PATHOPHYSIOLOGY PATHOPHYSIOLOGY OF CARBOHYDRATE OF CARBOHYDRATE METABOLISM METABOLISM
, MD, PhD Prof. J. Hanacacekek, MD, PhD Prof. J. Han
urinováá
Technical co-operative: L.ŠŠurinov Technical co-operative: L.
Carbohydrates are present in
in food in
various forms:: food in various forms
A. Physiologic remarks: A. Physiologic remarks: Carbohydrates are present
monosaccharides simple sugars monosaccharides
1. 1. simple sugars
disaccharides complex chemical units disaccharides
2. 2. complex chemical units
polysaccharides polysaccharides
(cid:0) (cid:0)
(cid:0)
cleaving proces(cid:0) cleaving proces stomach, absorbtion in stomach, absorbtion in
Processing of carbohydrates in GIT Ingested carbohydrates (cid:0) Ingested carbohydrates (cid:0) monosaccharides monosaccharides (cid:0) (cid:0) duodenum and proximal jejunum duodenum and proximal jejunum
Disturbancies in Carbohydrate Resorbtion B. B. Disturbancies in Carbohydrate Resorbtion
1.1. Disaccharidase deficiency syndrome Disaccharidase deficiency syndrome
= enzyme which hydroly
saccharase
saccharase = saccharose
enzyme which hydrolysesses disaccharide disaccharide (to fructose and glucose)) saccharose (to fructose and glucose
laktase = = enzyme which splits disaccharide lactose laktase enzyme which splits disaccharide lactose galactose) glucose and and galactose)
((to to glucose
maltase = = enzyme which splits disaccharide maltose maltase enzyme which splits disaccharide maltose (to two molecule of glucose) (to two molecule of glucose)
(cid:0)
(cid:0) (cid:0) decreased decreased decreased resorbtion of substrate (cid:0) decreased resorbtion of substrate
(cid:0)
(cid:0)
Pathomechanismss Pathomechanism Activity of disaccharidase is decreased (cid:0) a)a) Activity of disaccharidase is decreased f disaccharide (cid:0) hydrolysis o of disaccharide hydrolysis increased concentration of disaccharide in small intestine increased concentration of disaccharide in small intestine lumen (cid:0) increased osmotic activity of the lumen lumen increased osmotic activity of the lumen fluidfluid (cid:0)
diarrhea diarrhea
(cid:0) increased increased
(cid:0)
(cid:0) (cid:0)
(cid:0) (cid:0) increased concentration of disaccharide in large intestine (cid:0) increased concentration of disaccharide in large intestine disaccharide disaccharide fermentation by bacteria (cid:0) fermentation by bacteria increased increased
(cid:0)
(cid:0) abdominal cramps, abdominal cramps,
Activity of disaccharidase is decreased (cid:0) b)b) Activity of disaccharidase is decreased concentration of disaccharide in small intestine lumen (cid:0) concentration of disaccharide in small intestine lumen (cid:0) (cid:0) concentration of lactic acid and fatty acids (cid:0) concentration of lactic acid and fatty acids (cid:0) stimulation of intestine wall stimulation of intestine wall (cid:0) (cid:0) bloating, diarrhea, acidic stools, explosive diarrhea bloating, diarrhea, acidic stools, explosive diarrhea
Lactase deficiency syndrome Lactase deficiency syndrome Causes of lactase deficiency
Causes of lactase deficiency::
(primary) genetic defect (primary) genetic defect
secondary to a wide variety of gastrointesti diseases secondary to a wide variety of gastrointestinal nal diseases
that damage the mucosa of the that damage the mucosa of the small small intestine (secondary) intestine (secondary)
Disaccharide lactose Disaccharide lactose is the principal carbohydrate in milk.. is the principal carbohydrate in milk
, Asians, and Bantus population African Americanss, Asians, and Bantus population
Many persons showing milk intolerance prove to be lactase Many persons showing milk intolerance prove to be lactase – – deficient deficient Primary lactase deficiency incidence is as high as 80 % to 90 % Primary lactase deficiency incidence is as high as 80 % to 90 % among African American among Milk intolerance may not become clinically apparent until Milk intolerance may not become clinically apparent until adolescence adolescence
Causes of secondary lactase deficiency:: Causes of secondary lactase deficiency
nontropical nontropical (celiac disease) (celiac disease)and tropical sprue, and tropical sprue,
regional enteritis, regional enteritis,
viral and bacterial infections of the intestina tract, viral and bacterial infections of the intestinal l tract,
giardiasis, cystic fibrosis, ulcerative colitis, giardiasis, cystic fibrosis, ulcerative colitis,
kwashiorkor, coeliac disease kwashiorkor, coeliac disease
previous page Symptoms and signs are mentioned at previous page Symptoms and signs are mentioned at
Monosaccharides malabsorbtion Monosaccharides malabsorbtion
Small intestine ability to resorb glucose and galactose is Small intestine ability to resorb glucose and galactose is
decreased decreased Specific transport system for galactose and glucose Cause: Specific transport system for galactose and glucose Cause:
absorbtion in cells of small intestine is insufficient absorbtion in cells of small intestine is insufficient Symptoms and signs similar to disaccharidase Results: Symptoms and signs similar to disaccharidase Results:
deficiency syndrome deficiency syndrome
Glycogenosis (glycogen storage disease) Glycogenosis (glycogen storage disease)
Autosomal recessive disease emzymopathy) emzymopathy) There are defects in degradation
(inborn errors of metabolism, Autosomal recessive disease (inborn errors of metabolism,
of glycogen. There are defects in degradation of glycogen.
The disturbances result in storage of abnormal glycogen, The disturbances result in storage of abnormal glycogen, or storage of abnormal amount of glycogen in various or storage of abnormal amount of glycogen in various organs of the body organs of the body
Example: Hepatorenal glycogenosis (Morbus Gierke) von Gierke)
Example: Cause: Hepatorenal glycogenosis (Morbus von Deficit of glucose6fosfatase in liver and kidney Cause: Deficit of glucose6fosfatase in liver and kidney
Results: Hypoglycemia in fasting individuals, Results: Hypoglycemia in fasting individuals, hyperlipemia, ketonemia hyperlipemia, ketonemia There are other types of glycogenosis There are 9 9 other types of glycogenosis
DIABETES MELLITUS
DIABETES MELLITUS
DM – complex chronic metabolic disorder leading to multiorgan complications
Main pathophysiological questions related to DM
Why and how the DM develops?
Why and how develop the complications of DM?
What are the mechanisms involved in manifestation of diabetic symptoms and signs
Regulation of the blood glucose level depends on liver: Regulation of the blood glucose level depends on liver:
from blood 1. extracting glucose from blood 1. extracting glucose
2. synthesizing glycogen 2. synthesizing glycogen
3. performing glycogenolysis 3. performing glycogenolysis
(muscle and adipocytes) use glucose peripheral tissues (muscle and adipocytes) use glucose
4. performing gluconeogenesis 4. performing gluconeogenesis To a lesser extent peripheral tissues To a lesser extent for their energy needs, thus contributing to maintinance of normal blood for their energy needs, thus contributing to maintinance of normal blood
glucose level glucose level
lucose by by
(cid:0) s uptake and output of glucose and the use of The liver(cid:0) s uptake and output of glucose and the use of gglucose The liver peripheral tissues depend on the physiologic balance of several peripheral tissues depend on the physiologic balance of several
glucagon, epinephrine, GH, GH,
hormones that: hormones that: insulin 1. lower blood glucose level insulin 1. lower blood glucose level 2. rise blood glucose level glucagon, epinephrine, 2. rise blood glucose level glucocorticoids... glucocorticoids...
Definition of DM Definition of DM
or relative complex syndrome induced by induced by absolute or
DM is a chronic complex syndrome DM is a chronic deficit of insuline which is characterized by which is characterized by metabolic disorders of metabolic disorders of
carbohydrates, lipids and proteins. carbohydrates, lipids and proteins.
The metabolic disturbances are accompanied by loss of carbohydrate loss of carbohydrate The metabolic disturbances are accompanied by
tolerance, fasting hyperglycemia, ketoacidosis, decreased tolerance, fasting hyperglycemia, ketoacidosis, decreased
and some lipogenesis, increased lipolysis, increased proteolysis and some lipogenesis, increased lipolysis, increased proteolysis
other metabolic disorders other metabolic disorders
CClassification of DM lassification of DM
(according to International Expert Committee, 1997) (according to International Expert Committee, 1997)
Base for the classification are etiopathogenetic mechanisms etiopathogenetic mechanisms Base for the classification are involved in onset and development of DM involved in onset and development of DM
Types of DM Types of DM
Diabetes mellitus type 1: due to destruction of beta I. I. Diabetes mellitus type 1: due to destruction of beta of pancreatic islets cellcellss of pancreatic islets
Consequence: absolute deficit of insulin Consequence: absolute deficit of insulin
subtype: induced by autoimmunity processes induced by autoimmunity processes
A. A. subtype:
subtype: idiopathic mechanism idiopathic mechanism
B. B. subtype:
at the beginningpredominance predominance
(normo or relative deficit of insulin(normo or and relative deficit of insulin
combination of impa red insulin impaiired insulin
(hypoinsulinemia, ,
insulin resistance
II.II.Diabetes mellitus type 2: Diabetes mellitus type 2: at the beginning of insulin resistance resistance and of insulin hyper insulinemia), later on combination of hyper insulinemia), later on secretion and simultaneous insulin resistance (hypoinsulinemia secretion and simultaneous insulin resistance insulin resistance))
III. Other specific types of DM III. Other specific types of DM
(cid:0) DM due to
(cid:0) to
of pancreas islets and due of beta cells of pancreas islets and due genetic defects of beta cells
DM due to genetic defects to genetic defect of insulin function genetic defect of insulin function
(cid:0) DM due to diseases influencing exocrine functions of pancreas – – DM due to diseases influencing exocrine functions of pancreas
(cid:0) secondary is damaged endocrine function, too. secondary is damaged endocrine function, too.
(cid:0) DM due to infections, endocrinopathies, drugs, chemicals, infections,
(cid:0) DM due to endocrinopathies, drugs, chemicals, metabolic and genetic disturbances metabolic and genetic disturbances
glucose intolerance which onset
glucose intolerance which onsetss
IV. Gestational DM IV.
Gestational DM
first time during pregnancy fofor r thethe first time during pregnancy
(cid:0) Main differences between “old” and “new” classification Main differences between “old” and “new” classification of diabetes mellitus of diabetes mellitus (cid:0) In new classification of DM In new classification of DM::
terms IDDM and NIDDM are not used terms IDDM and NIDDM are not used
term DM due to malnutrition is not used term DM due to malnutrition is not used
terms primary and secondary DM are not used terms primary and secondary DM are not used
(cid:0) New termss w wereere introduced to new classification of DM: introduced ininto new classification of DM:
(cid:0) New term ** impaired fasting impaired fasting plasma plasma glucose FPG) glucose((FPG)
impaired glucose tolerance(IGT) ** impaired glucose tolerance(IGT) WhyWhy??
(cid:0) Normal fasting value of plasmatic glucose concentration: Normal fasting value of plasmatic glucose concentration:
(cid:0) (cid:0)
(cid:0)
6.1 mmol/l 6.1 mmol/l
(cid:0) ●● Normal value of PGTT – Normal value of PGTT – blood glucose concentration of test (cid:0) after beginning of test after beginning blood glucose concentration 2 h2 hss 7.8 mmol/l 7.8 mmol/l
(cid:0)
(cid:0) New criteria for diagnose of DM New criteria for diagnose of DM
(polyuria, classic symptoms and signs of DM are present (polyuria, polydipsia, weeight loss), blood glucose increased daytime blood glucose concentration to 11.1 mmol/l
11stst: : classic symptoms and signs of DM are present ight loss), and polydipsia, w and increased daytime and more 11.1 mmol/l and more concentration to oror
fasting glucose level isis 7.0 mmol/l and more 7.0 mmol/l and more
22ndnd: : fasting glucose level oror 33rdrd: : 2 hours glucose level in 2 hours glucose level in PGTT is PGTT is 11.1 mmol/l 11.1 mmol/l and and moremore
itivity each of the mentioned For confirmation of diagnosis DM p poossitivity each of the mentioned For confirmation of diagnosis DM parameters have to be cconfirmed parameters have to be itivity any of next day by possitivity any of onfirmed next day by po
the mentioned parametereter the mentioned param
(cid:0) glucose: plasma glucose:
(cid:0) Impaired fasting Impaired fasting plasma
(cid:0) (cid:0) (cid:0) 6.1 but (cid:0) 6.1 but 7.0 mmol/l 7.0 mmol/l
(cid:0)
(cid:0) Impaired glucose tolerance (IGT):: Impaired glucose tolerance (IGT)
Glucose tolerance test shows abnormal values but these Glucose tolerance test shows abnormal values but these and they do not meet the criteria patients are asymptomatic patients are asymptomatic and they do not meet the criteria
for diagnosis of DM. for diagnosis of DM.
than normal (from 7.87.8mmol/l intake glucose is plasma glucose mmol/l to 11.1 level higher glucose is plasma glucose level higher mmol/l) to 11.1mmol/l)
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 than normal (from The individuals with IGT The individuals higher risk than the are recognized as being at higher risk than the
with IGT are recognized as being at 4.0 % of ation for the development of DM (about 1.5 4.0 % of
(cid:0) general popullation for the development of DM (about 1.5 general popu patients with IGT (cid:0) patients with IGT
DM). DM).
Syndrome X (metabolic X syndrome) Syndrome X (metabolic X syndrome)
frequently occurs in people suffering form
frequently occurs in people suffering form visceral obesity visceral obesity
Characteristic features:: Characteristic features
(cid:0)
(cid:0)
(cid:0)
(cid:0) (cid:0) LDL, LDL, (cid:0) (cid:0) TG, TG, (cid:0) (cid:0) HDL) HDL)
(cid:0) (cid:0) insuline resistance insuline resistance (cid:0) compensatory hyperinsulinemia compensatory hyperinsulinemia (cid:0) visceral obesity visceral obesity (cid:0) dyslipidemia ( dyslipidemia ((cid:0) (cid:0) systemic hypertension systemic hypertension
Increased probability of DMtype2 development Increased probability of DMtype2 development
(IR) Insuline Resistance (IR)
IR is one of the mechanisms mechanisms involved in pathogenesis of IGT involved in pathogenesis of IGT
Insuline Resistance IR is one of the and DM,
and DM, especially in DM type 2 especially in DM type 2
Causes of insuline resistance: Causes of insuline resistance:
1. autoimmune reactions 1. autoimmune reactions
development of antiinsulin antibodies development of antiinsulin antibodies
development of antiinsulin receptor antibodies development of antiinsulin receptor antibodies 2. defects in the insulin receptor at the cell surface 2. defects in the insulin receptor at the cell surface
a) defect in receptor processing a) defect in receptor processing
decrease in receptor number b) b) decrease 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 defect 4. postreceptor defect
5. increased concentration of antiinsulin 5. increased concentration of anti hormones insulinicic hormones
Etiopathogenesis of DM Etiopathogenesis of DM
Type 1 DM characteristics Type 1 DM characteristics
of age (juvenile DM) under 30 years of age (juvenile DM) it is most typical in individuals under 30 years
it is most typical in individuals 80 % 90 % of beta cells in the islets of Langerhans 80 % 90 % of beta cells in the islets of Langerhans destroyed areare destroyed Possible mechanisms of beta cells destruction: Possible mechanisms of beta cells destruction: a) by islet cell antibodies of the IgG class a) by islet cell antibodies of the IgG class b) by nonimmune mechanism (idiopathic up to now) b) by nonimmune mechanism (idiopathic up to now)
rocess DM is caused by a gradual pprocess Evidence suggest that type 11 DM is caused by a gradual Evidence suggest that type ooff autoimmune destruction of beta cells in genetically susceptive individuals
he result of beta cells destruction: TThe result of beta cells destruction:
is produced almost no or absolute no functional insulin is produced
almost no or absolute no functional insulin glucagon is present in relative excess glucagon is present in relative excess
individuals are prone to ketoacidosis insulin resistance is rare insulin resistance is rare patients are patients are insulin dependentt insulin dependen
Type 2 DM characteristics
1. Primary disturbance: (cid:0) biological activity of insuline
2. Compensatory hyperinsulinemia due to (cid:0) concentration of blood glucose
3. Insulinoresistentia: (cid:0) ability of insuline to inhibit production of glucose in liver (cid:0) (cid:0) glucose production
Type 2 DM characteristics Type 2 DM characteristics
is rare in populations not affected by urban modernization is rare in populations not affected by urban modernization
adult onset (mostly after 40 years of age, slow, insidious adult onset (mostly after 40 years of age, slow, insidious onset) onset)
abnormal genes genes ; inherited ; inherited
results from the action of several abnormal results from the action of several susceptibility, familial tendency stronger than for type susceptibility, familial tendency stronger than for type 1 DM1 DM
associated with long duration obesity (mainly visceral) associated with long duration obesity (mainly 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) of islet cells (damage) of islet cells
usually not insulin dependent usually not insulin dependent
under stress) bodies under stress) individuals are not ketosis prone (but they may form individuals are not ketosis prone (but they may form keton bodies keton
Main symptomes and signs of DM and mechanisms Main symptomes and signs of DM and mechanisms
of their onset of their onset
(cid:0) (cid:0) transport of (cid:0) transport of
(cid:0) (cid:0)
(cid:0) (cid:0) (cid:0) (cid:0) (cid:0) glycemia glycemia (cid:0) gluconeogenesis in liver gluconeogenesis in liver (cid:0) (cid:0) blood level of blood level of
(cid:0) Hyperglycemia: Hyperglycemia: (cid:0) relative or absolute deficiency of insulin effect relative or absolute deficiency of insulin effect (cid:0) glucose to muscle and fat cells (cid:0) glucose to muscle and fat cells (cid:0) (cid:0) (cid:0) insulin effect insulin effect (cid:0) glucose glucose (cid:0) glycogenolysis (cid:0) (cid:0) (?) glycogenolysis (?)
(cid:0) hyperglycemia (815 mmol/l) (cid:0) Glycosuria: hyperglycemia (815 mmol/l) Glycosuria: glycosuria glycosuria
(cid:0)
high blood level of glucose (cid:0) Polyuria: high blood level of glucose Polyuria: filtered by the glomeruli of the kidney (cid:0) filtered by the glomeruli of the kidney of renal tubules for glucose is exceeded (cid:0) of renal tubules for glucose is exceeded increased amount of glucose increased amount of glucose (cid:0) absorbtion capacity absorbtion capacity (cid:0) glycosuria results glycosuria results,,
amounts of water lost in the urine accompanied by large amounts of water lost in the urine
accompanied by large (osmotic effect of glucose) (osmotic effect of glucose)
(cid:0)
(cid:0) hyperosmolality of hyperosmolality of to ECF (IVF) (cid:0) water moves from cells to ECF (IVF) (cid:0) water moves from cells
(cid:0)
(cid:0) (cid:0) of thirst feeling hypothalamus) ) (cid:0) feeling ((inin hypothalamus
(cid:0) high blood level of glucose (cid:0) Polydipsia : high blood level of glucose Polydipsia : plasma (cid:0) plasma (cid:0)(cid:0) (cid:0) (cid:0) intracellular dehydratation (cid:0) intracellular dehydratation creation of thirst creation (cid:0) intake of fluids (cid:0) intake of fluids
depletion of cellular stores of carbohydrates, fats, Polyphagia: depletion of cellular stores of carbohydrates, fats, Polyphagia:
and proteins results in and proteins results in cellular starvation and a cellular starvation and a
corresponding increase in hunger corresponding increase in hunger
Weight loss : fluid loss Weight loss : fluid loss in in osmotic diuresis loss of body tissue osmotic diuresis, , loss of body tissue
as fats and proteins are used for energy creation as fats and proteins are used for energy creation
Fatigue : metabolic changes result in Fatigue :
(cid:0) lethargy and fatique lethargy and fatique
metabolic changes result in poor use of food poor use of food products (cid:0) products
Complications of Diabetes Mellitus Complications of Diabetes Mellitus
Acute complications A.A. Acute complications Hypoglycemia •• Hypoglycemia Ketoacidosis •• Ketoacidosis Hyperosmolar hyperglycemic nonketotic coma •• Hyperosmolar hyperglycemic nonketotic coma
Chronic complications B.B. Chronic complications
•• Diabetic micro and macro
Diabetic micro and macrovascular
changes vascular changes
Diabetic neuropathy •• Diabetic neuropathy Diabetic retinopathy •• Diabetic retinopathy Diabetic nephropathy •• Diabetic nephropathy Other complications •• Other complications
(cid:0) ) results from: mmol/l of blood glucose) results from:
Acute complications A.A. Acute complications 1. Hypoglycemia ( ((cid:0) 1. Hypoglycemia
3.33.3mmol/l of blood glucose
a) exogenous causes
exercise a) exogenous causes overdose of insuline plus inadequate overdose of insuline plus inadequate food intake, increasedd exercise food intake, increase
overdose of oral hypoglycemi agents overdose of oral hypoglycemicc agents alcohol alcohol other agents (e.g. salicylates) other agents (e.g. salicylates)
b) endogenous causes insulinoma (neoplasm of beta cells b) endogenous causes insulinoma (neoplasm of beta cells of islet of Langerhans) of islet of Langerhans) extrapancreatic neoplasm (hepatomas, extrapancreatic neoplasm (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 b epinephrine Symptoms and signs of hypoglycemia are caused by y epinephrine
(sweating, shakiness, headache, palpitation) and by and by lack lack of of
release (sweating, shakiness, headache, palpitation) release glucose in the brain (bizarre behavio glucose in the brain (bizarre behaviouur, dullness coma). r, dullness, , 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
(cid:0) or loss of neurotransmiter production on hypoglycemic stimulus
(cid:0) reactivity of peripheral tissues counterregulatory hormones
Consequences: Deep hypoglycemia (cid:0) hypoglycemic coma (cid:0)
(cid:0) death
2.2. Diabetic ketoacidosis Diabetic ketoacidosis the most serious metabolic the most serious metabolic complication of DM complication of DM
(cid:0) glycosuria hyperglycemia and glycosuria hyperglycemia and
– – It develops when there is It develops when there is severe insulin insufficiency severe insulin insufficiency Insulin insufficiency triggers a complex metabolic reactions – Insulin insufficiency triggers a complex metabolic reactions – which involve: which involve: decreased glucose utilisation (cid:0) decreased glucose utilisation
(cid:0) hyperglycemia hyperglycemia acceleration of gluconeogenesis (cid:0) acceleration of gluconeogenesis
(cid:0) increase increase
(cid:0) production of ketone bodies production of ketone bodies
(cid:0) hyperketonemia hyperketonemia
(cid:0) (cid:0) decreased lipogenesis and increased lipolysis(cid:0) decreased lipogenesis and increased lipolysis free fatty acids (cid:0) oxidation of free fatty acids oxidation of (acetoacetate, hydroxy (aceto metabolic acidosis (cid:0) (cid:0) metabolic acidosis butyrate, and acetone) ) (cid:0) acetate, hydroxybutyrate, and acetone coma coma
3.3. Hyperosmolar hyperglycemic nonketotic coma (HHNC) Hyperosmolar hyperglycemic nonketotic coma(HHNC) (hyperosmolar hyperglycemic syndrome) (hyperosmolar hyperglycemic syndrome)
(cid:0) insulin is present to some degree (cid:0) a)a) insulin is present to some degree it inhibits fat it inhibits fat
(cid:0) breakdown (cid:0) breakdown lack of ketosis lack of ketosis
(cid:0) insulin is present to some degree (cid:0) b)b) insulin is present to some degree its effectivity is its effectivity is
(cid:0)
(cid:0) (cid:0) glycosuria and polyuria (cid:0) glycosuria and polyuria body fluids body fluids
(cid:0) (cid:0) less than needed for effective glucose transport (cid:0) less than needed for effective glucose transport hyperglycemia (cid:0) hyperglycemia depletion (cid:0) depletion intracellular dehydration (cid:0) intracellular dehydration neurologic neurologic
disturbancies (stupor , coma)) disturbancies (stupor, coma
Chronic complications B.B. Chronic complications Today, longterm survival of patient suffering from DM is the Today, longterm survival of patient suffering from DM is the neuropathy, microvascular rule. As a result, the problems of neuropathy, microvascular rule. As a result, the problems of
have become important disease, and macrovascular disease have become important
probably the most common (DN) probably the most common
Pathogenesis: disease, and macrovascular disease 1.1. Diabetic neuropathies Diabetic neuropathies(DN) complication in DM complication in DM Pathogenesis:
of vasa nervorum a) vascular damage of vasa nervorum a) vascular damage
b) metabolic damage of nerve cels b) metabolic damage of nerve cels c) nonenzymatic glycation of proteins c) nonenzymatic glycation of proteins
The very first The very first morphologic morphologic and functional and functional change changess: :
axonal degeneration preferentially involved unmyelinated fibers axonal 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
....)) hypotension....
autonomic neuropathy (diabetic diarrhea, orthostatic autonomic neuropathy (diabetic diarrhea, orthostatic hypotension Possible mechanisms Possible mechanisms involved in development involved in development ofof DN DN
blood supply to nerves is decreased because of microvascular blood supply to nerves is decreased because of microvascular
damage damage (vasa nervorum may be damaged) (vasa nervorum may be damaged)
energy source for normal rest membrane potential maintain is energy source for normal rest membrane potential maintain is insufficient insufficient
increased accumulation of sorbitol and fructose, decreased increased accumulation of sorbitol and fructose, decreased concentration of myoinositol concentration of myoinositol
nonenzymatic glycation of protein nonenzymatic glycation of proteins s
2. Diabetic micro and macroangiopathies
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
Microvascular disease specific lesion of DM that affect A)A) Microvascular disease capillaries specific lesion of DM that affect capillaries and arterioles of the retina, renal glomeruli, peripheral nerves, muscles and arterioles of the retina, renal glomeruli, peripheral nerves, muscles and skin and skin
of the capillary basement membrane basement membrane
Characteristic lesion : Characteristic lesion : thickening thickening of the capillary increased accumulation of glycoprotein in wall of small increased accumulation of glycoprotein in wall of small arteries and capillaries arteries and capillaries
a)a)Retinopathy
microangiopathy
Retinopathy it is the result of retinal ischemia caused by it is the result of retinal ischemia caused by microangiopathy
involved in retinopathy occurence::
Pathomechanisms involved 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
ation and fibrous tissue formation within neovascularissation and fibrous tissue formation within
(cid:0) Pathomechanisms the retina the retina retinal scars formation (cid:0) retinal scars formation
blindness blindness
Vessels in retina in healthy man
Diabetic retinopathy – hard exudates, dotandblot hemorrhages, hard exudates attacks the fovea, cottonwool patches,microaneurysms
Diabetic retinopathy – neovascularisation of neural target
caused
nephropathy: Pathologic processes involved in diabetic diabetic nephropathy:
diffuse intercapillary glomerular enlargement diffuse intercapillary
b) Nephropathy it is the result of glomerular changes b) Nephropathy it is the result of glomerular changes caused by DMby DM Pathologic processes involved in glomerular enlargement
glomerular basement membrane
glomerulosclerosis glomerulosclerosis
(cid:0) (cid:0)
glomerular basement membrane thickening thickening proteinuria proteinuria (more than 0.3g/day)) hypertension often occurs (more than 0.3g/day systemic systemic hypertension often occurs 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
Macrovascular disease atherosclerotic lesion atherosclerotic lesion of larger arteries (coronary arteries, brain arteries,
(coronary arteries, brain arteries, peripheral arteries) peripheral arteries)
B)B) Macrovascular disease of larger arteries Main biochemical disturbancies leading to macrovascular Main biochemical disturbancies leading to macrovascular
disease:: disease
(cid:0)
by thrombus, occlusion by thrombus,
(cid:0)
accumulation of sorbitol in the vascular intima accumulation of sorbitol in the vascular intima hyperlipoproteinemia (cid:0) hyperlipoproteinemia vascular abnormality in blood vascular abnormality in blood coagulation coagulation,, occlusion accelerated atherosclerosis accelerated atherosclerosis Coronary artery disease (cid:0) a)a) Coronary artery disease acute or chronic myocardial acute or chronic myocardial infarction ischemia and/or infarction ischemia and/or
(cid:0) cerebral ischemia acute or chronic cerebral ischemia acute or chronic
(cid:0)
Stroke (cid:0) b)b) Stroke Peripheral vascular disease (cid:0) c)c) Peripheral vascular disease gangrene and amputation gangrene and amputation (diabetic foot) (diabetic foot)
Infection 3. 3. Infection
at increased risk for infection with DM are are at increased risk for infection
Persons Persons with DM throughout the body. throughout the body.
(cid:0)
(cid:0)
(cid:0) Causes: Causes: senses (neuropathy, retinopathy) (cid:0) disturbancies disturbancies of of senses (neuropathy, retinopathy) decreasing the function of early warning system (cid:0) decreasing the function of early warning system breaks in skin integrity breaks in skin integrity tissue hypoxia (macro and microangiopathy) tissue hypoxia (macro and microangiopathy) pathogens pathogens
increased level glucose in body fluids (cid:0) increased level glucose in body fluids to multiply rapidly areare ableable to 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
