PATHOPHYSIOLOGY PATHOPHYSIOLOGY OF CARBOHYDRATE OF CARBOHYDRATE

METABOLISMMETABOLISM

Prof. J. HanProf. J. Hanacacekek, MD, PhD , MD, PhD

Technical co-operative: L.Technical co-operative: L.ŠŠurinovurinováá

A. Physiologic remarks:A. Physiologic remarks: Carbohydrates are present Carbohydrates are present in in food in food in various formsvarious forms::

1. 1. simple sugarssimple sugars - monosaccharides- monosaccharides

2. 2. complex chemical unitscomplex chemical units - disaccharides- disaccharides - polysaccharides- polysaccharides Processing of carbohydrates in GIT Ingested carbohydrates Ingested carbohydrates cleaving procescleaving proces monosaccharides monosaccharides absorbtion in absorbtion in stomach, stomach, duodenum and proximal jejunumduodenum and proximal jejunum

B. B. Disturbancies in Carbohydrate ResorbtionDisturbancies in Carbohydrate Resorbtion

1.1. Disaccharidase deficiency syndromeDisaccharidase deficiency syndrome

saccharasesaccharase = = enzyme which hydrolyenzyme which hydrolysesses disaccharide disaccharide saccharosesaccharose (to fructose and glucose(to fructose and glucose))

laktase laktase = = enzyme which splits disaccharide lactose enzyme which splits disaccharide lactose

((to to glucoseglucose and and galactose) galactose)

maltase maltase = = enzyme which splits disaccharide maltoseenzyme which splits disaccharide maltose (to two molecule of glucose)(to two molecule of glucose)

PathomechanismPathomechanismss a)a) Activity of disaccharidase is decreasedActivity of disaccharidase is decreased decreaseddecreased hydrolysishydrolysis o of disaccharidef disaccharide decreased resorbtion of decreased resorbtion of

substratesubstrate increased concentration of disaccharide in increased concentration of disaccharide in small intestinesmall intestine

lumen lumen increased osmotic activity of the lumenincreased osmotic activity of the lumen fluidfluid diarrhea diarrhea

b)b) Activity of disaccharidase is decreasedActivity of disaccharidase is decreased increased increased concentration of disaccharide in small intestine lumenconcentration of disaccharide in small intestine lumen increased concentration of disaccharide in large intestineincreased concentration of disaccharide in large intestine disaccharide disaccharide fermentation fermentation by bacteriaby bacteria increased increased concentration of lactic acid and fatty acids concentration of lactic acid and fatty acids stimulation of intestine wallstimulation of intestine wall abdominal cramps, abdominal cramps, bloating, diarrhea, acidic stools, explosive diarrheabloating, diarrhea, acidic stools, explosive diarrhea

Lactase deficiency syndromeLactase deficiency syndrome Causes of lactase deficiencyCauses of lactase deficiency::

- genetic defect- genetic defect (primary) (primary) - secondary to a wide variety of gastrointesti- secondary to a wide variety of gastrointestinal nal diseases diseases that damage the mucosa of the that damage the mucosa of the smallsmall intestineintestine (secondary)(secondary)

Disaccharide lactoseDisaccharide lactose is the principal carbohydrateis the principal carbohydrate in milkin milk.. - - Many persons showing milk intolerance prove to be Many persons showing milk intolerance prove to be

lactaselactase – – deficientdeficient - - Primary lactase deficiency incidence is as high as 80 % Primary lactase deficiency incidence is as high as 80 % to 90 % to 90 % amongamong African - AmericanAfrican - Americanss, Asians, and Bantus , Asians, and Bantus populationpopulation - - Milk intolerance may not become clinically apparent until Milk intolerance may not become clinically apparent until adolescenceadolescence

Causes of secondary lactase deficiencyCauses of secondary lactase deficiency:: - - nontropical nontropical (celiac disease)(celiac disease)and tropicaland tropical sprue,sprue,

-- regional enteritis, regional enteritis,

- - viral and bacterial infections of the intestinaviral and bacterial infections of the intestinal l tract,tract,

-- giardiasis, cystic fibrosis, ulcerative colitis, giardiasis, cystic fibrosis, ulcerative colitis,

- - kwashiorkor, coeliac disease kwashiorkor, coeliac disease 

Symptoms and signs - are mentioned atSymptoms and signs - are mentioned at previous page previous page

Monosaccharides malabsorbtionMonosaccharides malabsorbtion

Small intestine ability to resorb glucose and galactose isSmall intestine ability to resorb glucose and galactose is decreaseddecreased Cause:Cause: Specific transport system for galactose and glucoseSpecific transport system for galactose and glucose absorbtion in cells of small intestine is insufficientabsorbtion in cells of small intestine is insufficient Results:Results: Symptoms and signs similar to disaccharidaseSymptoms and signs similar to disaccharidase deficiency syndromedeficiency syndrome

Glycogenosis (glycogen storage disease)Glycogenosis (glycogen storage disease)

Autosomal recessive diseaseAutosomal recessive disease (inborn errors of (inborn errors of metabolism,metabolism, emzymopathy)emzymopathy) There are defects in degradationThere are defects in degradation of glycogen. of glycogen.

The disturbances result in storage of abnormalThe disturbances result in storage of abnormal

glycogen, glycogen, or storage of abnormal amount of glycogen in various or storage of abnormal amount of glycogen in various organs of the bodyorgans of the body

Example:Example: Hepatorenal glycogenosis (Morbus Hepatorenal glycogenosis (Morbus von von

Gierke)Gierke) Cause:Cause: Deficit of glucose-6-fosfatase in liver and Deficit of glucose-6-fosfatase in liver and kidneykidney Results:Results: Hypoglycemia in fasting individuals, Hypoglycemia in fasting individuals, hyperlipemia, ketonemiahyperlipemia, ketonemia There are There are 9 9 other types of glycogenosisother types of glycogenosis

DIABETES MELLITUSDIABETES MELLITUS

DM – complex chronic metabolic disorder leading to multiorgan complications

Main pathophysiological questions related to DMWhy and how the DM develops?

Why and how develop the complications of DM?

What are the mechanisms involved in manifestationof diabetic symptoms and signs

Regulation of the blood glucose level depends on liver:Regulation of the blood glucose level depends on liver:1. extracting glucose1. extracting glucose from blood from blood

2. synthesizing glycogen2. synthesizing glycogen3. performing glycogenolysis3. performing glycogenolysis

4. performing gluconeogenesis4. performing gluconeogenesisTo a lesser extent To a lesser extent peripheral tissuesperipheral tissues (muscle and adipocytes) use (muscle and adipocytes) use glucose for their energy needs, thus contributing to maintinance glucose for their energy needs, thus contributing to maintinance of normal blood glucose levelof normal blood glucose level

The liverThe livers uptake and output of glucose and the use of s uptake and output of glucose and the use of gglucoselucose by peripheral tissues depend on the physiologic by peripheral tissues depend on the physiologic balance of several hormones that:balance of several hormones that:1. lower blood glucose level1. lower blood glucose level - insulin - insulin2. rise blood glucose level2. rise blood glucose level - glucagon, epinephrine, - glucagon, epinephrine, GH, GH, glucocorticoids...glucocorticoids...

DM is a chronicDM is a chronic complex syndromecomplex syndrome induced by induced by absolute or or relative deficit of insuline which is characterized by which is characterized by metabolic disorders of carbohydrates, lipids and proteins.metabolic disorders of carbohydrates, lipids and proteins.

The metabolic disturbances are accompanied by The metabolic disturbances are accompanied by loss of loss of carbohydrate tolerance, fasting hyperglycemia, carbohydrate tolerance, fasting hyperglycemia, ketoacidosis, decreased lipogenesis, increased lipolysis, ketoacidosis, decreased lipogenesis, increased lipolysis, increased proteolysisincreased proteolysis and some other metabolic and some other metabolic disordersdisorders

Definition of DMDefinition of DM

CClassification of DMlassification of DM(according to International Expert Committee, 1997)(according to International Expert Committee, 1997)

  Base for the classification are Base for the classification are etiopathogenetic mechanismsetiopathogenetic mechanismsinvolved in onset and development of DMinvolved in onset and development of DM

I. I. Diabetes mellitus - type 1:Diabetes mellitus - type 1: due to destruction of due to destruction of betabeta

cellcellss of pancreatic of pancreatic isletsislets

Consequence:Consequence: absolute deficit of insulinabsolute deficit of insulin  

A. A. subtype:subtype: induced by autoimmunity processesinduced by autoimmunity processes

B. B. subtype: subtype: idiopathic mechanismidiopathic mechanism

Types of DMTypes of DM

II.II.Diabetes mellitus -type 2:Diabetes mellitus -type 2: at the beginningat the beginning--predominancepredominance of insulinof insulin resistance resistance and and relative deficit of insulinrelative deficit of insulin(normo- or (normo- or hyper -insulinemia), later onhyper -insulinemia), later on - - combination of combination of impaimpaiired insulin red insulin secretion and simultaneous insulin resistancesecretion and simultaneous insulin resistance (hypoinsulinemia(hypoinsulinemia, , insulin resistanceinsulin resistance))

IV. IV. Gestational DMGestational DM - -

III. Other specific types of DMIII. Other specific types of DM

DM due to DM due to genetic defectsgenetic defects of beta cellsof beta cells of pancreas islets and due of pancreas islets and due to to genetic defect of insulin functiongenetic defect of insulin function

DM due to DM due to diseases influencing exocrine functions of pancreasdiseases influencing exocrine functions of pancreas – – - - secondary is damaged endocrine function,secondary is damaged endocrine function, too.too.

DM due to DM due to endocrinopathies, drugs, chemicals,endocrinopathies, drugs, chemicals, infections, infections, metabolic and genetic disturbancesmetabolic and genetic disturbances

glucose intolerance which onsetglucose intolerance which onsetss fofor r thethe first time during pregnancyfirst time during pregnancy

Main differences between “old” and “new” classificationMain differences between “old” and “new” classificationof diabetes mellitusof diabetes mellitus   In new classification of DMIn new classification of DM::

-- terms IDDM and NIDDM are not usedterms IDDM and NIDDM are not used-- term DM due to malnutrition is not usedterm DM due to malnutrition is not used- terms - primary and secondary DM are not used- terms - primary and secondary DM are not used

   New termNew termss w wereere introduced introduced ininto new classification of DM:to new classification of DM: ** impaired fasting impaired fasting plasma plasma glucoseglucose((FPG)FPG) ** impaired glucose tolerance(IGT) impaired glucose tolerance(IGT) WhyWhy??

Normal fasting value of plasmatic glucose concentration:Normal fasting value of plasmatic glucose concentration: 6.1 mmol/l6.1 mmol/l

●● Normal value of PGTT – Normal value of PGTT – blood glucose concentration blood glucose concentration 2 h2 hss after beginningafter beginning of test of test 7.8 mmol/l 7.8 mmol/l

New criteria for diagnose of DMNew criteria for diagnose of DM

11stst: : classic symptoms and signs of DM are presentclassic symptoms and signs of DM are present (polyuria, (polyuria, polydipsia, wpolydipsia, weeight loss), ight loss), and and increased day-timeincreased day-time blood glucose blood glucose concentration toconcentration to 11.1 mmol/l11.1 mmol/l and moreand more oror 22ndnd: : fasting glucose levelfasting glucose level isis 7.0 mmol/l7.0 mmol/l and moreand more oror 33rdrd: : 2 hours glucose level in2 hours glucose level in PGTT is PGTT is 11.1 mmol/l11.1 mmol/l and and moremore

For confirmation of diagnosis DMFor confirmation of diagnosis DM p poossitivity each of the mentioned itivity each of the mentioned parameters have to be parameters have to be cconfirmedonfirmed next day by ponext day by possitivity any of itivity any of the mentioned paramthe mentioned parametereter

Impaired fastingImpaired fasting plasma plasma glucose: glucose:

6.1 but 6.1 but 7.0 mmol/l 7.0 mmol/l

Impaired glucose toleranceImpaired glucose tolerance (IGT) (IGT)::

Glucose tolerance test shows abnormal values but these Glucose tolerance test shows abnormal values but these patients are asymptomaticpatients are asymptomatic and they do not meet the and they do not meet the criteria criteria for diagnosis of DM.for diagnosis of DM. IGT criteria:IGT criteria: - fasting plasma glucose level can be normal- fasting plasma glucose level can be normal - 2 hours after - 2 hours after intake intake glucose is plasma glucoseglucose is plasma glucose level level higher higher than normal (from than normal (from 7.87.8mmol/l mmol/l to 11.1to 11.1mmol/l)mmol/l) The individuals The individuals with IGT with IGT are recognized as being at are recognized as being at higher higher risk than the general popurisk than the general popullation for the development of ation for the development of DM (about 1.5 DM (about 1.5 -- 4.0 % of patients with IGT 4.0 % of patients with IGT DM). DM).

Syndrome X (metabolic X syndrome)Syndrome X (metabolic X syndrome) - - frequently occurs in people suffering formfrequently occurs in people suffering form visceral visceral obesityobesity Characteristic featuresCharacteristic features::

insuline resistanceinsuline resistance compensatory hyperinsulinemiacompensatory hyperinsulinemia visceral obesityvisceral obesity dyslipidemia (dyslipidemia ( LDL, LDL, TG, TG, HDL) HDL) systemic hypertensionsystemic hypertension

Increased probability of DM-type2 developmentIncreased probability of DM-type2 development

Insuline ResistanceInsuline Resistance (IR) (IR) IR is one of the IR is one of the mechanisms mechanisms involved in involved in pathogenesis pathogenesis of IGT of IGT and DM,and DM, especially in DM especially in DM type 2 type 2

Causes of insuline resistance:Causes of insuline resistance:

1. autoimmune reactions1. autoimmune reactions - development of anti-insulin antibodies- development of anti-insulin antibodies - development of anti-insulin receptor antibodies- development of anti-insulin receptor antibodies 2. defects in the insulin receptor at the cell surface2. defects in the insulin receptor at the cell surface a) defect in receptor processinga) defect in receptor processing b) b) decrease in receptor numberdecrease in receptor number

3. defective signal transduction 3. defective signal transduction (from the receptor to the plasma of cell)(from the receptor to the plasma of cell)

4. postreceptor defect4. postreceptor defect

5. increased concentration of anti5. increased concentration of anti--insulininsulinicic hormones hormones

Etiopathogenesis of DMEtiopathogenesis of DM

Type 1 DM - characteristicsType 1 DM - characteristics - it is most typical in individuals - it is most typical in individuals under 30 yearsunder 30 years of age of age (juvenile DM)(juvenile DM) - - 80 % - 90 % of beta cells in the islets of Langerhans 80 % - 90 % of beta cells in the islets of Langerhans areare destroyeddestroyed Possible mechanisms of beta cells destruction:Possible mechanisms of beta cells destruction: a) by islet cell antibodies of the IgG classa) by islet cell antibodies of the IgG class b) by non-immune mechanism (idiopathic up to b) by non-immune mechanism (idiopathic up to now)now)

Evidence suggest that type Evidence suggest that type 11 DM is caused by a gradual DM is caused by a gradual pprocessrocess ooff autoimmune destruction of beta cells in genetically susceptive individuals

TThe result of beta cells destruction:he result of beta cells destruction:

- - almost no or absolute no functional insulin almost no or absolute no functional insulin is producedis produced -- glucagon is present in relative excessglucagon is present in relative excess

- - individuals are prone to ketoacidosis - - insulin resistance is rareinsulin resistance is rare - - patients arepatients are insulininsulin dependen dependentt

Type 2 DM - characteristics

1. Primary disturbance: - biological activity of insuline

2. Compensatory hyperinsulinemia - due to concentration of blood glucose

3. Insulinoresistentia: - ability of insuline to inhibit production of glucose in liver glucose production

Type 2 DM -characteristicsType 2 DM -characteristics

- is rare in populations not affected by urban - is rare in populations not affected by urban

modernizationmodernization - adult onset (mostly after 40 years of age, slow, - adult onset (mostly after 40 years of age, slow, insidious insidious onset)onset) - results from the action of several - results from the action of several abnormal abnormal genesgenes ; - ; - inherited inherited susceptibility, familial tendency stronger than for type susceptibility, familial tendency stronger than for type 1 DM1 DM

- associated with long - duration obesity- associated with long - duration obesity (mainly (mainly

visceral)visceral)

- islet of Langerhans cells antibodies - islet of Langerhans cells antibodies are are rarerare - increased insulin resistance- increased insulin resistance

- nonspecific changes- nonspecific changes (damage) (damage) of islet cells of islet cells - usually not insulin dependent- usually not insulin dependent - individuals are not ketosis prone (but they may form - individuals are not ketosis prone (but they may form ketonketon bodies bodies under stress)under stress)

Main symptomes and signs of DM and mechanisms Main symptomes and signs of DM and mechanisms of their onsetof their onset

Hyperglycemia:Hyperglycemia: relative or absolute deficiency of insulin effect relative or absolute deficiency of insulin effect transport of transport of glucose to muscle and fat cells glucose to muscle and fat cells glycemia glycemia insulin effect insulin effect gluconeogenesis in liver gluconeogenesis in liver blood level of blood level of glucoseglucose glycogenolysisglycogenolysis (?) (?)

Glycosuria:Glycosuria: hyperglycemia (8-15 mmol/l) hyperglycemia (8-15 mmol/l) glycosuria glycosuria

Polyuria:Polyuria: high blood level of glucose high blood level of glucose increased amount of glucose increased amount of glucose filtered by the glomeruli of the kidney filtered by the glomeruli of the kidney absorbtion capacityabsorbtion capacity of renal tubules for glucose is exceededof renal tubules for glucose is exceeded glycosuria resultsglycosuria results,, accompanied by largeaccompanied by large amounts of water lost in the urine amounts of water lost in the urine (osmotic effect of glucose)(osmotic effect of glucose)

Polydipsia :Polydipsia : high blood level of glucose high blood level of glucose hyperosmolality hyperosmolality of of plasma plasma water moves from cellswater moves from cells to ECF (IVF) to ECF (IVF) intracellular dehydratationintracellular dehydratation

creation creation of thirstof thirst feeling feeling ((inin hypothalamushypothalamus) ) intake of fluidsintake of fluids

Polyphagia:Polyphagia: depletion of cellular stores of carbohydrates, depletion of cellular stores of carbohydrates, fats, fats, and proteins results in and proteins results in cellular starvationcellular starvation and and a a corresponding corresponding increase in hungerincrease in hunger

Weight loss :Weight loss : fluid lossfluid loss in in osmotic diuresisosmotic diuresis, , loss of body loss of body tissuetissue as fats and proteins are used for energyas fats and proteins are used for energy creationcreation

Fatigue :Fatigue : metabolic changes result in metabolic changes result in poor use of food poor use of food products products lethargy and fatique lethargy and fatique

Complications of Diabetes MellitusComplications of Diabetes Mellitus

A.A. Acute complicationsAcute complications •• HypoglycemiaHypoglycemia •• KetoacidosisKetoacidosis •• Hyperosmolar hyperglycemic nonketotic comaHyperosmolar hyperglycemic nonketotic coma

B.B. Chronic complicationsChronic complications •• Diabetic micro- and macroDiabetic micro- and macrovascularvascular changes changes •• Diabetic neuropathyDiabetic neuropathy •• Diabetic retinopathyDiabetic retinopathy •• Diabetic nephropathyDiabetic nephropathy •• Other complicationsOther complications

A.A. Acute complicationsAcute complications1. Hypoglycemia1. Hypoglycemia ( ( 3.33.3mmol/l of blood glucosemmol/l of blood glucose) - results from:) - results from: a) exogenous causesa) exogenous causes - overdose of insuline plus inadequate - overdose of insuline plus inadequate

food intake, increasefood intake, increasedd exercise exercise

- overdose of oral hypoglycemi- overdose of oral hypoglycemicc agents agents - alcohol- alcohol - other agents (e.g. salicylates)- other agents (e.g. salicylates)

b) endogenous causesb) endogenous causes - insulinoma (neoplasm of beta cells - insulinoma (neoplasm of beta cells of islet of Langerhans) of islet of Langerhans) - extrapancreatic neoplasm - extrapancreatic neoplasm

(hepatomas,(hepatomas, tumor of GIT)tumor of GIT) - inborn errors of metabolism (fructose - inborn errors of metabolism (fructose

intolerance)intolerance) Symptoms and signs of hypoglycemia are caused bSymptoms and signs of hypoglycemia are caused by y

epinephrine release epinephrine release (sweating, shakiness, headache, (sweating, shakiness, headache, palpitation)palpitation) and by and by lacklack of glucose in the brainof glucose in the brain (bizarre (bizarre behaviobehaviouur, dullnessr, dullness, , coma).coma).

Hypoglycemia unawareness (HU)

Cause: antihypoglycemic mechanisms are insufficient

Result: hypoglycemia develops without warning symptoms and signs

Pathomechanism involved in HU development: • Primary defect is localised to the CNS

- or loss of neurotransmiter production on hypoglycemic stimulus

- reactivity of peripheral tissues

counterregulatory hormones

Consequences: Deep hypoglycemia hypoglycemic

coma

death

2.2. Diabetic ketoacidosisDiabetic ketoacidosis - - the most serious metabolic the most serious metabolic complication of DMcomplication of DM

– – It develops when there is It develops when there is severe insulin insufficiencysevere insulin insufficiency – – Insulin insufficiency triggers a Insulin insufficiency triggers a complex metabolic reactionscomplex metabolic reactions which involve:which involve: - decreased glucose utilisation- decreased glucose utilisation hyperglycemia and hyperglycemia and

glycosuriaglycosuria

-- acceleration of gluconeogenesisacceleration of gluconeogenesis hyperglycemia hyperglycemia

- decreased lipogenesis and increased lipolysis- decreased lipogenesis and increased lipolysis increaseincrease oxidation ofoxidation of free fatty acids free fatty acids production of ketoneproduction of ketone bodiesbodies

(aceto(aceto--acetate, hydroxyacetate, hydroxy--butyrate, and acetonebutyrate, and acetone) ) hyperketonemiahyperketonemia

metabolic acidosismetabolic acidosis comacoma

3.3. Hyperosmolar hyperglycemic nonketotic Hyperosmolar hyperglycemic nonketotic comacoma(HHNC)(HHNC)

(hyperosmolar hyperglycemic syndrome)(hyperosmolar hyperglycemic syndrome)

a)a) - insulin is present to some degree- insulin is present to some degree it inhibits it inhibits fat fat

breakdownbreakdown lack of ketosislack of ketosis

b)b) - insulin is present to some degree- insulin is present to some degree its its effectivity is effectivity is

less than needed for effective glucose less than needed for effective glucose transport transport

hyperglycemiahyperglycemia glycosuria and polyuria glycosuria and polyuria body fluids body fluids

depletion depletion intracellular dehydration intracellular dehydration neurologic neurologic

disturbancies (stupordisturbancies (stupor, coma, coma))

B.B. Chronic complications Chronic complications Today, long-term survival of patient suffering from DM is the Today, long-term survival of patient suffering from DM is the rule. As a result, the problems ofrule. As a result, the problems of neuropathy, microvascularneuropathy, microvascular disease, and macrovascular diseasedisease, and macrovascular disease have become importanthave become important 1.1. Diabetic neuropathiesDiabetic neuropathies(DN)(DN) - - probably the most common probably the most common complication in DMcomplication in DM Pathogenesis:Pathogenesis:

a) vascular damagea) vascular damage of vasa nervorum of vasa nervorum b) metabolic damageb) metabolic damage of nerve cels of nerve cels c) non-enzymatic glycation of proteinsc) non-enzymatic glycation of proteins

The The very firstvery first morphologic morphologic and functional and functional change changess: : - - axonal degeneration preferentially involved unmyelinated fibersaxonal degeneration preferentially involved unmyelinated fibers (in spinal cord, the posterior root ganglia, peripheral nerves(in spinal cord, the posterior root ganglia, peripheral nerves))

Functional consequences:Functional consequences: - abnormalities in motor nerve function - abnormalities in motor nerve function (in advanced stages of DM)(in advanced stages of DM) - sensory nerve conduction is impaired- sensory nerve conduction is impaired - autonomic neuropathy (diabetic diarrhea, orthostatic - autonomic neuropathy (diabetic diarrhea, orthostatic hypotensionhypotension........)) Possible mechanismsPossible mechanisms involved in development involved in development ofof DN DN - blood supply to nerves is decreased because of - blood supply to nerves is decreased because of microvascular damagemicrovascular damage (vasa nervorum may be damaged)(vasa nervorum may be damaged)

- energy source for normal rest membrane potential maintain - energy source for normal rest membrane potential maintain

is is insufficientinsufficient - increased accumulation of sorbitol and fructose, decreased - increased accumulation of sorbitol and fructose, decreased concentration of myoinositol concentration of myoinositol - non-enzymatic glycation of protein- non-enzymatic glycation of proteins s

Main functions of vascular endotelium

• regulates vascular tone and permeability• regulates the balance between coagulation and fibrinolysis

• regulation of subendothelial matrix composition

• influences extravasation of leucocytes• influences the proliferation of vascular smooth muscle and renal mesangial cells

To curry out these functions, the endothelium produces components of extracellular matrix and variety of regulatory mediators

2. Diabetic micro- and macroangiopathies

A)A) Microvascular diseaseMicrovascular disease - - specific lesion of DM that affectspecific lesion of DM that affect capillariescapillaries and arterioles of the retina, renal glomeruli,and arterioles of the retina, renal glomeruli, peripheral nerves, musclesperipheral nerves, muscles and skinand skin

Characteristic lesion :Characteristic lesion : - - thickening thickening of the capillaryof the capillary basement membrane basement membrane - - increased accumulation of glycoprotein in wall of small increased accumulation of glycoprotein in wall of small arteries and capillaries arteries and capillaries

a)a)RetinopathyRetinopathy - - it is the result of retinal ischemia caused by it is the result of retinal ischemia caused by microangiopathymicroangiopathy

Pathomechanisms Pathomechanisms involved in retinopathy occurenceinvolved in retinopathy occurence:: - increased retinal capillary permeability, vein dilation- increased retinal capillary permeability, vein dilation - microaneurism formation and hemorrhages- microaneurism formation and hemorrhages - narrowing of small arteries lumen- narrowing of small arteries lumen - neovasculari- neovascularissation and fibrous tissue formation within ation and fibrous tissue formation within the retina the retina - retinal scars formation - retinal scars formation blindness blindness

Vessels in retina in healthy man

Diabetic retinopathy – hard exudates, dot-and-blot hemorrhages,hard exudates attacks the fovea, cotton-wool patches,microaneurysms

Diabetic retinopathy – neovascularisation of neural target

b) Nephropathyb) Nephropathy - - it is the result of glomerular changesit is the result of glomerular changes causedcaused by DMby DM Pathologic processes involved in Pathologic processes involved in diabetic diabetic nephropathy:nephropathy: - glomerular enlargement - glomerular enlargement - - diffuse intercapillary diffuse intercapillary - glomerular basement membrane- glomerular basement membrane glomerulosclerosisglomerulosclerosis thickeningthickening proteinuriaproteinuria - - systemic systemic hypertension often occurshypertension often occurs (more than 0.3g/day (more than 0.3g/day)) - neuropathy - see at B1.- neuropathy - see at B1.

Diabetic nephropathy - nodular glomerulosclerosis and hyalinic atherosclerosis of small artery

Diabeti changes of glomerulus – advanced changes of the glomerulus

B)B) Macrovascular disease Macrovascular disease -- atherosclerotic lesionatherosclerotic lesion of larger arteriesof larger arteries (coronary arteries, brain arteries, (coronary arteries, brain arteries, peripheralperipheral arteries)arteries) Main biochemical disturbancies leading to macrovascularMain biochemical disturbancies leading to macrovascular diseasedisease::

- accumulation of sorbitol in the vascular intima- accumulation of sorbitol in the vascular intima - hyperlipoproteinemia - hyperlipoproteinemia vascular abnormality in blood vascular abnormality in blood coagulationcoagulation,, occlusion occlusion by by thrombus,thrombus, accelerated atherosclerosisaccelerated atherosclerosis a)a) Coronary artery diseaseCoronary artery disease acute or chronicacute or chronic myocardialmyocardial ischemia and/orischemia and/or infarctioninfarction b)b) StrokeStroke acute or chronicacute or chronic cerebral ischemiacerebral ischemia c)c) Peripheral vascular diseasePeripheral vascular disease gangrene and gangrene and amputationamputation (diabetic foot)(diabetic foot)

3. 3. InfectionInfection Persons Persons with DM with DM are are at increased risk for infection at increased risk for infection throughout the body. throughout the body.

Causes:Causes: - - disturbanciesdisturbancies of of senses (neuropathy, retinopathy) senses (neuropathy, retinopathy) decreasing the function of early warning system decreasing the function of early warning system breaks in skin integritybreaks in skin integrity - tissue hypoxia (macro- and microangiopathy)- tissue hypoxia (macro- and microangiopathy) - increased level glucose in body fluids - increased level glucose in body fluids pathogens pathogens

areare ableable to multiply rapidlyto multiply rapidly - white blood cells supply to the tissue is decreased- white blood cells supply to the tissue is decreased - function of white blood cells is impaired- function of white blood cells is impaired

Diabetic nephropathy- infection present in renal pelvis