Нарушения на въглехидратната

обмяна.
Хипер– и хипогликемии. Захарен
диабет.
Нарушения на белтъчната обмяна

доц. д-р Палмена Ангелова

МФ на СУ
 sugar yields glucose and fructose, lactose is
converted to glucose and galactose, and
maltose is converted to two glucose
molecules. When the disaccharides are not
broken down to monosaccharides, they cannot
be absorbed but remain as osmotically active
particles in the contents of the digestive
system, causing diarrhea.

Persons who are deficient in
lactase, the enzyme that breaks
down lactose, get diarrhea
when they drink milk or eat dairy
products.

Fructose is transported across the intestinal mucosa

by facilitated diffusion, which does not require energy
expenditure. In this case, fructose moves along a
concentration gradient.
 Glucose and galactose are transported by sodium
dependent carrier system that uses ATP and the
Na+/K+-ATP-ase pump as an energy source.

Water absorption from the intestine is linked to
absorption of osmotically active particles, such as
glucose and sodium.

It is important that facilitation of the water transport

across the intestine wall (and decreasing diarrhea)
after temporary disruption in bowel function is to
include sodium and glucose in the fluids that are
taken.
• To the liver.
1. liver Here excess sugar from meals is
stored to cover sugar shortages between meals
and to make fat from excess sugar.
• Transport of sugar goes both to and from the liver.
The liver acts as "Sugar Central" between meals.

• 2. To the brain.
brain The brain is completely
dependent upon sugar combustion for its supply of
energy under normal conditions. It uses really
huge amounts of sugar.
• 3. To muscles and fat tissue- muscles can
use both fats and sugar to supply energy.
•
•The rate of sugar uptake and burning depends
on physical activity;
•
• Muscles take up and store glucose to cover
future activity but they cannot release sugar
back to the blood stream or act as "Sugar
Central".
•Fat tissue stores excess sugar as fat.
 Blood Glucose & Hormones
Hormone Action

 Insulin   Glucose
 Glucortocoids   Glucose
 Glucagon   Glucose
 Growth Hormone   Glucose
 Epinephrine   Glucose
 Counter-insulin hormones
ACTH, growth hormone, cortisol, thyroid hormone,
glucagon, adrenaline
1. Stimulate absorption of carbohydrates
(cortisol, thyroid hormone)
2.  glycogenolysis in liver and muscles,  glycogenesis
(adrenaline, cortisol, thyroid)
3. Inhibit hexokinase activity and therefore utilization
of glucose
(cortisol, growth hormone)
4. Stimulate gluconeogenesis
(cortisol, thyroid, glucagon)
5. Activate insulinase
(growth hormone, thyroid)
 Byosynthesis of insulin
➢ preproinsulin
➢ proinsulin – similar to IL-GF 1 and 2
➢ А and В-chain and С-peptide
➢ С-peptide – marker of internal insulin
secretion
 Secretion of insulin
➢ glucose >3.9 mmol/l
➢ To lesser extent – amino acids,
ketones,GIT peptides
➢ Glucose enters the beta cells through
facilitated transport .
➢ It is phosphorilised by glucokinase –
limiting enzyme
Incretins – increased insulin secretion

GLP -1 (glucagon-like peptide 1) increased insulin

secretion , secreted by guts
●

●Membrane receptor- metabolic and mytogenic

effects

Translocation of GLUT4 over the membrane

●
Glucagon – glycogenolysis and GNG
●

Most of the glucose is used into muscles

●

●Brain – takes up glucose without insulin

participation
 Захарен диабет
A group of metabolic disorders with a common
phenotype - hyperglycaemia.
Causes of hyperglycemia:
Reduced insulin secretion
Reduced use of glucose
Increased glucose production

DM is the leading cause of renal failure,

amputation of the lower limb with non-traumatic
cause and blindness in adults.
 classification
Pathogenetic, not based on age of appearance and type of
treatment.
Type 1 - insulin deficiency
Type 2 - heterogeneous group of diseases - varying degrees of
insulin resistance, impaired insulin secretion and increased
glucose production
Both types are preceded by impaired glucose homeostasis -
impaired glucose tolerance / changes in fasting blood glucose.

Type 1 occurs predominantly before 30 years but also

afterwards.
Type 2 occurs also in children, especially in obese
adolescents.
 Type-I Type-II
 Less common  More common
 Age < 25 Years  Adult >25 Years
 Insulin- Dependent  Insulin Independent
 Onset: Weeks  Months to years
 Acute Metabolic  Chronic Vascular
complications complications
 Autoantibody: Yes  No
 
 Insulin levels: very  Normal or high *
low  Normal / Exhaustion
 Islets: Insulitis  60-80% in twins
 50% in twins
 Other types of DM
● MODY (maturity onset of diabetes of the young) -
inheritance, started before 25 years, impaired insulin
secretion
● in exocrine pancreas diseases - cystic fibrosis, pancreatitis,
neoplasia, hemochromatosis,
● In endocrinopathies - acromegaly and Cushing's disease,
hyperthyroidism, etc.
● Viruses - very rare, congenital rubella CMV,
● drug Induced - diazoxide, beta-agonists, thiazides, alpha-
interferon
● Gestational diabetes - increased insulin requirements. About
7% of pregnancies. After the birth most women recover to
normal glucose tolerance, but they have an increased risk
35-60% of developing DM in the next 10-20 years.
 Diagnostic criteria
➢ Symptoms of diabetes (polyuria,
polydipsia, weight loss) and accidentally
taken blood sugar> 11.1 mmol / l
➢ Blood sugar during fasting> 7.0 mmol / l
➢ A1C> 6.5%
➢ Blood sugar> 11.1mmol / l 2 hours after
oral glucose tolerance test
 Патогенеза на ЗД тип 1
➢ Result of the interaction between genetic,
environmental and immunological factors
leading to the destruction of beta cells
➢ An autoimmune process that is triggered by an
infectious or environmental factor
➢ DM occurs when the destruction of about 70-
80% of beta cells occurs
➢ Diabetes develops with increased insulin
requirements - infection, puberty
 Enviromental factors
➢ Viruses - coxacie, rubella, enteroviruses
➢ Cow milk proteins
➢ nitrosourea
 Pathogenesis type 2 DM
➢ Impaired insulin secretion
➢ Insulin resistance
➢ Overproduction of glucose by the liver
➢ Impaired fatty metabolism
➢ Obesity - central / visceral at 80%
 Metabolism in muscle and fat cells
➢ Insulin resistance - due to genetic factors and
obesity
➢ Reduces maximum glucose utilization by 30-
60%
➢ The production of glucose by the liver increases
and both factors together contribute to
hyperglycemia.
➢ Elevated liver production is cause of the
increased fasting blood sugar, and insulin
resistance is the cause of increased blood sugar
postprandially.
➢ Increased adipokine production may result in
insulin resistance.
➢

➢FFA disturb glucose utilization in skeletal

muscles, increases glucose production in the liver
and impacts beta cell function - lipid toxicity
➢

➢Adiponectin increases insulin sensitivity, but its

production is reduced in obesity.
Adipokins cause inflammation with an increase in
IL-6 and CRP.

Cells of inflammation in the adipose tissue also

appear.
 Нарушена инсулинова секреция

➢Insulin secretion initially increases with insulin

resistance
➢

➢Over time, secretion decreases, amyloid

accumulates in the islands
➢

➢Hyperglycemia damages beta cells - "glucose

toxicity"
➢

➢Increased FFA also damage beta cells - "lipid

toxicity"
 Changed liver metabolism
➢Insulin resistance in the liver is expressed in the
inability of hyperinsulinemia to suppress
gluconeogenesis → fasting hyperglycaemia
➢

and reduced glycogen storage in the liver after a

➢

meal.
➢

➢Elevated glucose production by the liver is

manifested early in the course of the disease.
Insulin resistance in adipose tissue → increased
lipolysis and triglyceride production

→ increased production of VLDL and TG in

hepatocytes

→ steatosis and abnormal liver function

This is also reason for dyslipidemia in DM -

increased TG and LDL, decreased HDL
 Metabolic syndrome

➢ Insulin resistance
➢

➢ Hypertension
➢

➢ Dyslipidemia - ↑ TG and ↓ HDL

➢

➢ Central or visceral obesity

➢

➢DM 2 type / ↑ fasting blood glucose / impaired

glucose tolerance
➢

➢ Increased risk of cardiovascular disease

 Prevention of DM 2

lifestyle changes - diet and exercise 30

minutes / day 5 times a week in people with
impaired glucose tolerance prevents or slows
the development of Type 2 DM in about 60%
of cases
Acute complications of DM
Diabetic ketoacidosis (DKA) and
hyperglycemic hyperosmolar condition (HHC)

DKA occurs predominantly in the type 1 type,

and the HHC in type 2.
Both conditions are characterized by absolute
or relative insulin deficiency, hyperglycemia,
dehydration and acid base balance
abnormalities. Both conditions are potentially
life-threatening.
Hyperglycaemia leads to glucosuria, dehydration
and tachycardia.

There may be hypotension due to hypovolemia

and peripheral vasodilatation.

Brain edema is a severe complication, especially

in children.
 DKA
It is due to an absolute or relative insulin deficiency
and an excess of counter-insular hormones. A
deficiency of insulin and excess glucagon is required
to develop DKA.

This stimulates the GNG (gluconeogenesis),

glycolysis and ketone production in the liver and
mobilizes substrates from skeletal and adipose tissue
for GNG.

In the DKA and in the hyperosmolar state, markers of

inflammation - CRP, cytokines have been raised.
 DKA
Hyperglycaemia
Bicarbonate <10 mmol / l
Arterial pH = 6.8 - 7.3
Hyperkalaemia, despite the general deficiency,
causes potassium to does out from the cells due to
acidosis

Leukocytosis, ↑ TG and lipoproteins.

Increased urea and creatinine - because of

hypovolemia
 Hyperosmolar coma

Typical for Type 2 DM.

Polyuria, weight loss, dehydration and hyperosmolarity
- hypotension, tachycardia and altered consciousness.

There is no nausea, vomiting, abdominal pain and

Kussmaul breathing.

HC is often caused by other diseases - myocardial

infarction, sepsis, pneumonia, stroke.
Causes of HC - relative insulin deficiency and
inadequate water intake (dementia - dementia, stroke)

Osmotic diuresis due to glycosuria and dehydration

There is no ketogenesis and elevation of FFA, levels

of contrainsulin hormones are lower than those of
DKA. Possible explanation - insulin deficiency is
relative and not so pronounced
 HC
Extreme hyperglycemia - can reach over 55
mmol / l
Hypersomolarity> 350 mcg / l

prerenal azotemia

Mild or absent acidosis and ketonemia

Metabolic lactic acidosis

Mechanism of complications

First theory: Formation of glycosylated

products -

accelerate atherosclerosis, glomerular

dysfunction, suppress NOS, induce
endothelial dysfunction, alter the extracellular
matrix.
Second theory: hyperglycaemia enhances the
metabolism of glucose via the sorbitol pathway.
The sorbitol changes the redox potential of the
cell, increases its osmolarity, forms free radicals

The third theory: hyperglycemia activates the

pathway of formation of DAG and protein kinase -
genomic effects

Fourth theory: the hexosamine pathway is

activated - glycosylation of proteins and changes
in gene expression
Growth factors play an important role:

Vascular endothelial growth factor (VEGF-A) -

increased in retinopathy

TGF beta - in nephropathy, stimulates the

mesangial production of collagen and fibronectin

Hyperglycaemia causes the formation of free

radicals and activates all these pathways
nephropathy
Stages of nephropathy
neuropathy
 Хипогликемия
Most often they are due to drugs for DM or alcohol-
containing medicines.

Other reasons:
Organ failure
Sepsis and malnutrition
Hormonal deficiency - cortisol, adrenaline
Insulinum

Whipple Triad:
1. Symptoms of hypoglycaemia
2. measured low blood sugar with a precise method
3. disappearance of symptoms after blood sugar rises
 Exogenous
hypoglycemia
• Insulin injection

• Alcohol (develops 6-36 hours after

heavy consumption)

• Some drugs (e.g. salicylates)

• Long term physical exercise

Hypoglycaemia should be considered in any case
of confusion, loss of consciousness or seizure.
Liver glycogenolysis - capable of providing normal
blood sugar during 8 hours starvation or less
when increased exercise or depleted glycogen
stores from disease / starvation.

GNG - requires a minimal amount of counter-

insulating hormones and substrates - lactate,
pyruvate, alanine, glutamine, and others.
Aminoacids from the muscles; FFA and glycerol
from fat tissue
Defence mecanism against
hypoglycemia
1. Insulin - the first level of protection, insulin
has a dominant role in glucose homeostasis.
2. Glucagon - second level of protection
3. Adrenaline - its role is not critical, but it
becomes more important in glucagon
deficiency. Third level of protection.
4. Cortisol and growth hormone - for
hypoglycaemia over 4 hours. smaller effects,
20% of that of adrenaline
5. Behavioral changes at even lower levels of
glucose - food intake
 Hypoglycemia

Exogenous
Functional
Endogenous
These thresholds are dynamic. In poorly
controlled diabetes are higher - symptoms of
hypoglycaemia occur at normal blood sugar
levels.

In too aggressivelly controlled diabetes, frequent

episodes of hypoglycaemia and insulinoma - the
thresholds are lower.
These symptoms are nonspecific and diagnosis
requires the presence of the Whipple triad
(symptoms + measured low blood sugar +
disappearance of symptoms after the glucose
level is increased)
 etiology
Most often hypoglycaemia is due to the
treatment of diabetes.

In people with type 1 diabetes, hypoglycemia

is part of their life. They have an average of
two episodes of symptomatic hypoglycaemia
per week and one episode of severe
hypoglycemia per year. 6-10% of people with
type 1 DM die from hypoglycemia.

Hypoglycaemia is less common in Type 2 AD.

Unconscious hypoglycemia
It is due to the reduced sympathetic
adrenergic and cholinergic response. There
are no warning symptoms.

A vicious circle is created. These reactions are

reversible and functional. They can be altered
by a few weeks of strict control of glycaemia,
avoiding episodes of hypoglycaemia.
 Other causes of
hypoglycemia
1. Drugs
Ethanol blocks the GNG, but not glycolysis.
Hypoglycaemia occurs after several daily
alcoholic loads with relative fasting.

ACE inhibitors, AT2-inhibitors, beta blockers,

quinolones, indomethacin, quinine and
sulfonamides
2. Severe illness
Hepatic failure - fasting hypoglycemia
Heart failure - ? cause-stagnation and hypoxia in
the liver
Renal insufficiency - decreased insulin clearance,
decreased GND
Sepsis - increased glucose utilization - cytokines
in macrophages of liver, spleen and lung;
suppressed GNG, glycogen stores, hepatic and
renal hypoperfusion

starvation - lack of substrates for GNG

3. Hormonal Deficiency
Cortisol and growth hormone deficiency can cause
hypoglycemia in prolonged fasting, increased glucose
utilization (physical exercise, pregnancy), or reduced
glucose (alcohol consumption).

In children, growth hormone deficiency causes

hypoglycaemia.

In ↓ adrenaline no hypoglycaemia was observed at

normal cortisol levels
4. Tumors

5. Endogenous hyperinsulinism

Insulinoma
Antibodies to insulin and its receptors
Use of the sulphanyl urea drugs
Ectopic insulin production - very rare
Protein metabolism
 phenylketonuria
Congenital inability to convert phenylalanyline to
tyrosine
Most foods contain about 15% FA, which is an
essential amino acid
Tyrosine is used for:
- Synthesis of proteins
- melanin
- thyroxine
- catecholamines
FA-hydroxylase deficiency

Increased levels of FA lead to:

- disturbances in the development of the cortex
- defective myelination
- cystic degeneration of the gray and white matter

Brain injury is a fact even before the metabolites are recorded in the
urine
The failure continues until FA levels are increased

Mental retardation, hyperactivity and convulsions

A non-selective screening of all newborns occurs

Decreased levels of tyrosine result in:
- reduced tryptophan - serotonin
- reduced DOPA and catecholamines
- reduced melanin - light skin, blue eyes,
blond hair
 ammonia

Ammonia is formed by the degradation of

unresorbed amino acids by intestinal bacteria
and in all tissues in the metabolism of
glutamate.
It detoxifies by turning into urea and glutamine
mainly in the liver
Excreted mainly by the kidneys
 hyperammoniemia
1. Increased production
In slow intestinal passage - constipation
Respiratory alkalosis
Hypokalaemia
2. decreased kidney function
3. detoxification in the liver
Effects - hepatic encephalopathy
 azotemia
Increased in urea, creatine, uric acid,
amino acids, etc.
1. productional - acute infectious
diseases, protein degradation in burns,
hemolysis
2. retentional -renal failure
 gout
Incomplete purine metabolism
Hyperuricaemia
1. reduced excretion - 90%
2. Increased production
gout arthritis - urate crystals deposition
and a powerful inflammatory response
Risk factors - male sex, age (peak between 40-
50 years), high intake of alcohol, red meat and
fructose
The strongest risk is plasma urate
concentration
The solubility of urats is critical for the formation
of crystals
The solubility in the urine increases when it is
alkalinized

Decreasing the temperature reduces solubility

 symptoms

1. hyperuricemia
2. recurrent episodes of monoarthritis
3. deposition of urate salts - toffy in and around
the joints
4. kidney involvement - glomerular, tubular,
interstitial
5. Formation of uterine stones