1. Regulation of protein metabolism.

2. Starvation.
3. Kwashiorkor.
4. Marasmus.
5. Regulation of glucose metabolism.
6. Diabetus mellitus.
7. Types of diabetus mellitus.
8. Complications of diabetus
mellitus.
 • Disorders related to malnutrition,
malnutrition while potentially preventable, produce
moderate to severe disabilities.
• Nearly 800 million people in the world do not have enough to eat, most
of them living in developing countries. In these regions, inadequate
amounts of food (causing conditions such as child malnutrition and
retarded growth) and inadequate diversity of food (causing micronutrient
deficiencies) continue to be priority health problems.
• Malnutrition increases the risk of disease and early death and affects all
age groups, but it is especially common among poor people and those with
inadequate access to health education, clean water, and sanitation.
• Diabetes mellitus is a disease resulting from
absolute or relative insulin insufficiency and
accompanying by disturbance of metabolism
mainly, carbohydrate one.
• The main manifestation of diabetes mellitus
is hyperglycemia, sometimes reaching 25
mmol/l, glucosuria with glucose in urine up to
555-666 mmol/l (100-200 g/day), polyuria (to
10-12 L of urine per day), polyphagia and polydipsia.
 Proteins from the diet must be broken into amino acids to be absorbed.
Protein digestion begins in the stomach with the action of pepsin.
Pepsinogen, the enzyme precursor of pepsin, is secreted by the chief cells
in response to a meal and acid pH.
 Acid in the stomach is required for the conversion of pepsinogen to pepsin.
Pepsin is inactivated when it enters the intestine by the alkaline pH.
 Proteins are broken down further by pancreatic enzymes, such as trypsin,
chymotrypsin, carboxypeptidase, and elastase.
 As with pepsin, the pancreatic enzymes are secreted as precursor
molecules. Trypsinogen, which lacks enzymatic activity, is activated by an
enzyme located on the brush border cells of the duodenal enterocytes.
Activated trypsin activates additional trypsinogen molecules and other
pancreatic precursor proteolytic enzymes.
 The amino acids are liberated intramurally or on the surface of the villi by
brush border enzymes that degrade proteins into peptides that are one, two,
or three amino acids long. Similar to glucose, many amino acids are
transported across the mucosal membrane in a sodium-linked process that
uses the Na+/K+- ATPase pump as an energy source.
 Starvation is a state of overall
deprivation of nutrients. Its causes may
be the following:
 I) deliberate fasting—religious or political;
 II) famine conditions in a country or
community;
 III) secondary undernutrition such as due
to chronic wasting diseases (infections,
inflammatory conditions, liver disease),
cancer etc.
 Cancer results in malignant cachexia as
a result of which cytokines are
elaborated e.g. tumour necrosis factor-α,
elastases, proteases etc.
 A starved individual has lax, dry skin,
wasted muscles and atrophy of internal
organs.
  Anorexia nervosa
 1. Pathogenesis Isabelle Caro
 a. Self-induced starvation leading to PEM
 b. Distorted body image
 2. Clinical findings:
 a. Secondary amenorrhea
 1) Decreased gonadotropin-releasing hormone
 • Caused by excessive loss of body fat and weight
 2) Decreased serum gonadotropins produces
hypoestrinism.
 b. Osteoporosis
 1) Caused by hypoestrinism
French model
and actress
 • Estrogen normally enhances osteoblastic activity and
Isabelle Caro inhibits osteoclastic activity,
 2) Lack of estrogen leads to decreased osteoblastic
activity and increased osteoclastic activity.
 c. Increased lanugo (fine, downy hair)
 d. Increased hormones associated with stress (e.g.,
cortisol, growth hormone)
 e. Most common cause of death is ventricular
arrhythmia
 Ex-model Frail
Jeremy
Gillitzer has
suffered from
anorexia for
25 years.
 He now

weighes only
41.275 kg
Bulimia nervosa
1. Pathogenesis
• Bingeing with self-induced
vomiting
2. Clinical findings:
a. Complications of vomiting
1) Acid injury to tooth enamel
2) Hypokalemia and metabolic alkalosis
b. Ventricular arrhythmia is the
must common cause of death.
 PROTEIN-ENERGY MALNUTRITION
 The inadequate consumption of protein and energy as a
result of primary dietary deficiency or conditioned deficiency
may cause loss of body mass and adipose tissue, resulting
in protein energy or protein calorie malnutrition (PEM
or PCM).
 The primary deficiency is more frequent due to
socioeconomic factors limiting the quantity and quality of
dietary intake, particularly prevalent in the developing
countries of Africa, Asia and South America. The impact
of deficiency is marked in infants and children.
 The spectrum of clinical syndromes produced as a result of PEM
includes the following:
 1. Kwashiorkor which is related to protein deficiency though calorie
intake may be sufficient.

 2. Marasmus is starvation in infants occurring due to overall lack of

calories.
 However, it must be remembered that mixed forms of
kwashiorkor-marasmus syndrome may also occur. Marasmic
kwashiorkor (edematous, severe childhood malnutrition) is a
combination of chronic energy deficiency and chronic or acute
protein deficiency.
 1. Pathogenesis
a. Inadequate protein intake
b. Adequate caloric intake consisting mainly of carbohydrates
c. Protein in liver and other organs (i.e., visceral protein) is
decreased.
d. Muscle protein (i.e., somatic protein)
is relatively unchanged.
 2. Clinical findings:
a. Pitting edema and ascites
 • Caused by hypoalbuminemia
and loss of plasma oncotic pressure.
b. Fatty liver
1) Caused by decreased synthesis of apolipoproteins.
2) Apolipoprotein B-100 is required for assembly and secretion
of very low density lipoproteins (VLDLs) in the liver.
c. Diarrhea - caused by loss of the brush border enzymes and
parasitic infections
d. Anemia and defects in cell-mediated immunity (CMI)
Erosions and scaling in kwashiorkor.
1. Pathogenesis
a. Dietary deficiency of both protein and
calories
b. Decrease in somatic protein (muscle
protein)
2. Clinical findings:
a. Extreme muscle wasting ("broomstick
extremities")
1) Breakdown of muscle protein for
energy;
2) Loss of subcutaneous fat;
b. Growth retardation; anemia; defects in
cell-mediated immunity (CMI)
c. Typically occurs in children younger than
1 y.o., who are deprived of breast-feeding
and do not have an adequate intake of
substitute nutrients.
 Feature Kwashiorkor Marasmus
Protein deficiency with sufficient Starvation in infants with overall
Definition
calorie intake lack of calories
Clinical Occurs in children between 6 months Common in infants under 1 year of
features and 3 years of age age
Growth failure Growth failure
Wasting of muscles but preserved Wasting of all tissues including
adipose tissues muscles and adipose tissues
Oedema, localised or generalised,
Oedema absent
present
Enlarged fatty liver No hepatic enlargement
Serum proteins low Serum proteins low
Anaemia present Anaemia present
‘Flag sign’—alternate bands of light
Monkey-like face, protuberant
(depigmented) and dark (pigmented)
abdomen, thin limbs
hair
Morphology Enlarged fatty liver No fatty liver
Atrophy of different tissues and
Atrophy of different tissues and
organs but subcutaneous fat
organs including subcutaneous fat
preserved
Holodomor
 Gout is a syndrome caused by an
inflammatory response to uric acid
production or excretion resulting in high
levels of uric acid in the blood
( hyperuricemia ) and in other body
fluids, including synovial fluid.
Manifested by the following features,
occurring singly or in combination:
1. Increased serum uric acid concentration (hyperuricaemia).
hyperuricaemia
2. Recurrent attacks of characteristic type of acute arthritis in which crystals of
monosodium urate monohydrate may be demonstrable in the leucocytes present
in the synovial fluid.
3. Aggregated deposits of monosodium urate monohydrate (tophi) tophi in and
around the joints of the extremities.
4. Renal disease involving interstitial tissue and blood vessels.
5. Uric acid nephrolithiasis.
nephrolithiasis
6 . Other factors include age (rare before 30 years), genetic predisposition (X-linked
alteration of enzyme hypoxanthine-guanine phosphoribosyltransferase
[HGPRT]),
[HGPRT] excessive alcohol consumption,
obesity, certain drugs (especially thiazides),
thiazides
and lead toxicity.
 When the uric acid reaches a certain
concentration in fluids, it crystallizes,
forming insoluble precipitates that
are deposited in connective tissues
throughout the body.

Crystallization in synovial fluid

causes acute, painful inflammation
of the joint, a condition known as
gouty arthritis.
With time, crystal deposition in
subcutaneous tissues causes the
formation of small, white nodules,
or tophi, that are visible through
the skin. Crystal aggregates deposited
in the kidneys can form urate renal
stones and lead to renal failure.
In classic gouty arthritis, monosodium urate
crystals form and cause joint inflammation.
Pseudogout is caused by the formation
of calcium pyrophosphate dihydrate (CPPD)
crystals. The effect of either crystal is the same—
the onset of a cytokinemediated acute
inflammatory response.
 Carbohydrates must be broken down into monosaccharides, or single
sugars, before they can be absorbed from the small intestine.
 The average daily intake of carbohydrate in the American diet is
approximately 350 to 400 g. Starch makes up approximately 50% of this
total, sucrose (i.e., table sugar) approximately 30%, lactose (i.e., milk
sugar) approximately 6%, and maltose approximately 1.5%.
 Digestion of starch begins in the mouth with the action of amylase.
Pancreatic secretions also contain an amylase. Amylase breaks down
starch into several disaccharides, including maltose, isomaltose, and α-
dextrins. The brush border enzymes convert the disaccharides into
monosaccharides that can be absorbed.

Dietary Carbohydrates Enzyme Monosaccharides Produced

Lactose Lactase Glucose and galactose
Sucrose Sucrase Fructose and glucose
Starch Amylase Maltose, maltotriase, and α-dextrins
Maltose and maltotriose Maltase Glucose and glucose
α-Dextrins α-Dextrimase Glucose and glucose
 Sucrose 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, experience 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 way of a sodiumdependent carrier
system that uses adenosine triphosphate and the Na+/K+-ATPase pump as an
energy source.
 Water absorption from the intestine is linked to absorption of osmotically active
particles, such as glucose and sodium. It follows that an important consideration in
facilitating the transport of water across the intestine (and decreasing diarrhea) after
temporary disruption in bowel function is to include sodium and glucose in the fluids
that are taken.
 • 1.  To the liver.  Here excess sugar 
To the liver
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 fills the 
"Sugar Central" between meals.

• 2.  To the brain.  The brain is 
To the brain
completely dependent upon sugar 
combustion for its supply of energy, 
in any case under normal 
conditions. It uses really huge 
amounts of sugar.
•    3.  To muscles and fat tissue.  At 
. 
least 40% of the body is comprised of 
skeletal muscles. These can use both 
fats and sugar to supply energy. 
•The rate of sugar uptake and burning 
follows physical activity; more work; 
more sugar burned. 
• Muscles do take up and store 
Muscles
glucose to cover future activity but 
they cannot release sugar back to the 
blood stream or "Sugar Central". 
•Fat tissue stores surplus sugar as 
Fat tissue 
fat.  About half of this comes from the 
liver, the rest is made by fat itself.
 Regulation of glucose metabolism
 The glucose concentration in
blood describes carbohydrates
metabolism both of healthy man
and sick. Illnesses base of which
is disorder of carbohydrates
metabolism can flow with rise of
glucose concentration in blood
and with lowering of it.
 Rise of glucose concentration
is named hyperglicemia
lowering hypoglicemia .
 For example, hyperglicemia is
very typical for diabetes mellitus,
hypoglycemia – for
glycogenosis. 
 Impairments of glucose balance

Normal glucose level in the blood 65 -110 mg/%

3.85 - 6.05 mmol/L
(5.5 mmol/L)
• Hypoglycemia (less than 2.5 mmol/L results in coma)
• Hyperglycemia

3.85 6.05
Hypoglycemia NORM Hyperglycemia

GLUCOSE
 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 its utilization

( cortisol, growth hormone)

4. Stimulate gluconeogenesis
( cortisol, thyroid, glucagon)
5. Activate insulinase
 Hypoglycemia

Exogenous
Functional
Endogenous
 Exogenous
hypoglycemia
• Insulin injection

• Alcohol (develops 6-36 hours

after heavy consumption)

• Some drugs (e.g. salicylates)

• Long term physical exercise

 Endogenous
hypoglycemia
 insulinoma (hyperplasia
of β-cells)
 glycogenosis
 hereditary fructose intolerance
 insufficiency in
phosphoenolpyruvate
carboxykinase
Islet blood flow during hyperglycemia and hypoglycemia.
Images taken at peak fluorescence intensity in the same
islet under experimental design 1 during hyperglycemia (A
(A)
 Hepatocellular insufficiency and hypoglycemia (B (B) or under experimental design 2
during hypoglycemia (C (C) and hyperglycemia (D
(D).

 Impaired absorption
Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo 
Lara R. Nyman , Eric Ford , Alvin C. Powers , David W. Piston / American Journal of
Physiology - Endocrinology and MetabolismPublished 1 April 2010Vol. 298no. E807-
E814DOI: 10.1152/ajpendo.00715.2009
 Functional Hypoglycemia
1. Alimentary (after gastrectomy, demping syndrome)
2. Spontaneous reactive (cause is not known → diarrhea,
tachycardy, tremor, headache, weakness)
3. Alcohol (consumption in hungry state)
4. Endocrine insufficiency (decrease in counter-insulin
hormone ↓)
5. Hepatic failure
6. Malnutrition
7. Heavy physical load (without carbohydrate uptake)
8. Transient functional hypoglycemia of children
• Neonatal (10%)
• Maternal diabetes
• Erythroblastosis
• Ketogenic
 Manifestations of hyperglycemia
 Glucosuria
 Polyuria
 Polydypsia
 Hypohydration of the organism
 Arterial hypotension

Manifestations of hypoglycemia
 Starvation
 Tremor
 Excessive sweating
 Tachycardia
 Headache, dizziness
 Impaired vision
 Anxiety, fear
 Impaired cognition
 • Diabetes mellitus is not a single disease but a 
group of clinically heterogeneous disorders that
have glucose intolerance in common. It
encompasses many causally unrelated diseases and
includes many different etiologies of disturbed
glucose tolerance.

• The term diabetes mellitus is used to describe a 
syndrome characterized by chronic 
hyperglycemia and other disturbances of 
carbohydrate, fat, and protein metabolism.
 Classification
 Primary DM – (primary - no other disease)
 Type I – IDDM / Juvenile – 10%. (absolute insulin deficiency)
Subtype 1A (immune-mediated) DM characterised by autoimmune destruction
of β-cells which usually leads to insulin deficiency.
Subtype 1B (idiopathic) DM characterised by insulin deficiency with tendency
to develop ketosis but these patients are negative for autoimmune markers.
 Type II – NIDDM /Adult onset – 80%.
(insulin resistance with an insulin secretory deficit)
 MODY (Maturity-onset diabetes of the young) – 5% maturity
onset - Genetic (other specific types)
 Gestational Diabetes
 Secondary DM – (secondary to other dis.)
 Pancreatitis, tumors, hemochromatosis.
 Infectious – congenital rubella, CMV.
 Endocrinopathy.
 Drugs – Corticosteroids.
The criteria for the diagnosis of diabetes include
symptoms, elevated fasting plasma glucose
(FPG) concentration, and/or abnormal oral
glucose tolerance test (OGTT).

Two conditions associated with a high risk for

diabetes, impaired fasting glucose (IFG) and
impaired glucose tolerance (IGT), are considered
prediabetes.
 Normal Pancreatic Islet:
ß α

ß cells (Insulin) α cells (Glucagon)

δ cells (Somatostatin) pp Cells (pan prot)
 Type-I
 Less common
 Age < 25 Years
 Insulin- Dependent
 Onset: Weeks
 Acute Metabolic
complications
 Autoantibody: Yes
 Family History: No
 Insulin levels: very low
 Islets: Insulitis
 50% in twins
Type-II
 More common
 Adult >25 Years
 Insulin Independent *
 Months to years
 Chronic Vascular
complications
 No
 Yes
 Normal or high *
 Normal / Exhaustion
 60-80% in twins
Insulin-dependent diabetes mellitus
 Insulin-dependent diabetes 
mellitus arises as result of
absolute insulin insufficiency.
 It is described by
insulinopenia and by
inclination to ketoacidosis.
 This diabetes occur more
frequently is in children and
young peoples (till 30 years).
 Insulin is needed for
sustentation of patient life.
Attached to it’s absence
ketoacidic coma develops.
 Carbohydrate metabolism in normal conditions and
diabetes mellitus
INSULIN

1. Increase in permeability of myocyte and adipocyte membranes

for glucose (Glut-4)
2. Increase in activity of glucokinase, glycogen-sythetase, aerobic

IMPAIRMENT
glycolysis, pentose-phosphate shunt and Krebs cycle enzymes
3. Increased rate of glycogen synthesis in liver
4. Increase in synthesis of lipids from glucose
5. Inhibition of gluconeogenesis

HYPERGLYCEMIA
 Forms of insulin-dependent
diabetes mellitus

 Autoimmune – DR3
 Virus-induced – DR4
 Maturity-onset diabetes of the young

• Chr. – 2 HNF4a (MODY I ) - Hepatic Nuclear

factor 4 α gene
• Chr.-7 glucokinase (MODY I I )
• Chr.-11, 12 HNF1a (MODY I I I ) - Hepatic
Nuclear factor mutation
• Mitochondrial DNA mutations, other genetic
defects
 Genetic
HLA-DR3/4 Environment
Viral infe..? Autoimmune Insulitis
1. Drugs, chemicals Ab to ß cells/insulin
(streptozotocin, alloxane,
pentamidine)
2. Dietary (cow milk, high
nitrosamine levels) ß cell
3. Viruses (Coxsackie, measles) Destruction
(molecular mymicry)

Type I / IDDM Insulin deficiency

 PATHOGENESIS OF DIABETES MELLITUS

Insulin insufficiency

Fatty acids ↑
Blood glucose level ↑
Ketone bodies ↑

β - hydroxybutirate, acetoacetate glucosuria

accumulation in blood

Metabolic polyuria
acidosis Ketonuria
dehydration→ Poly-
Kussmaul's CNS depression thirst ↑ dipsia
respiration
SHOCK
Hypovolemia
 Autoimmune insulin-dependent
diabetes arises in persons with genome 
DR3. It is associated with other
autoimmune endocrinopathies, for
example, with illnesses of thyroid gland
(autoimmune thyroiditis, diffuse toxic
goiter), adrenal gland (Addison’s
disease).
 This diabetes type develops in any age
more frequent in women.
 Autoimmune is diabetes described by
presence in blood of patient
autoantibodies against of Langergans
islets.
• Virus-induced insulin-dependent diabetes mellitus binded
with genome DR4 and different from autoimmune on
mechanisms of development. In this case there are no 
autoantibodies against islets of pancreas. Its certainly can
appear in blood but rapidly (pending of year) disappear. They
do not perform essential role in pathogenesis of illness.
• Development of this
diabetes type frequently
precede from viral
infectious epidemic
parotitis, german
measles, measles,
viral hepatitis.
• Pathogenic viruses
action is not specific. It
consists in development
of inflammatory process
in Langergans islets.
Insulitis arises.
Lymphoid infiltration of
damaged islets develops
at first after then
• Sometimes the specific (immune) destruction mechanisms of β-
cells are linked. The viruses pervert antigen membranes
properties of affected β-cells and are followed with attack of
autoimmune mechanisms.
• There is one more possibility. Membrane β-cells is lightly
damaged by much chemical substances even in insignificant
concentrations.
• Such substances are called
β-cytotoxic. They are, for
example, alloxane and
streptosocine. They create
a favourable background for
immediate viruses action on
membrane of β-cells.
• Virus-induced diabetes
arises early before 30 years
of life. It is identically
widespread and among
males, both among women.
 Insulin-independent diabetes mellitus
 This diabetes type principle differs from the first.
 Patients, as a rule don’t need to exogenic insulin.
 Metabolic disorders attached to this diabetes are
minimal. Diet therapy and per oral glucose
decreasing medicines are sufficiently for their
compensation.
 Only in stress (trauma action, sharp infection)
conditions patient use insulin.
 Illness can course for years without hyperglycemia.
Sometimes it is disclosed in age more 40 years.
 There are three factors group, which play a decisive
role in forming of this diabetes type. Here are:

the genetic functional disturbance insulin

factors of β-cells resistance
 Genetic factors determine
hereditary liability to disease.
Specific genetic marker (special
diabetogenic gene) is not found.
It is known only, that inclination
to insulin-independent diabetes
is not coupled with major
complex of histocompatibility.
 Function of β-cells of patient
with insulin-independent
diabetes is violated. Amount of
them is diminished. Attached to
loading by glucose they do not
multiply insulin secretion in
necessary amount.
Diabetologist connects these
violations with amyloidosis of
Langergans islets.
 Pathogenesis of Type II DM
Genetic /
Obesity /
ß cell defect
Life style ?

Abnor. Secretion
Insulin Resistance

Relative
IDDM Insulin Def.
ß cell
exhaustion
Type II NIDDM
 Insulin-resistance
• Insulin-resistance arises or on genetic base or as result of influence
of external factors (risk factors). Biological insulin action is mediated
over receptors. They are localized on cells-targets membranes
(myocytes, lypocytes). Interaction of insulin and receptor is followed
with changes of physical state of cells-targets membrane.
• As result of this transport system is activated, which carries glucose
over cellular membrane.
• Transmembrane moving of
glucose is provided by proteins-
transmitters.
• Amount of glucose carried in cell
depends on closeness of insulin
receptors on membrane and on
receptor affinity to insulin. These
parameters depend on insulin level in
blood.
• Hyperinsulinemia diminishes
amount of receptors and their
affinity to insulin.
Hypoinsulinemia on the
contrary multiplies amount of
receptors and their affinity to
 •  Chronic resistance of insulin
receptors causes a chronic
hyperfunction of β-cells and surplus
production of insulin. This in turn
raises receptor resistance. Thus arises
a vicious circle. Protracted loading of
β-cells conduces to exhaustion of their
functions.
 About 4% pregnant women develop
DM due to metabolic changes during
pregnancy. Although they revert back to
normal glycaemia after delivery, these
women are prone to develop DM later in
their life.

Mitochondrial DNA is inherited maternally

and encodes several genes in the oxidative
phosphorylation pathway, ribosomal RNAs, and 22
transfer RNAs (tRNAs). In rare cases, (<1%),
diabetes is associated with point mutations in a
mitochondrial tRNA gene, tRNALeu(UUR).
Mitochondrial diabetes is caused by a primary
defect in β-cell function. Recall that ATP is
required for insulin secretion in β cells, and
impairment of mitochondrial ATP synthesis results
in decreased insulin secretion.
1. Genetic defects of b-cell 3. Exocrine
5. Endocrinopathies
function pancreatic defects
• Acromegaly
Maturity-onset diabetes of the • Chronic pancreatitis
young (MODY), caused by • Cushing syndrome
• Pancreatectomy
mutations in: • Hyperthyroidism
• Neoplasia
• Hepatocyte nuclear factor 4a • Pheochromocytoma
• Cystic fibrosis
[HNF-4a] (MODY1) • Glucagonoma
• Hemachromatosis
• Glucokinase (MODY2) • Fibrocalculous
• Hepatocyte nuclear factor 1a pancreatopathy 6. Genetic
[HNF-1a] (MODY3) syndromes
• Insulin promoter factor [IPF-1] 4. Drugs associated with
(MODY4) • Glucocorticoids diabetes
• Hepatocyte nuclear factor 1b • Thyroid hormone • Down syndrome
[HNF-1b] (MODY5) • α-interferon • Kleinfelter syndrome
• Neurogenic differentiation • Protease inhibitors • Turner syndrome
factor 1 [Neuro D1] (MODY6) • β-adrenergic
• Mitochondrial DNA mutations agonists 7. Infections
• Thiazides • Cytomegalovirus
2. Genetic defects in insulin
• Nicotinic acid • Coxsackie virus B
processing or insulin action:
• Phenytoin
• Defects in proinsulin conversion
8. Gestational Diabetes Mellitus
• Insulin gene mutations
• Diabetes associated with pregnancy
• Insulin receptor mutations
 IMPAIRMENT OF LIPID METABOLISM IN DIABETES MELLITUS

Insulin deficiency

Decreased glucose utilization

Decreased lipogenesis

Mobilization of fats to depoes

Hyperlipidemia

Metabolic acidosis Increased ketogenesis and

cholesterol productoin

Ketonemia and Ketonuria

hypercholesterolemia
Loss of Na+

Keto-acidotic coma
IMPAIRMENT OF PROTEIN METABOLISM IN DIABETES MELLITUS

Insulin deficiency

Decreased glucose utilization

Increase in proteolysis

Aminacidemia, increased uptake of aminoacids by the liver

1. Activation of gluconeogenesis

2. Increased removal of nitrogen via urea

Loss of potassium and other ions by the cells

Dehydration of the Potassium loss by the

cells organism
Symptoms of diabetes mellitus
Major symptoms are:
• hyperglycemia,
• glucosuria and
• polyuria.
Pathogenesis of diabetes mellitus
symptoms
  In healthy man practically has not
glucose in urine. It is excreated in
Glucosuria amount not more 1 g. Attached to
sugar diabetes amount of excreted
glucose increases repeatedly.
 If glucose concentration in blood and
primary urine does not exceed 9
mmol/l, epithelium of canaliculi
reabsorbed it. This maximum
concentration is called nephritic
threshold. 10 mmol/L
 If a glucose concentration exceeds a
nephritic threshold (9 mmol/l), part of
glucose goes in secondary urine
(glucosuria).
 Chronic hyperglycemia

Increased RBF (hyperperfusion)

Renal vasodilation Increased Protein glycation

intraglomerular
capillary pressure
Increased GFR
Hypertension
Increased protein excretion

Microalbuminuria Glomerular damage

Macroalbuminuria • Loss of negative charge
• Glomerulosclerosis
• Thickening of basement membrane
• Mesangial expansion

RBF - Renal blood flow Decreased GFR and renal failure

GFR - Glomerular filtration rate
 Polyuria
• Glucose is osmotic active
substance.
• Increasing of it’s concentration in
primary urine raises osmotic
pressure.
• Water is exuded from organism
together with glucose (osmotic
diuresis).
• Patient excretes 3-4 L of urine per
day, sometimes till 10 L.
PATHOGENESIS OF HYPERGLYCEMIC COMA

Insulin deficiency

Decreased glucose utilization

Increased glucose production

Hyperglycemia

Glucosuria

Osmotic diuresis

Hyperosmolarity and dehydration

DIC syndrome

COMA DEATH SHOCK

 Complication of diabetes mellitus

The very frequent

diabetes complications
are following:
♦ ketoacidosis,
♦ macroangiopathy,
♦ microangiopathy, angiopathy
♦ neuropathy.
 Ketoacidosis. In healthy peoples synthesis of
ketone bodies in liver is strictly controled. Main
regulatory mechanism is access limitation of fat
acids in mytochondries of hepatocytes. Over head
permissible concentration limit of ketone bodies in
blood is approximately 0,1 mmol/L.
 In case of exceeding this level regulatory
mechanisms are stated. Foremost ketone bodies
put specific receptors back up on membrane β-cells
of Langergan’s islets. Insulin excretion in blood
increases. Insulin stimulates resynthesis of fat acids.
First stage of resynthesis is derivation of malonil-
CоА. Surplus amount of malonil-CоА oppresses
penetration of fat acids in mytochondries. Synthesis
of ketone bodies slows.
 Attached to diabetes mellitus disturb mechanism of
both synthesis regulation of ketone bodies – both on
level of β-cells, and on level of hepatocytes.
Receptor stimulation of β-cells by ketone bodies
does not cause increased excretion insulin in blood.
 In conditions of insulinopenia fat acids penetrate in
hepatocytes in unrestricted amount. Liver
synthesizes many ketone bodies. Extrahepatic
tissues can not utilize them. Amount of ketone
bodies in blood increases. Metabolic acidosis occur.
It can complete by ketoacid coma.
 Seldom attached to diabetes mellitus lactoacidosis
occur. It is attached to insulin-independent diabetes
mellitus, attached to combination of diabetes with
hypoxia, sepsis, shock.
 Macroangiopathy
 Macroangiopathy is vessels atherosclerosis
of cerebrum, heart, kidneys, legs. Diabetes
lead to atherosclerosis development.
 There are three acceleration way of
atherogenesis in patients with diabetes. In
conditions of insulin insufficiency growth
hormone synthesis increases. Here upon
proliferation of smooth myocites accelerates
key stage of atherogenesis. Attached to
diabetes vessels endothelium damages.
 Synthesis of thromboxane increase, and this
helps to adhesion of thrombocytes.
Thrombocytes excret mitogene thrombocytic
growth factor (TGF). It also stimulates
proliferation of smooth myocytes.
 Attached to diabetes concentration of
lipoproteids low density, increase
concentration of lipoproteids of high density.
• Microangiopathy develop in shallow vessels
– arterials, venues, capillaries. Two process
form their pathogenic base – thickining of
basal membrane and reproduction
endothelium.
• Direct cause of microangiopathy is
hyperglycemia and synthesis of glycoproteids
in basal membrane.
• There are two main clinical forms
microangiopathy: diabetic retinopathy
diabetic nephropathy
 A composite photograph showing a pretreatment fundus photograph (A), and a
photograph demonstrating radiation retinopathy at 24 months (B). A fluorescein
angiogram demonstrates intraretinal microangiopathy next to the tumour (C), and
regression to chorioretinal scar after laser photocoagulation (D).
 Neuropathy
• Neuropathy manifest
by violation of nerves
function sensible,
motor, vegetative.
Essence of these
decreases is
demyelinisation of
nervous fibres,
decrease of
axoplasmatic flow.
• This is hereditary
illness. In it’s base lies
an blockade of
galactose metabolism.
In organism
intermediate
metabolits accumulate.
• There are two the main
forms of galactosemia
on base of:
 transferase
insufficiency and
galactokinase
insufficiency.
 Deficit of glucose-1-phosphat
uridyltransferase.
• This enzyme converts galactose-1-phosphate in glucose-1-phosphate.
Attached to it’s insufficiency galactose-1-phosphate and sugar alcohol
of galactose (galactit) accumulates in tissues lens of the eye, liver,
brain, kidneys. Mammal and cow milk contains lactose.
• Therefore the illness symptoms appear with first days of child life.
• Diarrhea, vomiting, dehydrotation occur.
• Liver increases (splenomegalia). Hepatocytes lose ability to conjugate
bilirubine. Children become yellowish.
• Affection of kidneys displays in proteinuria, aminoaciduria and
acidosis.
• For galactosemia cataract is very typical. Their beginnings related to
accumulation of osmotic active galactite in vitreous bodies of eyes.
Galactite absorb in water, and water breaks tissues.
• Dangerous consequences arise in the brain. This foremost is delay of
mental development.
• Mortal end is possible.
• Cure method is diet without galactose.
 Deficit of galactokinase.
 Attached to this illness
variant a process of
phosphorilation of galactose
is blocked, that is
transformation of galactose in
galactose-1-phosphat. Illness
displays in cataracts.
 Other symptoms are absent
or minor. Cure is diet without
galactose.
 GLYCOGENOSIS
 Type І – Girke disease . Deficit of glucoso-6-
phosphatase
 Type ІІ – Pompe disease . Deficit of acidic maltase
(α-1,4-glucosidase)
 Type ІІІ – Cori disease , Forbs disease . Deficit of
amylo-1,6- glucosidase
 Type ІV – Anderson disease . Deficit of amylo-
1,4,1,6-transglucosidase
 Type V – McArdel disease Deficit of phosphorilase
of myocytes
 Т ype VІ – Hers disease . Deficit of phosphorilasic
complex in liver
 Т ype VІІ. Deficit of muscle phosphofructokinase
• Simple carbohydrates deposit in organism as polysaccharides.
• In muscles and liver accumulates glycogen. It consist of 4 % of liver
weight and 2 % of muscles weight.
• Muscles glycogen is used as of ready fuel source for immediate
guaranteeing by energy. Liver – without interruption provides cerebrum
and erythrocytes with glucose .
• Synthesis and splitting of glycogen are exactly adjusted and coordinated
processes. Attached to immediate need in glucose α–cells of pancreas
secret glucagone. It activates adenylatcyclase of hepatic cells.
• Adenilatcyclase stimulates derivation of cAMP. Under action of cAMP
takes place activation of proteinkinase and this enzyme raises activity
glycogenphosphorilase and oppresses activity of glucogensynthase.
Here upon starts intensive glycogenolysis. Supplementary amount of
glucose is secreted in blood.
• In other situation after consuming of carbohydrates in blood
accumulates surplus of glucose. β-cells of pancreas multiply insulin
synthesis. Insulin raises activity of glycogensyntase. Active
glucogenesis starts too. Surplus of glucose reserves in appearance of
glucogen in liver and muscles.
• There are illnesses in base of which is accumulation of glycogen in
organs. They are called glycogenoses.
glycogenoses All of them are hereditary
enzymopathy. There are seven main types of glycogenoses.
 Glycogenosis type I – Girke’s disease.
• Girke’s disease cause deficit of
glucose-6-phosphatase. This
enzyme provides 90 % of glucose
which disengages in liver from
glycogen. It play central role in normal
glucose homeostasis. Glucose which
disengages attached to disintegration
of glycogen or is derivated in process
of gluconeogenesis obligatory goes
over stage of glucose-6-phosphate.
• Enzyme glucose-6-phosphatase tears
away a phosphate group from glucose.
There free glucose is formed it goes
out in blood. Attached to Girke’s
disease stage of tearing phosphate
group is blocked. There are no free
glucose hypoglycemia occur.
Hypoglycemia arises. Attached to
Girke’s disease glycogen is deposed in
liver and kidneys.
 Glycogen Storage Disorders:
• Type 1= Von Gierke’s:
– Shortly after birth: Severe lifethreatening Hypoglycemia
– Lactic acidosis –due to isolated glycolysis of G6Po
– Hyper-uricemia, hyper lipidemia
– Increased association with epistaxis
– *Hepatomegaly
– **Adverse response to Glucagon with worsening Lactic acidosis
• Management requires IV glucose, and then as output,
close NG corn-starch or glucose solution administration
to achieve close to nl glucose homeostasis.
• Frequent snacks and meals. Continuous nighttime
glucose infusions up to the age of 2.
 Type ІІ glycogenosis – Pompe’s disease.
• Illness is related to
deficit of lysosomal
enzyme – sour
maltase, or α-1,4-
glucosidase.
• This enzyme slits
glycogene to glucose
in digestive vacuoles.
Attached to it’s deficit
glycogen
accumulates at first in
lysosomes and
then in cytosole of
hepatocytes and
myocytes.
 Type 2- Pompe’s disease:
• Normal Glucose
• Do to an accumulation of
glycogen in lysosomes.
• **Ancient city of Pompeii was destroyed
by Mt. Vesuvius- 79 AD**

• Manifested by massive
Cardiomegaly, Hepatomegaly,
Macroglossia.
• Fatal If results in CHF.
• Limited therapies in Neonatal
Variant.
– Attempts at enzyme replacement
ongoing.
 Type ІІІ glycogenosis –
Cori’s disease,
Forbs’ disease
 This illness is named Glycogen in Muscle Cells
limited ecstrinosis. In
it’s base lies a deficit of Glycogen in the Liver (left stained
amylo-1,6-glucosidase. to show glycogen, right normal)
 Degradation of
glycogen pauses in
sites of branching.
 Glycogen
accumulates in liver
and muscles. Cure is
diet with big proteins
maintenance.
 Type ІV glycogenosis –
Anderson’s disease.
• It is called by deficit of amilo-
1,4,1,6-transglucosidase
(branching enzyme).
• As result of this there is derivated
anomalous glycogen with very
long branches and rare points of
branching. It is not exposed to
degradation and accumulates in
liver, heart, kidneys, spleen,
lymphatic nods, skeletal
muscles.
• It’s cause is deficit of phosphorilase
of myocytes. Typical pain displays in
muscles after physical loading.
• Glycogene does not slit only in
muscles. Here it accumulates. In liver
mobilization of glycogen comes
normal.
• Illness arises as result of insufficiency of
hepatic phosphorilase complex.
• Glycogen accumulates in liver.
• Typical sign is hepatomegalia.
• Type VІІ glycogenosis. Illness
essence is in oppression of muscle
phosphofrutkinase. Symptoms are
similar to McArdles disease.
disease
1. ROBBINS BASIC PATHOLOGY / [edited by] Vinay Kumar, Abul K. Abbas, Jon
C. Aster. – 9th ed. – 2013.
2. Kathryn L. McCance . Pathophysiology: the biologic basis for disease in adults
and children / [edited by] Kathryn L. McCance, Sue E. Huether; section editors,
Valentina L. Brashers, Neal S. Rote - 6th ed. – 2010.
3. Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L.
Banasic // Elsevier Inc. – 2010.
4. General and clinical pathophysiology. Edited by prof. A.V. Kubyskin. Simferopol.
– 2011.
5. Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth,
Glenn Matfin.– New York, Milwaukee. – 2009.
6. Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott
Williams & Wilkins), Trade paperback (2003) / Carol Mattson Porth, Kathryn J.
Gaspard. Chapter 32
7. Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme.
Stuttgart. New York. – 2000.
8. Symeonova N.K. Pathophysiology / N.K. Symeonova // Kyiv, AUS medicine
Publishing. – 2010.