I-Biological Macromolecules

A-Carbohydrate

Continued Education Program

Biology

Presented by:Dr. Shaimaa Nasr Amin

Lecturer of Medical Physiology

2

•Organic compounds:are Compounds

that contain CARBON .

•Macromolecules are large organic

molecules.

Macromolecule

A large oraganic molecule, such as a polymer

or protein, consisting of many smaller

structural units linked together.

MACROMOLECULES OF LIFE

• Found in all living things

• Building blocks of all cells

• Made up of the atoms: Carbon, oxygen, hydrogen, Nitrogen, Phosphorus, and Sulfur

• There are 4

1. Carbohydrates C, H, & O

2. Lipids C, H, & O

3. Proteins C, H, O, N, & S

4. Nucleic Acids C, H, O, N, & P

All biological macro-molecule are made

up of a small number of elements:

Carbon, Hydrogen, Oxygen, Nitrogen,

Phosphorus and Sulfur

• 96% of living organisms is

made of:

carbon (C)

oxygen (O)

hydrogen (H)

nitrogen (N)

phosphorus (P)

Elements of Life

Molecules of Life• Put C, H, O, P, and N together in different

ways to build living organisms

• What are bodies made of?

• carbohydrates

• sugars & starches

• proteins

• fats (lipids)

• nucleic acids

• DNA, RNA

• Water

• 65% of your body is H2O

• water is inorganic

• doesn’t contain carbon

• Rest of you is made of carbon molecules

• organic molecules

• carbohydrates

• proteins

• fats

• nucleic acids

Don’t forget water

I. Polymers

• What is a polymer?

• Poly = many; mer = part. A polymer is a large molecule

consisting of many smaller sub-units bonded together.

• What is a monomer?

• A monomer is a sub-unit of a polymer.

A. Making and Breaking Polymers

• How are covalent linkages between monomers formed in the creation of organic polymers?

• Condensation or dehydration synthesis reactions.

• Monomers are covalently linked to one another through

the removal of water.

Condensation Synthesis

Hydrolysis

• What is a hydrolysis reaction?

• Polymers are broken down into monomers.

• Hydro = water; lysis = loosening/

• Water is added and the lysis of the polymer occurs.

Hydrolysis

II. Classes of Organic Molecules:

• What are the four classes of organic molecules?

• Carbohydrates

• Lipids

• Proteins

• Nucleic Acids

A-CARBOHYDRATE

A. Carbohydrates• Sugars

• Carbo = carbon, hydrate = water; carbohydrates have

the molecular formula (CH2O)n

• Functions:

• Store energy in chemical bonds

• Glucose is the most common monosaccharide

• Glucose is produced by photosynthetic autotrophs

• Carbohydrates are placed in to one of three catagories,

depending on the number of monosaccharide units, or

residues, they contain.

• Monosaccharides, contain a single monosaccharide residue.

• Oligosaccharides, contain 2 to 10 monosaccharide residues.

• These include the disaccharides, which contain 2 monosaccharide

residues.

• Polysaccharides, which contain more than 10 monosaccharide

residues.

• These can contain thousands of monosaccharide residues.

Monosaccharides• Monosaccharides are

classified according

to the number of

carbons and whether

they contain an

aldehyde or ketone.

• The “-ose” ending is

used to designate

carbohydrates.

Monosaccharides

• The physical properties of

monosaccharides are heavily

influenced by the large number

of hydroxy groups that they

contain.

• There ability to participate in

numerous hydrogen bonds gives

them high melting points and high

solubilities in water.

• Each hydroxyl group has two

hydrogen bonding acceptor sites and

one hydogen bonding donor site.

• Each carbonyl group has two acceptor

sites.

C

C

O H

O

H

H

H

O H

H O

H

H

OH

H

O H

H

O H

Monosaccharides• Monosaccharides contain chiral carbon atoms.

• This is what accounts for the large number of different

monosacchides.

• For each chiral carbon, n, a monosacharide has 2n stereoisomers.

• These will be divided among 2n/2 pairs of enantiomers.

•Glucose contains 4 chiral carbons

•Glucose has 24 = 16 stereoisomers

•These stereoisomers can be grouped

into 16/2 = 8 pairs of enantiomers.

O

C

H

C

C

C

C

C

H

H

HO

H

H

H OH

OH

OH

OH

OH

D-glucose

Monosaccharides

• Fischer projections

are used to distinguish

the different

stereoisomers.

• The letters D and L are

used to distinguish

between the members of

a pair of enantiomers.

• The D or L designation is

based on the chiral

carbon furthest from the

carbonyl carbon.

Fischer projection:

Monosaccharides

• Diasteriomers are stereoisomers that are not

enantiomers.

• Diasteriomers have have different names

• Enatiomers have the same name and are distinguished by a D or L.

enantiomers

diastereomers

Monosaccharides

• Important monosaccharides.

• pentose and hexoses are the most abundant

• Pentoses

• D-ribose and D-2-deoxyribose are found in DNA, RNA and

nucleotides such as FADH2 and NADH

Monosaccharides

• Important monosaccharides.

• pentose and hexoses are the most

abundant

• Hexoses

• D-glucose (dextrose or blood surgar) -

major metabolite and strorage form of

chemical energy.

• D-galactose - combines with glucose to

produce lactose (milk sugar)

• D-fructose (fruit sugar) - major metabolite

and sweetest tasting natural sugar.

• fructose is a ketose

25

Monosaccharides

• Monosaccharide derivatives

• Deoxy sugars.

• One or more -OH’s are replaced with -H’s

Monosaccharides

• Monosaccharide derivatives

• Amino sugars.

• One or more -OH’s are replaced with -NH2’s

• Often these are acetylated to form amides.

Monosaccharides

• Monosaccharide derivatives

• Alcohol sugars.

• The ketone or aldehyde is reduced to an alcohol are reduced to

Monosaccharides

• Monosaccharide derivatives

• Carboxylic acid sugars.

• The ketone, aldehyde, or primary alcohol is oxidized to a carboxylic acid.

2. Structure of Disaccharides• Double sugar that consists of 2 monosaccharides,

joined by a glycosidic linkage.

• What reaction forms the glycosidic linkage?

• Condensation synthesis

Examples of Disaccharides:

Lactose = glucose + galactose Sucrose = glucose + fructose

3. Polysaccharides• Structure: Polymers of a few hundred or a few thousand monosaccharides.

• Functions: energy storage molecules or for structural support:

• Starch is a plant storage from of energy, easily

hydrolyzed to glucose units

• Cellulose is a fiber-like structureal material - tough and

insoluble - used in plant cell walls

• Glycogen is a highly branched chain used by animals to

store energy in muscles and the liver.

• Chitin is a polysaccharide used as a structural material

in arthropod exoskeleton and fungal cell walls.

CARBOHYDRATE DIGESTION

AND ABSORPTION

Carbohydrate Digestion

• break down into glucose• body is able to absorb and use

• large starch molecules• extensive breakdown

• disaccharides• broken once

• monosaccharides• don’t need to be broken down

• begins in mouth

• chewing releases saliva

• enzyme amylase hydrolyzes starch to polysaccharides and maltose

• Pre-stomach – Salivary amylase : a 1-4 endoglycosidase

GG

GG

G

GG

Ga 1-4 linkG

G

G

G a 1-6 link

G

GG

GGG G G G

G

G

G

G G

G

maltose

G

G

G

isomaltose

amylase

maltotriose

G

G

G

G

a Limit dextrins

Carbohydrate Digestionbegins in mouth chewing releases saliva enzyme amylase

hydrolyzes starch to polysaccharides and maltose

Stomach

• Not much carbohydrate digestion

• Acid and pepsin to unfold proteins

• Ruminants have forestomachs with extensive

microbial populations to breakdown and

anaerobically ferment feed

• small intestine

• majority of carbohydrate digestion takes place here

• pancreatic amylase reduces carbs to glucose chains or disaccharides

• specific enzymes finish the job

• maltase

• maltose into 2 glucose

• sucrase

• sucrose into glucose and fructose

• lactase

• lactose into glucose and galactose

Small Intestine

• Pancreatic enzymes

a-amylase

G G GG G

G

G G G

G G GG

GG G

amylose

amylopectin

G G G G G

a amylase

+

G

G G

G G

maltotriose maltose

a Limit dextrins

G

Oligosaccharide digestion..cont

G

G G

G G

G

G

G

G G

G

G

Glucoamylase (maltase)

or

a-dextrinase

G G

G

G

G

a-dextrinase

G GG

G

G G

Gmaltase

sucrase

a Limit dextrins G

Small intestine Portal for transport of virtually

all nutrients

Water and electrolyte balance

Enzymes associated with

intestinal surface membranes

i. Sucrase

ii. a dextrinase

iii. Glucoamylase (maltase)

iv. Lactase

v. peptidases

Carbohydrate absorption

apical basolateral

• large intestine

• 1-4 hours for sugars and starches to be digested

• only fibers remain

• attract water, which softens stool

• bacteria ferment some fibers

• water, gas, short-chain fatty acids (used for energy)

Carbohydrate Absorption

• glucose can be absorbed in the mouth

• majority absorbed in small intestine

• active transport

• glucose and galactic

• facilitated diffusion

• fructose

• smaller rise in blood glucose

Lactose Intolerance• more lactose is consumed than can be digested

• lactose molecules attract water

• cause floating, abdominal discomfort, diarrhea

• intestinal bacteria feed on undigested lactose

• produce acid and gas

Lactose Intolerance

• age, damage, medication, diarrhea, malnutrition

• management requires dietary change

• 6 grams (1/2 cup) usually tolerable

• take in gradually

• hard cheeses & cottage cheese

• enzyme drops or tablets

• lactose free diet is extremely difficult to accomplish

CARBOHYDRATE

METABOLISM

Carbohydrate Metabolism• 1/3 of body’s glycogen is stored in liver

• released as glucose to bloodstream

1. eat – intake glucose

2. liver condenses extra glucose to glycogen

3. blood glucose falls

4. liver hydrolyzes glycogen to glucose

Glycogen is bulky, so we store only so much: short term energy supply

Fat is the long term energy supply.

Glucose for Energy

• enzymes break apart glucose – yielding energy

• inadequate supply of carbohydrates• ketone bodies (fat fragments) are an alternate energy source

during starvation

• excess ketones can lead to ketosis: imbalance of acids in body

• minimum of 50 – 100 grams of carbs/day are needed to avoid ketosis

Glucose

Glucose-6-P

Pyruvate

Hexokinase

Pentose

Phosphate

Shunt

glycolysis

Carbohydrates• Serve as primary source of energy in the cell

• Central to all metabolic processes

Glc-1- phosphate

glycogen

Cytosol - anaerobic

Pyruvatecytosol

Aceytl CoAmitochondria

(aerobic)

Krebs

cycleReducing

equivalents

Oxidative

Phosphorylation

(ATP)

AMINO

ACIDS

FATTY ACIDS

Fasted State

Glucose

Glucose-6-P

Pyruvate

Hexokinase

Pentose

Phosphate

Shunt

glycolysis

Glc-1- phosphate

glycogen

Need 13.8 kJ/mol

ATP = -30 kJ/mol

-16.7 kJ/mol

GNG

G-6-Pase

Control of enzyme activity

Rate limiting step

Glycogen synthase

(active)

OHP

Glycogen synthase

(inactive)

Glycogen formation

Glycogen synthase kinase

(active)OH

IRinsulin

P

PProtein Kinase B

(active)Protein Kinase B

(inactive)OH

P Glycogen synthase kinase

(inactive)

Carbohydrate Metabolism/ Utilization-

Tissue Specificity• Muscle – cardiac and skeletal

• Oxidize glucose/produce and store glycogen (fed)• Breakdown glycogen (fasted state)• Shift to other fuels in fasting state (fatty acids)

• Adipose and liver• Glucose acetyl CoA• Glucose to glycerol for triglyceride synthesis• Liver releases glucose for other tissues

• Nervous system• Always use glucose except during extreme fasts

• Reproductive tract/mammary• Glucose required by fetus• Lactose major milk carbohydrate

• Red blood cells• No mitochondria• Oxidize glucose to lactate• Lactate returned to liver for Gluconeogenesis

Glucose Homeostasis

• maintaining an even balance of glucose is controlled by

insulin and glucagon

• insulin

• moves glucose into the blood

• glucagon

• brings glucose out of storage

• maintaining balance

• balanced meals at regular intervals

• fiber and some fat slow the digestive process down

• glucose gets into the blood slow and steady

Maintaining

Blood Glucose

Homeostasis

IntestineWhen a person eats,

blood glucose rises.

1

2

Insulin stimulates the uptake of

glucose into cells and storage

as glycogen in the liver and

muscles. Insulin also stimulates

the conversion of excess

glucose into fat for storage.

3

4

5

6

7 Blood glucose begins to

rise.

a The stress hormone

epinephrine and other hormones

also bring glucose out of storage.

Glucose

Insulin

Glucagon

Glycogen

Glucagon stimulates liver

cells to break down glycogen

and release glucose into the

blood.a

Liver

Low blood glucose stimulates

the pancreas to release

glucagon into the bloodstream.

As the body's cells use

glucose, blood levels decline.

Glucagon

Pancreas

Fat cell

Liver

Muscle

High blood glucose stimulates

the pancreas to release insulin.

Pancreas

Insulin

Imbalance

• diabetes• after food intake, blood glucose rises and is not regulated because

insulin is inadequate

• hypoglycemia• blood glucose drops dramatically

• too much insulin, activity, inadequate food intake, illness

• diet adjustment includes fiber-rich carbs and protein

Glycemic Index

• way of classifying food

according to their ability to

raise blood glucose

• much controversy

Sugar

• ½ comes from natural sources, ½ from refined and

added

• sucrose, corn syrup, honey

• excess can lead to nutrient deficiencies and tooth

decay

• empty calories

• sugar and starch break down in the mouth

Sugar

• recommended intake

• added sugar = no more than 10% of energy intake

Starch and Fiber

• diet that includes starch, fiber and natural sugars

• whole grains, vegetables, legumes, fruits

• may protect against heart disease and stroke

• reduces the risk of type 2 diabetes

• enhances the health of the large intestine

• can promote weight loss

Starch and Fiber• starch intake

• 45-65%

• 225 – 325 grams (DV is 300 grams)

• 900-1300 kcal/2000 kcal

• RDA is 130 grams

• fiber intake

• Daily Value is 25 grams/2000 kcal

Artificial Sweeteners

• help keep sugar and energy intake down

• anything we eat has FDA approval

• saccharin

• aspartame

• acesulfame potassium

• sucralose

• neotame

Sugar Replacers

• sugar alcohols

• provide bulk and sweetness

• cookies, gum, candy, jelly

• do contain minimal kcal

• low glycemic response

• absorbed slowly

• do not cause dental caries

DISTURBANCE IN

CARBOHYDRATE METABOLISM

1. 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)

Pathomechanisms

a) Activity of disaccharidase is decreased 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

Lactase deficiency syndrome

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

Causes of secondary lactase deficiency:

- 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

Monosaccharides malabsorbtion

Small intestine ability to 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

Glycogenosis (glycogen storage 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

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 manifestationof diabetic symptoms and signs

Regulation of the blood glucose level depends on liver:

1. extracting 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 livers 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...

DM is a chronic complex syndrome induced by absolute or 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

I. Diabetes mellitus - type 1: due to destruction 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)

IV. Gestational DM -

III. Other specific types of DM

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

Main differences between “old” and “new” classification

of diabetes mellitus

In 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?

Normal fasting value of plasmatic glucose concentration:

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 fasting plasma glucose:

6.1 but 7.0 mmol/l

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).

Syndrome X (metabolic X syndrome)

- frequently occurs in people suffering form visceral obesity

Characteristic features:

insuline resistance

compensatory hyperinsulinemia

visceral obesity

dyslipidemia ( LDL, TG, HDL)

systemic hypertension

Increased probability of DM-type2 development

Insuline 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

3. defective signal transduction

(from the receptor to the plasma of cell)

4. postreceptor defect

5. increased concentration of anti-insulinic hormones

Etiopathogenesis of DM

Type 1 DM - characteristics

- 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)

Evidence suggest that type 1 DM is caused by a 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

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 -characteristics

- is rare in populations 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)

Main symptomes and signs of DM and mechanisms of their 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)

Polydipsia : high blood level of glucose hyperosmolality of 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

Complications of Diabetes Mellitus

A. Acute complications

• Hypoglycemia

• Ketoacidosis

• Hyperosmolar hyperglycemic nonketotic coma

B. Chronic complications

• Diabetic micro- and macrovascular changes

• Diabetic neuropathy

• Diabetic retinopathy

• Diabetic nephropathy

• Other complications

A. Acute complications

1. Hypoglycemia ( 3.3mmol/l of blood glucose) - results 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).

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. Diabetic ketoacidosis - the most serious metabolic

complication of 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

3. Hyperosmolar hyperglycemic nonketotic coma(HHNC)(hyperosmolar hyperglycemic syndrome)

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)

B. Chronic complications

Today, long-term survival 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)

Functional consequences:

- abnormalities in 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

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 muscleand 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) Microvascular disease - specific lesion of DM that affect capillaries

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