormones ACTH, growth hormone, cortisol, thyroid hormone, glucagon, adrenaline 1.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)

6. Blood glucose balance regulation Insulin Permeability of cellular membranes Permeability of cellular membranes glucokinase reaction rate glucokinase reaction rate synthesis of glycolytic enzymes synthesis of glycolytic enzymes gluconeogenesis gluconeogenesis glucose-6-phosphate production glucose-6-phosphate production Counter- insulin hormones (glucagon, adrenaline, thyroids, glucocorticoids sgrowth hormone, ACTH) inhibition activation

7. 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 glycogenesisglycogenesis Inhibition of glycogenolysisglycogenolysis Stimulation of amino acid uptake Stimulation of protein synthesis Inhibition of protein degradation Stimulation of fatty acid and triglyceride synthesisfatty acid and triglyceride synthesis Inhibition of lipolysis Stimulation of lipoproteins uptake The 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.

8. The Metabolic Effects of Glucagon The Liver Muscle Adipose Stimulation of glycogenolysis Inhibition of glycogenesis Stimulation of gluconeogenesisgluconeogenesis Stimulation of lipolysis Stimulation of ketone formationketone formation Stimulation of amino acid uptake Like insulin, glucagon is a polypeptide hormone. However, in contrast to insulin, receptors for glucagon are not as abundant in cells throughout the body. The action 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.

9. Hypoglycemia Exogenous Endogenous Functional

10. Exogenous hypoglycemia Insulin injection Alcohol (develops 6-36 hours after heavy consumption) Some drugs (e.g. salicylates) Long term physical exercise

11. Endogenous hypoglycemia insulinoma (hyperplasia of  -cells) insulinoma (hyperplasia of  -cells) glycogenosis glycogenosis hereditary fructose intolerance hereditary fructose intolerance insufficiency in phosphoenolpyruvate carboxykinase insufficiency in phosphoenolpyruvate carboxykinase Hepatocellular insufficiency Hepatocellular insufficiency Impaired absorption Impaired absorption

12. 1.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 failure 6. Malnutrition 7. Heavy physical load (without carbohydrate uptake) 8. Transient functional hypoglycemia of children Neonatal (10%) Maternal diabetes Erythroblastosis Ketogenic Functional Hypoglycemia

14. Manifestations of hyperglycemia Glucosuria Glucosuria Polyuria Polyuria Polydypsia Polydypsia Hypohydration of the organism Hypohydration of the organism Arterial hypotension Arterial hypotension Manifestations of hypoglycemia Starvation Starvation Tremor Tremor Excessive sweating Excessive sweating Tachycardia Tachycardia Headache, dizziness Headache, dizziness Impaired vision Impaired vision Anxiety, fear Anxiety, fear Impaired cognition Impaired cognition

15. mellitus

16. 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

17. Classification Primary DM – (primary - no other disease) Primary DM – (primary - no other disease) Type I – IDDM / Juvenile – 10%. Type I – IDDM / Juvenile – 10%. Type II – NIDDM /Adult onset – 80%. Type II – NIDDM /Adult onset – 80%. MODY – 5% maturity onset - Genetic MODY – 5% maturity onset - Genetic Gestational Diabetes Gestational Diabetes Secondary DM – (secondary to other dis.) Secondary DM – (secondary to other dis.) Pancreatitis, tumors, hemochromatosis. Pancreatitis, tumors, hemochromatosis. Infectious – congenital rubella, CMV. Infectious – congenital rubella, CMV. Endocrinopathy. Endocrinopathy. Drugs – Corticosteroids. Drugs – Corticosteroids.

18. 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.

19. Normal Pancreatic Islet: ß cells α cells ß cells (Insulin) α cells (Glucagon) δ cells pp Cells δ cells (Somatostatin) pp Cells (pan prot) ß α

20. Type-I Type-II Less common Less common Age < 25 Years Age < 25 Years Insulin- Dependent Insulin- Dependent Onset: Weeks Onset: Weeks Acute Metabolic complications Acute Metabolic complications Autoantibody: Yes Autoantibody: Yes Family History: No Family History: No Insulin levels: very low Insulin levels: very low Islets: Insulitis Islets: Insulitis 50% in twins 50% in twins More common More common Adult >25 Years Adult >25 Years Insulin Independent * Insulin Independent * Months to years Months to years Chronic Vascular complications. Chronic Vascular complications. No No Yes Yes Normal or high * Normal or high * Normal / Exhaustion Normal / Exhaustion 60-80% in twins 60-80% in twins

21. 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. 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.

22. Carbohydrate metabolism in normal conditions and diabetes mellitusINSULINIMPAIRMENT 1. Increase in permeability of myocyte and adipocyte membranes for glucose (Glut-4) 2. Increase in activity of glucokinase, glycogen-sythetase, aerobic glycolysis, pentose-phosphate shunt and Krebs cycle enzymes 3. Increased rate of glycogen synthesis in liver 4. Increase in synthesis of lipids from glucose 5. Inhibition of gluconeogenesis HYPERGLYCEMIA

23. PATHOGENESIS OF DIABETES MELLITUS Insulin insufficiency Fatty acids  Ketone bodies   - hydroxybutirate, acetoacetate accumulation in blood Metabolic acidosis Ketonuria Kussmaul's respiration CNS depression Blood glucose level  glucosuria polyuria dehydration  thirst  Hypovolemia SHOCK Poly- dipsia

25. 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. 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. 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.

26. Pathogenesis of insulin- independent diabetes mellitus  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.

27. 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.

28. IMPAIRMENT OF LIPID METABOLISM IN DIABETES MELLITUS Decreased glucose utilization Decreased lipogenesis Mobilization of fats to depoes Hyperlipidemia Metabolic acidosis Increased ketogenesis and cholesterol productoin Ketonemia and hypercholesterolemia Ketonuria Loss of Na + Keto-acidotic coma Insulin deficiency

29. 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 cells Potassium loss by the organism Insulin deficiency IMPAIRMENT OF PROTEIN METABOLISM IN DIABETES MELLITUS

30. Symptoms of diabetes mellitus Major symptoms are: hyperglycemia, glucosuria and polyuria.

31. Pathogenesis of diabetes mellitus symptoms

32. 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).

33. 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). 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).

34. 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.

35. Decreased glucose utilization Increased glucose production Hyperglycemia Glucosuria Osmotic diuresis Hyperosmolarity and dehydration PATHOGENESIS OF HYPERGLYCEMIC COMA C O M A SHOCK DEATH DIC syndrome Insulin deficiency

36. Complication of diabetes mellitus The very frequent diabetes complications are following:  ketoacidosis,  macroangiopathy,  microangiopathy,  neuropathy. angiopathy

37. 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. 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. 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. 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. Seldom attached to diabetes mellitus lactoacidosis occur. It is attached to insulin-independent diabetes mellitus, attached to combination of diabetes with hypoxia, sepsis, shock.

39. Macroangiopathy Macroangiopathy is vessels atherosclerosis of cerebrum, heart, kidneys, legs. Diabetes lead to atherosclerosis development. There are three acceleration way of atherogenesis in patients with diabetes. In conditions of insulin insufficiency growth hormone synthesis increases. Here upon proliferation of smooth myocites accelerates key stage of atherogenesis. Attached to diabetes vessels endothelium damages. Synthesis of thromboxane increase, and this helps to adhesion of thrombocytes. Thrombocytes excret mitogene (thrombocytic growth factor). It also stimulates proliferation of smooth myocytes. Attached to diabetes concentration of lipoproteids low density, increase concentration of lipoproteids of high density.

43. 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.

45. A composite photograph showing a pretreatment fundus photograph (A), and a photograph demonstrating radiation retinopathy at 24 months (B). A fluorescein angiogram demonstrates intraretinal microangiopathy next to the tumour (C), and regression to chorioretinal scar after laser photocoagulation (D).

46. 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.

47. GLYCOGENOSIS Type І –Girke disease. Deficit of glucoso-6- phosphatase Type І –Girke disease. Deficit of glucoso-6- phosphatase Type ІІ –Pompe disease. Deficit of acidic maltase (α-1,4-glucosidase) 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 ІІІ –Cori disease, Forbs disease. Deficit of amylo-1,6- glucosidase Type ІV –Anderson disease. Deficit of amylo- 1,4,1,6-transglucosidase Type ІV –Anderson disease. Deficit of amylo- 1,4,1,6-transglucosidase Type V –McArdel disease Deficit of phosphorilase of myocytes Type V –McArdel disease Deficit of phosphorilase of myocytes Тype VІ –Hers disease. Deficit of phosphorilasic complex in liver Тype VІ –Hers disease. Deficit of phosphorilasic complex in liver Тype VІІ. Deficit of muscle phosphofrutкinase Тype VІІ. Deficit of muscle phosphofrutкinase

48. 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.

50. 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.

51. 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.

52. 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.

53. 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.

54. Type ІІІ glycogenosis – Cori’s disease, Forbs’ disease This illness is named limited ecstrinosis. In it’s base lies a deficit of amylo-1,6-glucosidase. Degradation of glycogen pauses in sites of branching. Glycogen accumulates in liver and muscles. Cure is diet with big proteins maintenance. Glycogen in the Liver (left stained to show glycogen, right normal) Glycogen in Muscle Cells

55. 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.

56. 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.

57. Type VІ glycogenosis – Hers’ disease. Illness arises as result of insufficiency of hepatic phosphorilase complex. Glycogen accumulates in liver. Typical sign is hepatomegalia.

58. Type VІІ glycogenosis. Illness essence is in oppression of muscle phosphofrutkinase. Symptoms are similar to McArdles disease. Type VІІ glycogenosis. Illness essence is in oppression of muscle phosphofrutkinase. Symptoms are similar to McArdles disease.