DISORDER OF CARBOHYDRATE METABOLISM.
Major index which describes metabolism of carbohydrates, is a sugar level in blood. In healthy peoples it is 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.
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.
Diabetes mellitus
Diabetes mellitus, or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
There are three main types of diabetes mellitus (DM).
Type 1 DM results from the body’s failure to produce insulin, and currently requires the person to inject insulin or wear an insulin pump. This form was previously referred to as “insulin-dependent diabetes mellitus” (IDDM) or “juvenile diabetes”.
Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. This form was previously referred to as non insulin-dependent diabetes mellitus (NIDDM) or “adult-onset diabetes”.
The third main form, gestational diabetes, occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. It may precede development of type 2 DM.
Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes.
Untreated, diabetes can cause many complications. Acute complications include diabetic ketoacidosis and nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease,chronic
renal failure
, and diabetic retinopathy (retinal damage). Adequate treatment of diabetes is thus important, as well as blood pressure control and lifestyle factors such as stopping smoking and maintaining a healthy body weight.
All forms of diabetes have been treatable since insulin became available in 1921, and type 2 diabetes may be controlled with medications. Insulin and some oral medications can cause hypoglycemia (low blood sugars), which can be dangerous if severe. Both types 1 and 2 are chronic conditions that cannot be cured. Pancreas transplants have been tried with limited success in type 1 DM; gastric bypass surgery has been successful in many with morbid obesity and type 2 DM. Gestational diabetes usually resolves after delivery.
Major index which describes metabolism of carbohydrates, is a sugar level in blood. In healthy peoples it is 4,4-6,6 mmol/l.
Diabetes mellitus is heterogenic diseases group which arise on base of absolute or relative insulin insufficiency and have hyperglicemia as general symptom.
Classification of diabetes mellitus up to nows remains clinical. Main types – insulin-dependent diabetes mellitus and insulin-independent diabetes mellitus. These two diabetes types affect the majority of patient. 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.
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 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).
DIAGNOSIS
Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)
Plasma glucose ≥ 11.1 mmol/l (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test
Symptoms of hyperglycemia and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)
Glycated hemoglobin (Hb A1C) ≥ 6.5%.
A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above methods on a different day. It is preferable to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test. According to the current definition, two fasting glucose measurements above 126 mg/dl (7.0 mmol/l) is considered diagnostic for diabetes mellitus.
People with fasting glucose levels from 110 to 125 mg/dl (6.1 to 6.9 mmol/l) are considered to have impaired fasting glucose. Patients with plasma glucose at or above 140 mg/dL (7.8 mmol/L), but not over 200 mg/dL (11.1 mmol/L), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus, as well as cardiovascular disease.
Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause
Glycated hemoglobin or glycosylated hemoglobin (hemoglobin A1c, HbA1c, A1C, or Hb1c; sometimes also HbA1c) is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. It is formed in a non-enzymatic glycation pathway by hemoglobin’s exposure to plasma glucose. Normal levels of glucose produce a normal amount of glycated hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. This serves as a marker for average blood glucose levels over the previous months prior to the measurement.
In diabetes mellitus, higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have been associated with cardiovascular disease, nephropathy, and retinopathy. Monitoring HbA1c in type 1 diabetic patients may improve outcomes.
Glycation of proteins is a frequent occurrence, but in the case of hemoglobin, a nonenzymatic reaction occurs between glucose and the N-end of the beta chain. This forms a Schiff base which is itself converted to 1-deoxyfructose. This rearrangement is known as Amadori rearrangement.
When blood glucose levels are high, glucose molecules attach to the hemoglobin in red blood cells. The longer hyperglycemia occurs in blood, the more glucose binds to hemoglobin in the red blood cells and the higher the glycated hemoglobin.
Glucose levels are intermittently raised in portal vessels carrying absorbed glucose to the liver for regulation. Passing red cells will have increased glycation after sugary drink or porridge.
Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red cell, therefore, reflects the average level of glucose to which the cell has been exposed during its life-cycle. Measuring glycated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose regulation. The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months. Some researchers state that the major proportion of its value is weighted toward the most recent 2 to 4 weeks.
Pathogenesis of insulin-dependent diabetes mellitus
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.
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.
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.
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.
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 iecessary amount. Diabetologist connects these violations with amyloidosis of Langergans islets.
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: iminution 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.
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.
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.
symptoms of diabetes mellitus
Major symptoms are hyperglycemia, glucosuria and polyuria.
Hyperglucemia 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).
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).
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.
Pathogenesis of diabetes mellitus symptoms
Complication of diabetes mellitus
The very frequent diabetes complications are following: ketoacidosis, macroangiopathy, microangiopathy, neuropathy.
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 caot 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.
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.
Microangipathy 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 microangipathy : diabetic retinopathy and diabetic nephropathy.
Neuropathy manifest by violation of nerves function sensible, motor, vegetative. Essence of these decreases is demyelinisation of nervous fibres, decrease of axoplasmatic flow.
Diabetic retinopathy
Diabetic nephropathy
Pathogenesis of diabetic neuropathy
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.
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, buds. 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.
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.
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 a–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.
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 iormal 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.
Type ІІ glycogenosis – Pompe’s disease. Illness is related to deficit of lysosomal enzyme – sour maltase, or a-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.
Type ІІІ glycogenosis – Cori’s disease, Forbs’ disease. This illness is named limitdecstrinosis. 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.
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.
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.
Type VІ glycogenosis – Hers’ disease. Illness arises as result of insufficiency of hepatic phosphorilase complex. Glycogen accumulates in liver. Typical sign is hepatomegalia.
Type VІІ glycogenosis. Illness essence is in oppression of muscle phosphofrutkinase. Symptoms are similar to McArdles disease.
