PATHOPHYSIOLOGY OF CARBOHYDRATE METABOLISM

co-operative: L.Šurinová

present in food in various forms:

1. simple

sugars - monosaccharides

2. complex chemical units - disaccharides
- polysaccharides

Processing of carbohydrates in GIT

Ingested carbohydrates  cleaving proces
monosaccharides  absorbtion in stomach,
duodenum and proximal jejunum

Disaccharidase deficiency syndrome

saccharase = enzyme

which hydrolyses disaccharide
saccharose (to fructose and glucose)

laktase = enzyme which splits disaccharide lactose
(to glucose and galactose)

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

 decreased
hydrolysis of disaccharide  decreased resorbtion

of substrate  increased concentration of disaccharide in small intestine
lumen  increased osmotic activity of the lumen fluid
 diarrhea

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

Causes of lactase deficiency:
- genetic defect (primary)

- secondary to a wide variety of gastrointestinal diseases
that damage the mucosa of the small intestine (secondary)

Disaccharide lactose is the principal carbohydrate in milk.
- Many persons showing milk intolerance prove to be lactase –
deficient

- Primary lactase deficiency incidence is as high as 80 % to 90 %
among African - Americans, Asians, and Bantus population

- Milk intolerance may not become clinically apparent until
adolescence

nontropical (celiac disease)and tropical sprue,
- regional

enteritis,
- viral and bacterial infections of the intestinal tract,
- giardiasis, cystic fibrosis, ulcerative colitis,
- kwashiorkor, coeliac disease 

Symptoms and signs - are mentioned at previous page

resorb glucose and galactose is
decreased

Cause: Specific transport system for galactose and glucose
absorbtion in cells of small intestine is insufficient

Results: Symptoms and signs similar to disaccharidase
deficiency syndrome

disease)

Autosomal recessive disease (inborn errors of

metabolism,
emzymopathy)

There are defects in degradation of glycogen.
The disturbances result in storage of abnormal glycogen,
or storage of abnormal amount of glycogen in various
organs of the body
Example: Hepatorenal glycogenosis (Morbus von Gierke)
Cause: Deficit of glucose-6-fosfatase in liver and kidney
Results: Hypoglycemia in fasting individuals,
hyperlipemia, ketonemia

There are 9 other types of glycogenosis

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

glucose from blood
2. synthesizing glycogen
3. performing glycogenolysis

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

The livers uptake and output of glucose and the use of glucose by peripheral tissues depend on the physiologic balance of several hormones that:
1. lower blood glucose level - insulin
2. rise blood glucose level - glucagon, epinephrine, GH,
glucocorticoids...

relative deficit of insuline which is characterized by metabolic disorders

of carbohydrates, lipids and proteins.

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

Definition of DM

Classification of DM
(according to International Expert Committee, 1997)
 
Base for the classification are etiopathogenetic mechanisms
involved in onset and development of DM

of beta

cells of pancreatic islets
Consequence: absolute deficit of insulin
 
A. subtype: induced by autoimmunity processes
B. subtype: idiopathic mechanism

Types of DM

II.Diabetes mellitus -type 2: at the beginning-predominance
of insulin resistance and relative deficit of insulin(normo- or
hyper -insulinemia), later on - combination of impaired insulin
secretion and simultaneous insulin resistance (hypoinsulinemia,
insulin resistance)

 DM due to genetic defects of beta

cells of pancreas islets and due
to genetic defect of insulin function

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

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

glucose intolerance which onsets
for the first time during pregnancy

new classification of DM:
- terms IDDM and NIDDM are not

used
- term DM due to malnutrition is not used
- terms - primary and secondary DM are not used
 
 New terms were introduced into new classification of DM:

* impaired fasting plasma glucose(FPG)
* impaired glucose tolerance(IGT)

Why?

 6.1 mmol/l
● Normal value

of PGTT – blood glucose concentration 2 hs
after beginning of test  7.8 mmol/l

 New criteria for diagnose of DM

1st: classic symptoms and signs of DM are present (polyuria,
polydipsia, weight loss), and increased day-time blood glucose
concentration to 11.1 mmol/l and more
or
2nd: fasting glucose level is 7.0 mmol/l and more
or
3rd: 2 hours glucose level in PGTT is 11.1 mmol/l and more
For confirmation of diagnosis DM positivity each of the mentioned
parameters have to be confirmed next day by positivity any of
the mentioned parameter

Impaired glucose tolerance (IGT):

Glucose tolerance test shows abnormal values but these
patients are asymptomatic and they do not meet the criteria
for diagnosis of DM.
IGT criteria:
- fasting plasma glucose level can be normal
- 2 hours after intake glucose is plasma glucose level higher
than normal (from 7.8mmol/l to 11.1mmol/l)

The individuals with IGT are recognized as being at higher risk than the general population for the development of DM (about 1.5 - 4.0 % of patients with IGT  DM).

suffering form visceral obesity

Characteristic features:
 insuline resistance
 compensatory

hyperinsulinemia
 visceral obesity
 dyslipidemia ( LDL,  TG,  HDL)
 systemic hypertension

Increased probability of DM-type2 development

Resistance (IR)

IR is one

of the mechanisms involved in pathogenesis of IGT
and DM, especially in DM type 2
Causes of insuline resistance:
1. autoimmune reactions
- development of anti-insulin antibodies
- development of anti-insulin receptor antibodies

2. defects in the insulin receptor at the cell surface
a) defect in receptor processing
b) decrease in receptor number

to the plasma of cell)

4. postreceptor defect

5. increased concentration of

anti-insulinic hormones

- it is most typical in individuals under 30

years of age (juvenile DM)

- 80 % - 90 % of beta cells in the islets of Langerhans
are destroyed

Possible mechanisms of beta cells destruction:

a) by islet cell antibodies of the IgG class

b) by non-immune mechanism (idiopathic up to now)

gradual process
of autoimmune destruction of beta cells in genetically

susceptive
individuals

The result of beta cells destruction:
- almost no or absolute no functional insulin is produced

- glucagon is present in relative excess

- individuals are prone to ketoacidosis

- insulin resistance is rare

- patients are insulin dependent

-  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

not affected by urban modernization
- adult onset (mostly after

40 years of age, slow, insidious
onset)
- results from the action of several abnormal genes ; - inherited
susceptibility, familial tendency stronger than for type 1 DM
- associated with long - duration obesity (mainly visceral)
- islet of Langerhans cells antibodies are rare
- increased insulin resistance
- nonspecific changes (damage) of islet cells
- usually not insulin dependent
- individuals are not ketosis prone (but they may form
keton bodies under stress)

onset
Hyperglycemia:
relative or absolute deficiency of insulin effect  

transport of
glucose to muscle and fat cells  glycemia
 insulin effect  gluconeogenesis in liver  blood level of
glucose
  glycogenolysis (?)

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

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

plasma water moves from cells to ECF (IVF) 
 intracellular dehydratation 
 creation of thirst feeling (in hypothalamus) 
 intake of fluids

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

Weight loss : fluid loss in osmotic diuresis, loss of body tissue
as fats and proteins are used for energy creation

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

• Ketoacidosis
• Hyperosmolar hyperglycemic nonketotic coma

B. Chronic complications
• Diabetic micro- and macrovascular changes
• Diabetic neuropathy
• Diabetic retinopathy
• Diabetic nephropathy
• Other complications

from:
a) exogenous causes - overdose

of insuline plus inadequate
food intake, increased exercise
- overdose of oral hypoglycemic agents
- alcohol
- other agents (e.g. salicylates)
b) endogenous causes - insulinoma (neoplasm of beta cells
of islet of Langerhans)
- extrapancreatic neoplasm (hepatomas,
tumor of GIT)
- inborn errors of metabolism (fructose
intolerance)
Symptoms and signs of hypoglycemia are caused by epinephrine release (sweating, shakiness, headache, palpitation) and by lack of glucose in the brain (bizarre behaviour, dullness, coma).

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

DM
– It develops when there is severe

insulin insufficiency
– Insulin insufficiency triggers a complex metabolic reactions
which involve:
- decreased glucose utilisation  hyperglycemia and glycosuria

- acceleration of gluconeogenesis  hyperglycemia

- decreased lipogenesis and increased lipolysis increase
oxidation of free fatty acids  production of ketone bodies
(aceto-acetate, hydroxy-butyrate, and acetone)  hyperketonemia
 metabolic acidosis  coma

a) - insulin is present

to some degree  it inhibits fat
breakdown  lack of ketosis

b) - insulin is present to some degree  its effectivity is
less than needed for effective glucose transport 
hyperglycemia  glycosuria and polyuria  body fluids
depletion  intracellular dehydration  neurologic
disturbancies (stupor, coma)

of patient suffering from DM is the
rule.

As a result, the problems of neuropathy, microvascular
disease, and macrovascular disease have become important

1. Diabetic neuropathies(DN) - probably the most common
complication in DM
Pathogenesis:
a) vascular damage of vasa nervorum
b) metabolic damage of nerve cels
c) non-enzymatic glycation of proteins

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

motor nerve function
(in advanced stages

of DM)
- sensory nerve conduction is impaired
- autonomic neuropathy (diabetic diarrhea, orthostatic
hypotension....)

Possible mechanisms involved in development of DN
- blood supply to nerves is decreased because of microvascular damage
(vasa nervorum may be damaged)
- energy source for normal rest membrane potential maintain is
insufficient
- increased accumulation of sorbitol and fructose, decreased
concentration of myoinositol
- non-enzymatic glycation of proteins

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

and arterioles of the retina, renal

glomeruli, peripheral nerves, muscles
and skin
Characteristic lesion :
- thickening of the capillary basement membrane
- increased accumulation of glycoprotein in wall of small
arteries and capillaries

a)Retinopathy - it is the result of retinal ischemia caused by
microangiopathy
Pathomechanisms involved in retinopathy occurence:
- increased retinal capillary permeability, vein dilation
- microaneurism formation and hemorrhages
- narrowing of small arteries lumen
- neovascularisation and fibrous tissue formation within
the retina
- retinal scars formation  blindness

fovea, cotton-wool patches,microaneurysms

caused by DM


Pathologic processes involved in diabetic nephropathy:

- glomerular enlargement - diffuse intercapillary
- glomerular basement membrane glomerulosclerosis
thickening 
proteinuria
- systemic hypertension often occurs (more than 0.3g/day)
- neuropathy - see at B1.

artery

larger arteries (coronary arteries, brain arteries, peripheral arteries)

Main biochemical disturbancies leading to macrovascular
disease:
- accumulation of sorbitol in the vascular intima
- hyperlipoproteinemia  vascular abnormality in blood
coagulation, occlusion by thrombus,
accelerated atherosclerosis

a) Coronary artery disease  acute or chronic myocardial
ischemia and/or infarction
b) Stroke  acute or chronic cerebral ischemia
c) Peripheral vascular disease  gangrene and amputation
(diabetic foot)

for infection
throughout the body.

Causes:
- disturbancies of senses (neuropathy, retinopathy) 
decreasing the function of early warning system 
breaks in skin integrity

- tissue hypoxia (macro- and microangiopathy)

- increased level glucose in body fluids  pathogens
are able to multiply rapidly

- white blood cells supply to the tissue is decreased

- function of white blood cells is impaired