PATHOPHYSIOLOGY OF CARBOHYDRATE METABOLISM

(1)

PATHOPHYSIOLOGY

OF CARBOHYDRATE

METABOLISM

Prof. J. Han

ac

ek

, MD, PhD

Technical co-operative: L.

(2)

A. Physiologic remarks:

1. simple sugars

_{simple sugars}

- monosaccharides

2.

2. complex chemical units

complex chemical units

- disaccharides

- polysaccharides

Processing of carbohydrates in GIT

Ingested carbohydrates

_

cleaving proces

_

monosaccharides

_

absorbtion in

stomach,

(3)

(4)

(5)

B.

B. Disturbancies in Carbohydrate Resorbtion

Disturbancies in Carbohydrate Resorbtion

1.

1. Disaccharidase deficiency syndrome

Disaccharidase deficiency syndrome

saccharase

= enzyme which hydroly

=

enzyme which hydrolysesses disaccharide disaccharide

saccharosesaccharose (to fructose and glucose(to fructose and glucose))

laktase

= enzyme which splits disaccharide lactose

=

enzyme which splits disaccharide lactose

((to to glucoseglucose and and galactose) galactose)

maltase

= enzyme which splits disaccharide maltose

=

enzyme which splits disaccharide maltose

(6)

Pathomechanism

s

a)

a) Activity of disaccharidase is decreasedActivity of disaccharidase is decreased __ decreaseddecreased

hydrolysishydrolysis o of disaccharidef disaccharide __ decreased resorbtion of substratedecreased resorbtion of substrate



 increased concentration of disaccharide in small intestineincreased concentration of disaccharide in small 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,

(7)

Lactase deficiency syndrome

Causes of lactase deficiencyCauses of lactase deficiency:: - genetic defect

Disaccharide lactoseDisaccharide lactose is the principal carbohydrateis the principal carbohydrate in milkin milk..

- - Many persons showing milk intolerance prove to be lactaseMany persons showing milk intolerance prove to be lactase – –

deficientdeficient

- - Primary lactase deficiency incidence is as high as 80 % to 90 % Primary lactase deficiency incidence is as high as 80 % to 90 %

amongamong African - AmericanAfrican - Americanss, Asians, and Bantus population, Asians, and Bantus population

- - Milk intolerance may not become clinically apparent until Milk intolerance may not become clinically apparent until

(8)

Causes 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 at

(9)

Monosaccharides 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

(10)

Glycogenosis (glycogen storage disease)

Autosomal recessive diseaseAutosomal recessive disease (inborn errors of metabolism, (inborn errors of 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)

(11)

(12)

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?

(13)

Regulation of the blood glucose level depends on liver:

1. extracting glucose

1. extracting glucose from blood from blood

2. synthesizing glycogen

To a lesser extent peripheral tissuesperipheral tissues (muscle and adipocytes) use glucose (muscle and adipocytes) use glucose for their energy needs, thus contributing to maintinance of normal blood

for their energy needs, thus contributing to maintinance of normal blood

glucose level

The liver

The liver__s 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 balance of several

by peripheral tissues depend on the physiologic balance of several

hormones that:

1. lower blood glucose level

1. lower blood glucose level - insulin - insulin 2. rise blood glucose level

2. rise blood glucose level - glucagon, epinephrine, - glucagon, epinephrine, GH, GH,

(14)

DM is a chronic

DM is a chronic complex syndromecomplex syndrome induced by absolute induced by or relative or

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

The metabolic disturbances are accompanied by loss of carbohydrate loss of carbohydrate tolerance, fasting hyperglycemia, ketoacidosis, decreased

tolerance, fasting hyperglycemia, ketoacidosis, decreased

lipogenesis, increased lipolysis, increased proteolysis

lipogenesis, increased lipolysis, increased proteolysis and some and some other metabolic disorders

other metabolic disorders

Definition of DM

C

lassification of DM

(according to International Expert Committee, 1997)

Base for the classification are

etiopathogenetic mechanisms

involved in onset and development of DM

(15)

I.

I. Diabetes mellitus - type 1:

Diabetes mellitus - type 1:

due to destruction of beta

due to destruction of beta

cellcellss of pancreatic isletsof pancreatic islets

Consequence:

absolute deficit of insulinabsolute deficit of insulin

A.

A. subtype:

subtype:

induced by autoimmunity processesinduced by autoimmunity processes

B.

B. subtype: idiopathic mechanism

subtype:

idiopathic mechanism

Types 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, ,

(16)

IV.

IV. Gestational DM

Gestational DM

-

III. 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

(17)

Main differences between “old” and “new” classification

of 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



 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)

(18)

(19)

_

Normal fasting value of plasmatic glucose concentration:Normal fasting value of plasmatic glucose concentration:



New criteria for diagnose of DM

For 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 param

(20)



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 criteria and they do not meet the 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

The individuals with IGT with IGT are recognized as being at are recognized as being at higher risk than higher risk than the general popu

the general popullation for the development of DM (about 1.5 ation for the development of DM (about 1.5 -- 4.0 4.0 % of patients with IGT

(21)

Syndrome X (metabolic X syndrome)

- - frequently occurs in people suffering formfrequently occurs in people suffering form visceral obesityvisceral obesity

Characteristic features

Characteristic 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 development

(22)

- development of anti-insulin receptor antibodies- development of anti-insulin receptor antibodies

(23)

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 anti

(24)

Etiopathogenesis of DM

Type 1 DM - characteristics

- it is most typical in individuals - it is most typical in individuals under 30 yearsunder 30 years of age (juvenile DM) of age (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

(25)

Evidence suggest that type

Evidence suggest that type 11 DM is caused by a gradual DM is caused by a gradual pprocessrocess o

off autoimmune destruction of beta cells in genetically susceptive individuals

T

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

(26)

Type 2 DM - characteristics

1. Primary disturbance:

- _ biological activity of insuline

2. Compensatory hyperinsulinemia

- due to _concentration of blood glucose

3. Insulinoresistentia:

(27)

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)

- 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 visceral) (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) (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

(28)

(29)

Main symptomes and signs of DM and mechanisms

of their onset

Hyperglycemia:

 _{relative or absolute deficiency of insulin effect}_{relative or absolute deficiency of insulin effect}__ ___{transport of}_{transport of}

  glycogenolysisglycogenolysis (?) (?)

Glycosuria:

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

Polyuria:

(30)

Polydipsia :

Polydipsia : high blood level of glucose high blood level of glucose __ hyperosmolality of hyperosmolality 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, fats, depletion of cellular stores of carbohydrates, fats,

and proteins results in and proteins results in cellular starvationcellular starvation and a and a

corresponding corresponding increase in hungerincrease in hunger

Weight loss :

Weight loss : fluid lossfluid loss in in osmotic diuresisosmotic diuresis, , loss of body tissueloss of body tissue

as fats and proteins are used for energyas fats and proteins are used for energy creation creation

Fatigue :

Fatigue : metabolic changes result in metabolic changes result in poor use of food poor use of food

(31)

Complications of Diabetes Mellitus

A.

A. Acute complications

Acute complications

•

• Hypoglycemia

Hypoglycemia

•

• Ketoacidosis

Ketoacidosis

•

• Hyperosmolar hyperglycemic nonketotic coma

Hyperosmolar hyperglycemic nonketotic coma

B.

B. Chronic complications

Chronic complications

•

• Diabetic micro- and macro

Diabetic micro- and macro

vascular

changes

•

• Diabetic neuropathy

Diabetic neuropathy

•

• Diabetic retinopathy

Diabetic retinopathy

•

• Diabetic nephropathy

Diabetic nephropathy

(32)

A.

A. Acute complications

Acute complications

1. Hypoglycemia

1. 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

Symptoms and signs of hypoglycemia are caused bSymptoms and signs of hypoglycemia are caused by y epinephrine epinephrine release

release (sweating, shakiness, headache, palpitation)(sweating, shakiness, headache, palpitation) and by and by lacklack of glucose in the brain

(33)

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 _

(34)

2.

2. Diabetic ketoacidosis

Diabetic ketoacidosis

- - the most serious metabolic the most serious metabolic complication of DM

complication 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__ increase increase

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

(35)

3.

3. Hyperosmolar hyperglycemic nonketotic coma

Hyperosmolar hyperglycemic nonketotic coma

(HHNC)

(hyperosmolar hyperglycemic syndrome)

a)

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

breakdownbreakdown __ lack of ketosislack of ketosis

b)

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

less than needed for effective glucose transport less than needed for effective glucose transport __

hyperglycemiahyperglycemia __ glycosuria and polyuria glycosuria and polyuria __ body fluids body fluids

depletion depletion __ intracellular dehydration intracellular dehydration __ neurologic neurologic

(36)

(37)

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

a) 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

(38)

(39)

(40)

(41)

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 microvascular damage- blood supply to nerves is decreased because of microvascular 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

insufficientinsufficient

- increased accumulation of sorbitol and fructose, decreased - increased accumulation of sorbitol and fructose, decreased

concentration of myoinositol concentration of myoinositol

(42)

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

(43)

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

Pathomechanisms Pathomechanisms involved in retinopathy occurenceinvolved in retinopathy occurence::

(44)

(45)

Diabetic retinopathy – hard exudates, dot-and-blot hemorrhages,

(46)

(47)

b) Nephropathy

(48)

(49)

(50)

B)

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

a)a) Coronary artery diseaseCoronary artery disease __ acute or chronicacute or chronic myocardialmyocardial

ischemia and/orischemia and/or infarction infarction

b)b) StrokeStroke __ acute or chronicacute or chronic cerebral ischemiacerebral ischemia

c)c) Peripheral vascular diseasePeripheral vascular disease __ gangrene and amputationgangrene and amputation

(51)

(52)

(53)

3.

- tissue hypoxia (macro- and microangiopathy)- tissue hypoxia (macro- and microangiopathy)

- increased level glucose in body fluids - increased level glucose in body fluids __ pathogens pathogens

(54)