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Defining the essence of the disease
"The disease - it is a complex overall reaction to the damaging effects of environmental
factors; this is a new process of life, accompanied by structural, metabolic and functional changes
as a destructive and adaptive nature in tissues and organs, leading to a decrease in the body's
adaptability to ever-changing environmental conditions and to limit disability "AD Ado (2009).
Pathological reactions, pathological process, pathological condition
Pathological response - short-term, an unusual reaction to any impact. For example, a
transient increase in blood pressure under the influence of negative emotions, allergies, inadequate
psycho-emotional and behavioral reactions, abnormal reflexes (reflexes Rossolimo, Babinski et al.).
The pathological process - a combination of (complex) pathological and protective-adaptive
reactions in the affected tissues, organs or body, manifested in the form of morphological,
metabolic and functional disorders.
Formed and fixed in the process of evolution permanent combination or combinations of
various pathological processes and pathological reactions of individual cells and tissues are called
typical pathological processes. These include inflammation, fever, hypoxia, edema, and other tumor
Pathologic process underlies the disease, but it is not.
Differences between the pathological process of the disease:
1. The disease is always one main reason (producing a specific etiological factor), the disease
process is always polyetiological. For example, inflammation (disease process) may be caused by
the action of a variety of mechanical, chemical, physical and biological factors, and malaria can not
occur without the action of Plasmodium falciparum.
2. One and the same pathological process might result in different patterns of disease,
depending on the location, in other words, a place of localization of the pathological process
determines clinic disease (pneumonia - pneumonia, inflammation of the meninges - meningitis, an
inflammation of the heart muscle - myocarditis, etc.).
3. The disease usually - a combination of several pathological processes. For example, when
there is a lobar pneumonia combination (in relation) of pathological processes such as
inflammation, fever, hypoxia, acidosis, and others.
4. The pathological process is not accompanied by a decrease in the body's adaptability and
ability to work limitation (warts, lipoma, atheroma, etc.).
Pathological state - slowly (sluggish) current pathological process. It may be as a result of
past illnesses (eg, narrowing of the esophagus scar after burn injury, false joints, condition after
kidney resection, amputation, etc.) or as a result of violations of fetal development (clubfoot, flat
feet, a defect of the upper lip and palate and etc.). It's kind of ended up the process, which resulted
in persistently changed body structure having atypical replacement in certain tissues or parts of the
body. In some cases, a pathological condition may go again in the pathological process (illness). For
example, pigmented skin (birthmark) when exposed to a number of mechanical, chemical and
physical (radiation) factors can be transformed into a malignant tumor melanosarkoma.
1. Normal carbohydrates metabolism
Carbohydrates may be in form of monosaccharides, disaccharides, oligosaccharides (up to 6
monosaccharide residues) and polysaccharides (glycogen, starch). Depending on the carbohydrate
atomic number in monosaccharide molecule one distinguishes trioses, tetroses, pentoses, hexoses
and etc. Carbohydrates form compounds with proteins (glycoproteins and proteoglycanes), lipoids
(glycolipids) and other substances (heteromonosaccharides). Pentoses (included in the composition
of nucleic acid and coenzyme, NADP in particular) and hexoses (glucose, fructose, galactose) are
widely spread in the body.
On average, around 40-45 % of dietary calories are derived from carbohydrates. In а young
adult rа1е, for ехаmр1е, this represents about 300-350 g which is mainly in the form of starch
(plant sources) and glycogen (animal sources); in addition there mау be significant аmоunts оf the
disaccharides sucrose and lactose.
Carbohydrate Digestion and Absorption
Hydrolysis of glycogen and starch starts in the mouth under the influence of alfa-amilase of
saliva. Monosaccharides can be absorbed in the mouth. In the stomach there are no enzymes which
hydrolyze carbohydrates. In the duodenum and in the small intestine under the influence of alfaamilase they get hydrolyzed down to dextrine and maltose (cavity digestion). Such enzymes as
saccharase, maltase, lactase, isomaltase and et cetera are localized on the surface of microvilli
which split dextrines and disaccharides down to monosaccharide.
Glucose is the most important source of energy for most tissues.
In the postprandial state excess glucose is converted to both glycogen (glycogenesis) and
triglycerides (lipogenesis), and stored as such. In the fasting, or starvation, state the lack of
exogenous glucose is overcome by production of endogenous glucose by gluconeogenesis
(formation of glucose from amino acids, lactate and glycerol) and glycogenolysis (glycogen
breakdown). The major regulators of these metabolic processes are insulin and the counterregulatory hormones: glucagon, cortisol аnd catecholamines.
This is the metabolic pathway by which glucose is oxidised to pyruvate with the production of
2 АТР molecules. The control of this process is соmрlех but the main factors are insulin, which
enhances, and glucagon, which suppresses. Futher oxidation of pyruvate produces а further 36
molecules of АТР.
This process, which occurs in the liver аnd renal соrtех during glucose-starved states,
produces glucose from pyruvate which is in turn derived from protein (а1аninе) аnd lactate. It is an
energy-requiring process. Glycerol, an end-product of triglyceride breakdown, can also be convered
to glucose.
Тhе process occurs during fasting so that
predominant glucose-requiring tissues (brain, red
ce11s, etc) have а ready supply of energy. The
main controllers are insulin (which inhibits),
glucagon (which stimulates), and cortisol (which
stimulates the process by mobilising muscle
amino acids).
Glycogenesis and glycogenolysis
Glycogen synthesis (glycogenesis) from
glucose occurs during а plentiful glucose supply
Fig 1.Glucose metabolism in normal
(fed state). It is stimulated by insulin (by its
action on glycogen synthetase) and inhibited by
glucagon. The breakdown of glycogen to glucose-6-phosphate (glycogenolysis) occurs during
glucopenic states and is stimulated by glucagon and catecholamines and inhibited by insulin.
The hepatic glycogen stores represents а readily convertible source of glucose for а11 tissues glycogen is broken down to glucose-6-phosphate which is then converted to glucose by glucose-6phosphatase. Because muscle tissues lack the latter еnzуmе, glucose is not produced from muscle
glycogen. Rather, glycogen is соnvеrtеd to lactate which can then be transported to the liver to be
соnvеrtеd to glucose via gluconeogenesis, а process known as the Cori сус1е. These glycogen
stores are limited and are depleted after 18-24 hours of fasting.
Fatty acid β-oxidation
The conversion of fatty acids to асеtyl-СоА with the production of energy is referred to as βoxidation and takes р1асе in the mitochondria. It occurs during glucopenic states and plays an
important role in energy supply for many tissues during fasting. The acetyl-СоА can either enter the
citric acid (ТСА) сус1е and produce more energy (АТР) or mау be diverted to the production of
ketone bodies which are а major source of energy for the brain during prolonged fasting.
The formation of ketone bodies (acetoacetate, β-hydroxybutyrate and acetone) from асеtylСоА occurs almost exclusively in the liver although the rеnа1 соrtех is also сараble of ketogenesis.
Ketogenesis is раrt of а normal metabolic response to starvation. The aim is to switch energy
production from carbohydrate (glucose) to fat whereby: In the absence of exogenous fuels, energy
derived mainly from fat аnd ketogenesis is broug into р1ау to conserve tissue protein.
Carbohydrate metabolism regulation
For the continuity of the process of glycolysis and Crab's cycle glucose should be delivered
continuously to the tissues. It is possible due to a constant level of glucose (3,3-5,5 mmol/lit) in the
blood, which in physiological conditions never decreases to a critical level. Glucose level in the
blood can be identified by the speed of endogenic glucose production on the one hand and by the
speed of glucose utilization on the other. Several types of regulation of carbohydrate metabolism
can be distinguished: substrate, nervous, hormonal and renal.
Substrate regulation. Substrate regulation is realized according to the level of glycemia,
increasing or decreasing the synthesis of glycogen or glycogenolysis in the liver.
Nervus regulation. The irritation of the sympathetic nervous system results in increase of
level of glucose in the blood, and that of parasympathetic causes decrease ones.
Hormonal regulation. Insulin and counter-regulatory hormones
Insulin, secreted by the β-cells of the pancreas in response to а high blоod glucose. It is
produced as proinsulin. This is transported into the Golgi соmрlех where it is proteolysed to form
the biologically inactive C-peptide and active native insulin, both of which are secreted in
equimolar amounts. Glucose is the most important stimulus for insulin secretion but it can also be
stimulated by physiological concentrations of amino acids, ketone bodies, fatty acids, acetylcholine,
and adrenaline.
Insulin circulates in the plasma and acts by binding to insulin receptors present on most cells
of the body. Once bound, insulin works through a protein kinase messenger system to cause an
increase in the number of glucose-transporter molecules present on the outside of the cell
membrane. The glucose-transporter molecules, called glut-4 glucose transporters, are necessary for
the facilitated diffusion of glucose into most cells. When glucose is carried into the cell, it results in
decreased blood levels of glucose, reducing further stimulation of insulin release.
Insulin is the major anabolic (building) hormone of the body and has a variety of other effects
besides stimulating glucose transport. It also increases amino acid transport into cells, stimulates
protein synthesis, and inhibits the breakdown of fat, protein, and glycogen stores. Insulin also
inhibits gluconeogenesis. In summary, insulin serves to provide glucose to our cells, build protein,
and maintain low plasma glucose levels.
Counter-regulatory hormones.
This group of hormones are so саllеd because they oppose the action of insulin and excess
production of аnу of them results in hyperglycaemia. They are 'starvation hormones' which are
саllеd into рlау when exogenous glucose intake is 1ow and consequently stimulate the production
of glucose from glycogen (glycogenolysis) аnd protein (gluconeogenesis), аnd generation of energy
from fatty acids via β-oxidation.
Glucagon. This straight chain polypeptide is secreted by the α-cells of the pancreas in
response to hypoglycaemia (and inhibited by hyperglycaemia). Its main action is to increase glucose
release by the liver but, in association with а 1ow insulin, it also stimulates free fatty acid release
and increases ketogenesis. In summary, glucagon stimulates glycogenolysis, gluconeogenesis, βoxidation of fatty acids and ketogenesis; and inhibits glycogenesis, fatty acid synthesis
(lipogenesis), and glycolysis.
Cortisol. Cortisol, secreted by the adrenal соrtех, increases glucose production by:
а. Decreasing glucose and amino acid uptake by muscle;
b. Mobilising muscle protein to increase delivery оf amino acids to the liver for
с. Increasing gluconeogenesis.
Catecholamines. Adrenaline (аnd to а lesser extent noradrenaline) is secreted by the adrenal
mеdullа and the sympathetic nerve endings in response to hypoglycaemia. In the context of glucose
metabolism, catecholamines:
а. Increase release of fatty acids from adipose tissue
b. Stimulate glycogen degradation to glucose
с. Inhibit cellu1ar glucose uptake
d. Stimulate glucagon secretion аnd depresses insulin secretion.
The еnd result is increased glucose production by the liver.
Growth hormone. The relationship between growth hormone and glucose metabolism is
unclear but excessive secretion, as in acromegaly, is often associated with hyperglycaemia. Growth
hormone secretion responds to the blood glucose 1evels -hyperglycaemia suppresses, аnd
hypoglycaemia stimulates, secretion.
Renal regulation
Concentration of glucose in the blood and speed of glomerular filtration and the functional
condition of kidney affects on glucose reabsorption. If glycemia is more than 8,8-9,9 mmol/L (180
mg %) it results in glucosuria (kidney threshold).
So different stages of carbohydrate metabolism are controlled by a compound complex of
stimulators and inhibitors.
The liver and glucose metabolism
Glucose is transported into the hepatocyte by аn insulin-independant process аnd
phosphorylated to glucose-6-phosphate by the enzymes hexokinase and glucokinase. Further
metabolic processes dереnd оn the prevailing nutritional status and the action of the counterregulatory hormones (glucagon, growth hormone, cortisol, catecholamines). In the fed state, and
resultant high insulin activity, anabolic activities predominate with glucose entering several
metabolic ventures:
↑ glycogen synthesis and  glycogen breakdown ↑ glycogen storage
↑ fatty acid and triglyceride synthesis  fat storage
inhibition оf gluconeogenesis protein conservation
During starvation, as а result of relative insulinoреniа and increased activity of the counterregulatory hormones, the liver reverts into а glucose-producing organ. The immediate stimulus for
this activity is а 1ow insulin, glucagon ratio аnd increased cortisol and catecholamine activity,
which result in:
↓ glycogen synthesis and ↑ glycogen breakdown ↑ glucose
↑ glucose formation from protein (gluconeogenesis)
↓ fatty acid аnd triglyceride synthesis from glucose and ↑
breakdown of fat stores (1ipolysis)  energy аnd ketone bodies
2. Disfunction of caborhydrates metabolism
Disfunction of caborhydrates metabolism occurs due to a disorder of any of its main stages:
1. Breakdown and absorption of carbohydrates in the digestive tract.
2. Function of carbohydrate metabolism in the liver and extrahepatic tissues.
3. Utilisation of carbohydrates by the cells.
4. Disorders of neuro humeral regulation of carbohydrate metabolism
A disturbance of one stage of carbohydrate metabolism or of regulating mechanism causes
dysfunction of carbohydrate metabolism which is manifested in a change of glucose concentration
in blood. (hypo- or hyperglycemia), glycogenoses, aglycogenoses, pentose-, hexosemias.
Disorder of digestion and absorption of carbohydrates in the digestive tract
Disorder of digestion and absorption of carbohydrates may result from congenital or acquired
deficiency of one or more enzymes. Causes, mechanisms of development and consequences of
disorder of carbohydrates digestion and absorption are represented in the table 7.
Disaccharides block the place of absorption so that absorption of monosaccharides gets
disturbed. Let’s look at the pathology of disaccharide deficiency on the example of children with
congenital deficiency of lactase.
Undigested lactose enters the large intestine and gets split by the bacteria down to organic
acids (lactic acid, acetic acid). The increase of lactose and organic acids changes osmotic pressure
in the lumen of the intestine followed by an increase in fluid secretion and the volume of fecal
masses, the intestinal peristaltics increases, and osmotic diarrhea develops. At the same time the H+
ions which are formed by the splitting of organic acids enter the blood circulation and cause
acidosis. To remove the excess of H+ ions the lungs take part; the condition is manifested by an
increase of the concentration of oxygen in the expired air.
Tabl 7. Disorders of splitting and absorbtion carbohydrates
Changes in the
Hydrolysis of food
The inflammation and tumours of mucous
Disorder nervous and humoral
membranes of mouth, pancreas, intestines; fever;
regulation of gastroenteric tract
overheating; dehydration; resection of intestines;
(disorder peristaltics, stress, deficiency
hereditary enzymopathies; disorder of the
of insulin, glucocorticoids, thyroid
peristaltics of intestines
hormones); some poisoning
Deficiency of hydrolytic enzymes (amilase,
Disorder of splitting and
maltase, lactase)
phosphorylation of carbohydrates
Consequences are carbohydrate starvation, hypoglycemia, decrease in synthesis of the
glycogen in a liver and muscles, lose of weight owing to mobilization of fat from fatty depot,
intensifying of fermentation processes in thick intestines at fault of splitting. The
compensation reactions are activation of glucogenesis, gluconeogenesis, lipolysis
Due to the disorder of absorption of carbohydrates in the intestine of children hypoglycemia
and hypotrophy develops.
In physiological conditions glucose gets absorbed very fast in the small intestine because of
the existence of passive diffusion, easy transport and active transfer due to the energy which is
released by the ATP hydrolysis. All other sugars like mannose, xilose, arabinose get absorbed only
by passive diffusion. That’s why glucose and galactose get absorbed faster than the other
monosaccharides. The functional condition of gastrointestinal tract, the content of food products,
vitamins, microelements and etc. influence the absorption of carbohydrates. The absorption of
glucose decreases abruptly due to disturbance of its phosphorylisation in the cells of the intestinal
wall. The main cause of the given disorder is hexokinase enzyme deficiency which develops due to
inflammation of the intestinal wall or poisoning by: phloridizin, monoiodacytate. Due to
malabsorption of carbohydrates hypoglycemia and loss of body weight occur as fats and protein are
consumed for the synthesis of glucose by gluconeogenesis. In the intestine the unsplit carbohydrates
are metabolised by the bacteria which cause osmotic diarrhea.
3. Disorder of intermediate carbohydrate metabolism.
The cause. Disorders of blood circulation, hypoxia, lesion of liver by infection and toxin,
disorders of hormone regulation (insulin, glucagon, catecholamins, somatotropinum,
glucocorticoids, thyroxine), deficiency of vitamin В1, hereditary enzymopathy, heavy muscular
Pathogeneses. Disorders of glycolysis, glycogenesis, glycogenolysis, gluconeogenesis. Brake
dawn of the oxidation in liver and other organs at deficiency of enzymes.
Disorders of glycogen metabolism.
Glycogen disintegration increases in stress conditions, emotional strain (activation of
sympathetic nervous system), heavy physical work, starving, increase of hormonal activation
(glucagon, adrenalin) which stimulates glycogenolysis, diabetic ketoacidosis.
Due to a decrease of glycogen in the organism hypoglycemia is observed and energy
metabolism is provided for by metabolism of fats and proteins (glyconeogenesis). And this results
in accumulation of ketone bodies, ketoacidosis, intoxication and loss of plastic material by cells.
Aglycogenoses are inherited disorders characterized by low levels or absence of glycogen in the cell.
Aglycogenoses are caused by mutations in genes coding the enzymes of glycogen synthetic pathway, for
example, glycogen synthetase.
Glycogen storage diseases. If the breakdown of glycogen is blocked, glycogen overloading
and hypoglycemia result. This is caused by enzyme deficiencies. Considerable increase of glycogen
synthesis causes its excessive accumulation in the organs and in cells and their damage. It happens
in glycogenosis (glycogenic disease) where the congential enzyme deficiency takes place which
catalises the disintegration or synthesis of glycogen. Glycogenoses are inherited according to the
autosomal-recessive type. Usually they appear soon after birth.
To date 12 types of glycogenosis are described. Some of them have been very rare. Depending
on the primary effects of the enzyme deficiencies and pathogenesis of glycogenoses, one can
simplify the classification by dividing the glycogen storage diseases into liver (hepatic) types,
muscle (myopathic) types and other (miscellaneous) types . In the liver types hepatomegaly (due to
excess deposition of glycogen) and hypoglycemia are the prominent features, while in the muscle
types it is largely energy deficiency. Physicalwork does not increase plasma lactate and leads to
rapid fatigue, muscle cramps and muscle pain as well as to myoglobinuria, which may cause renal
The ketosis
The impairment intermediate carbohydrate metabolism results in ketosis manifestating the
increase of the level of ketonic bodies in the blood (ketonemia) and their release [excretion] in large
amount with urine (ketonuria). Ketonic bodies are group of organic compounds being intermediate
products of fat, carbohydrate and protein metabolism.
The causes of ketosis
 carbohydrate deficiency in the organism. Diabetes mellitus, fasting, fatty diet with a limited
quantity of carbohydrates (the people of the Far North are adjusted to it), fever, hard physical work
lead to the reduction of glycogen supply in the liver. Glucose utilization is impaired due to insulin
deficiency and energy deficiency develops in tissues. The stimulation of lipolysis occurs, the excess
of free fatty acids reaches the liver [saturated fatty acids] where synthesis of ketonic bodies
increases but utilization of acetyl-CoA in tricarbonic acid cycle is inhibited due to carbohydrate
deficiency since all metabolically available resources of the organism are converted into glucose,
hence, ketosis develops.
 stress during which carbohydrate resources of the organism are depleted due to the
activation of sympathetic nervous system and as a result ketosis develops. In addition during stress
albuminolysis results from the increase of glucocorticoid production and ketonic bodies are formed
from ketogenic amino acids;
 liver injury by toxic and infectious factors. This disturbs its ability to synthesize and store
glycogen, excessive supply of free fatty acids occurs in the liver.
 vitamin E deficiency inhibits oxidation of higher fatty acids;
 suppression of oxidation of ketonic bodies in Crab’s cycle is observed in hypoxic hypoxia,
impairment of carbohydrate oxidation in tissues (diabetes), excess of ammoniac salts (hepatic and
uremic coma).
 glycogenesis type I, II, and IV (see above). A deficient supply of glucose from the liver to
the blood leads to its deficiency in tissues and to the impairment of oxidation of ketonic bodies;
 resynthesis impairment of ketonic bodies in higher fatty acids in deficiency of hydrogen
sourses, essential for hydrogenation of β-keto- and unsaturated fatty acids;
 acetonic poisoning (occurs seldom);
 aminoacidopathies with metabolism impairment of branched-chain amino acids;
 alcoholic intoxication during which ketosis mechanisms are combined since chronic
alcoholics affected by alcoholic hepatopathy and pancreatitis do not take proper food while
consuming alcohol;
An acute form of ketosis leads to intoxication of the organism, to the impairment of
electrolytic balance due to loss of sodium with urine (sodium forms salts with acetoacetic and βhydroxybutyric acids) and to acidosis development
4. Disoders of carbohydrate metabolism regulation
Disorders of nerus or hormonal regulation are manifested as hyperglycemia or hypoglycemia.
A concentration of glucose in blood under 3,3 mmol/lit is called hypoglycemia. It requires an
immediate treatment, because hypoglycemia causes irreversible changes of the nervous cells; first it
disturbs the function of cortical layer of the brain then of midbrain (cerebral hypoglycemia).
2 types of hypoglycemia exist: physiological and pathological hypoglycemia.
Physiological hypoglycemia can be seen in a healthy person due to an increased muscular
work, where utilization of glucose is increased as a source of energy; neonatal hypoglycemia is a
hypoglycemia of new born babies, especially when the body mass is less than 2500 gr.
Hypoglycemia can be a result of pathological changes:
 over dose of insulin during the treatment of diabetes;
 increased production of insulin due to hyperfunction of pancreas (hyperplasia, insulinoma);
 deficiency of hormones promoting catalysis of carbohydrates: STH, trioxine, adrenalin,
 glycogen splitting deficiency in glycogenesis;
 mobilization of great amount of glycogen from liver;
 liver cell damage;
 disturbed absorption of carbohydrates in the intestine.
Clinical features. The clinical manifestations are due to activation of the autonomic nervous
system (adrenergic) and deprivation of the brain of glucose (CNS dysfunction, neuroglycopenic).
When the sugar level decreases to 3-4 mmol/lit symptoms like tachycardia, tremor resulting
from compensatory hyperproduction of adrenalin, feeling of hunger (low level of sugar in blood
stimulates the ventrolateral nucleus of hypothalamus) develop. The following symptoms develop
due to dysfunction of the nervous system: weakness, irritation, feeling of fear, with the increase of
hypoglycemia. These symptoms are accompanied by a decrease of sensitivity. Sometimes even
hallucinations occur. In hypoglycemia the use of oxygen by the brain sharply decreases so long and
frequent periods of hypoglycemia cause irreversible changes of the nervous cells. First the function
of cortical layer of brain is disturbed then that of the midbrain (serebral hypoglycemia) is disturbed
A concentration of glucose less than 2,5 mmol/L causes dysfunction of the central nervous
system. A decrease of oxydising processes and metabolic disorders in the brain cause the loss of
vascular tonus, vasodilatation of microcirculatory system, the increase of their penetration. Cerebral
oedema, epileptical cramps and hypoglycemic coma may develop. Cramps have a compensatory
character as they help splitting muscular glycogen and due to this from the produced lactic acid the
liver syntheses glucose and the sugar level in the blood increases.
Hyperglycaemia is increase of the concentration of glucose in blood more than 5,6 mmol/L
(or 120 mg/dl).
Hyperglycaemia may be physiological and pathological.
Physiological hyperglycaemia has an accommodative function as it provides the delivery of
easily utilized energy material to the tissues. Physiological hyperglycaemia arises after eat
(alimentary hyperglycaemia) and at emotional states.
A Pathological hyperglycaemia results from disturbance of carbohydrate metabolism and
accompanies varies diseases.
Diabetes mellitus
Diabetes mellitus (Greek diabaio – go through) according to the International Commission of
Experts on diagnostics and classification of diabetes mellitus in 1997: it is a group of metabolic
diseases, characterized by HYPERGLYCEMIA which is the result of insulin deficiency or an effect
of insulin, or both these combined factors.
It takes the 1st place in endocrine pathology and the 3rd place in death rate (after cardiac
diseases and oncological diseases).
The following types of diabetes mellitus are distinguished:
Primary diabetes mellitus (95%)
Type I: Insulin-dependent diabetes mellitus (IDDM)
Type II: Non-insulin-dependent diabetes mellitus (NIDDM)
Impaired glucose tolerance: IGT (latent diabetes)
Gestational diabetes mellitus1
Secondary diabetes mellitus (5%)
Destructive pancreatic disease
Endocrine diseases
Drug-induced diabetes
Stress diabetes1
Type 1 diabetes mellitus (T1DM), formerly known as insulin-dependent (IDDM) or juvenileonset diabetes, is caused by autoimmune destruction of the insulin-producing β-cells in the
pancreatic islets of Langerhans, and affects less than 10% of all patients with diabetes. By contrast,
type 2 diabetes mellitus, formerly known as non insulin-dependent (NIDDM) or maturity-onset
diabetes, is typically associated with obesity and results from a complex interrelationship between
resistance to the metabolic action of insulin in its target tissues and inadequate secretion of insulin
from the pancreas
Secondary diabetes mellitus
Drug-related. Some drugs (e.g., glucocorticoids, nicotinic acid, sympathetomimetic drugs) can
cause hyperglycaemia by producing tissue insensitivity to insulin; others (e.g., thiazide diuretics and
phenytoin), by inhibiting insulin secretion.
Non-pancreatic endocrine disease: Excessive production of the 'anti-insulin' hormones such as
growth hormone (acromegaly), cortisol (Cushing's syndrome), and catecholamines
(phaeochromocytoma) mау result in hyperglycaemia and indeed produce а diabetic picture.
Pancreatie disorders: Decreased insulin secretion and secondary diabetes mellitus mау be
associated with раrtiа1 pancreatectomy, chronic pancreatitis, аnd haemochromatosis.
Stress: Stress (physical аnd psychogenic) increases the secretion of а number of hormones,
including cortisol and the catecholamines, which mау induce fasting hyperglycaemia. However, the
blood glucose 1еvе1 reached is usually less than 10 mmо1/L. Неnсе 'stress-related' hyperglycaemia,
as mау occur during аn acute myocardial infarct, in excess of 10.0 mmо1/L usually indicates
underlying diabetes mellitus. Such patients should be appropriately re-evaluated after the period of
stress has resolved.
Type I diabetes mellitus (IDDM)
Etiology and pathogenesis of type – I diabetes. The exact cause of the disease is unknown but
it is thought to result from an infectious or toxic insult to the pancreatic islet cells.
Currently, the pathogenesis of type I diabetes is explained on the basis of 3 mutuallyinterlinked mechanisms, each with sufficient evidences in support. These are: genetic susceptibility,
autoimmunity, and certain environmental factors.
I. Genetic susceptibility. Diabetes mellitus runs in families has been known for years.
II. Autoimmunity. Type I diabetes is believed to be an autoimmune disease that results
inspecific immunologic destruction of β-cells of islet of Langerhans.
Cell-mediated immune mechanisms are fundamental to the pathogenesis of T1DM, and
cytotoxic T lymphocytes sensitized to β - cells in T1DM persist indefinitely, possibly for a lifetime.
III. Environmental factors. Epidemiologic studies in type I diabetes have revealed
involvement of certain environmental factors in its pathogenesis. These factors are certain viruses,
chemicals and common environmental toxins.
1.Certain viral infections may precede the onset of type I diabetes e.g. mumps, measles,
coxsackie В virus, cytomegalovirus and infectious mononucleosis.
2.Experimental induction of type I diabetes with certain chemicals has been possible e.g.
alloxan, streptozotocin and pentamidine.
3.Geographic variations in the incidence of type I diabetes suggest some common
environmental factors.
4.Patients transplanted with a donor pancreas or a preparation of purified islets must be treated
with immunosuppressive drugs. Ten percent of patients with T1DM manifest at least one other
organ-specific autoimmune disease, including Hashimoto thyroiditis, myasthenia gravis, Addison
disease, or pernicious anemia.
It can thus be summarised by interlinking the three mechanisms described above that in type I
diabetes, some “environmental factor" initiates the “autoimmune destruction” of β cells in
“genetically susceptible” individuals.
Clinical manifestion and metabolic desorders.
Type I diabetes usually manifests at early age, generally below the age of 40.
Characteristically, the plasma insulin levels are low and patients respond to exogenous insulin
therapy. The onset of symptoms is generally abrupt with polyuria, polydipsia and polyphagia. The
patients are not obese but have generally progressive loss of weight.
Because insulin is a major anabolic hormone in the body, a deficiency of insulin affects not
only glucose metabolism but also fat and protein metabolism. With insulin deficiency, the
assimilation of glucose into muscle and adipose tissue is sharply diminished or abolished. Not only
does storage of glycogen in liver and muscle cease, but also reserves are depleted by
glycogenolysis. Severe fasting hyperglycemia and glycosuria ensue. The glycosuria induces an
osmotic diuresis and thus polyuria, causing a profound loss of water and electrolytes (Na+, K+,
Mg++, PO4-. The obligatory renal water loss, combined with the hyperosmolarity resulting from the
increased levels of glucose in the blood, tends to deplete intracellular water, triggering the
osmoreceptors of the thirst centers of the brain. In this manner, intense thirst (polydipsia) appears.
With a deficiency of insulin, the scales swing from insulin-promoted anabolism to catabolism of
proteins and fats. Proteolysis follows, and the gluconeogenetic amino acids are removed by the liver
and used as building blocks for glucose. The catabolism of proteins and fats tends to induce a
negative energy balance and weight loss, which in turn leads to increasing appetite (polyphagia),
thus completing the classic clinical symptoms of diabetes. The combination of polyphagia and
weight loss is paradoxical and should always raise the suspicion of diabetes (or possibly
thyrotoxicosis). In patients with type 1 diabetes, regulation of glucose levels often requires multiple
daily injections of different types of insulins. Glucose control can be difficult to obtain (brittle
diabetes), in that the blood glucose level is quite sensitive to administered insulin, deviations from
normal dietary intake, unusual physical activity, infection, or other forms of stress. Inadequate fluid
intake or vomiting can rapidly lead to significant disturbances in fluid and electrolyte balance.
Therefore, these patients are vulnerable, on the one hand, to hypoglycemic episodes and, on the
other, to ketoacidosis. The insulin deficiency causes excessive breakdown of adipose stores,
resulting in increased levels of free fatty acids. Oxidation of free fatty acids within the liver through
acetyl coenzyme A produces ketone bodies (acetoacetic acid and β-hydroxybutyric acid). Glucagon
accelerates such fatty acid oxidation. The rate at which ketone bodies are formed may exceed the
rate at which acetoacetic acid and β-hydroxybutyric acid can be utilized by muscles and other
tissues, thus leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised
by dehydration, the plasma hydrogen ion concentration increases and systemic metabolic
ketoacidosis results. Release of ketogenic amino acids by protein catabolism aggravates the ketotic
state. Diabetic patients have increased susceptibility to certain types of infections. Because the
stress of infection increases insulin requirements, infections often precipitate diabetic ketoacidosis.
Type II diabetes
Type II diabetes, or maturity-onset diabetes, or noninsulindependent diabetes mellitus
(NIDDM); is more common and constitutes 80 - 90% cases of diabetes. Type II diabetes is further
of 2 subtypes - obese and non-obese.
Etiology and pathogenesis of type II diabetes.
The cause is unknown but the basic metabolic defect in this type of diabetes is either a delayed
insulin secretion relative to glucose load (deranged insulin secretion), or the peripheral tissues are
unable to respond to insulin (insulin resistance).
Though much less is known about the mechanisms involved in the pathogenesis of type II
diabetes, a number of factors have been implicated. HLA association and autoimmune phenomena
are, however, not involved. These factors are as under:
I. Genetic factors. Genetic susceptibility has a greater role in the pathogenesis of type II
diabetes than in type I diabetes. There is approximately 60-80% chance of developing diabetes in
the other identical twin if one twin has diabetes.
II. Obesity (Obese type II diabetes). Obesity is a common finding in type II diabetes. There is
impaired insulin sensitivity of peripheral tissues such as muscle and fat cells to the action of insulin
in obese individual’s insulin resistance).Weight reduction in such Obese patients produces
improvement in the diabetic state.
III. Insulin receptor defect (Non-obese type II diabetes). It has been observed that
insulinresistance is a factor not only in obese type II diabetes but also in non-obese type II diabetes.
In such individuals, the increased insulinresistance of peripheral tissues is due to either decrease in
the number of insulin receptors or there is post-receptor defect.
Thus, type II diabetes is a complex multi-factorial disease involving 'deranged insulin
secretion' and 'insulin resistance', with possible genetic defects, obesity and fault in the insulin
Clinical manifestion and metabolic desorders
This form of diabetes generally manifests in middle life or beyond, usually above the age of
40. The onset of symptoms in type II diabetes is slow and insidious. Generally, the patient is
asymptomatic when the diagnosis is made on the basis of glucosuria or hyperglycaemia during
physical examination. The patients are frequently obese and may present with polyuria, polydipsia,
unexplained weakness and loss of weight. In contrast to type I diabetes, plasma insulin levels in
type II diabetes are normal-to-high, though they are lower relative to the plasma glucose level i.e.
there is relative insulin deficiency. Metabolic complications such as ketoacidosis are infrequent.
Although patients with type 2 diabetes also have metabolic derangements, these are easier to
control and less severe. In the decompensated state, these patients develop hyperosmolar nonketotic
coma, a syndrome engendered by the severe dehydration resulting from sustained hyperglycemic
diuresis in patients who do not drink enough water to compensate for urinary losses. Typically, the
patient is elderly, is disabled by a stroke or an infection that increases hyperglycemia, and has
limited mobility and therefore inadequate water intake. The absence of ketoacidosis and its
symptoms (nausea, vomiting) often delays the seeking of medical attention in these patients until
severe dehydration occurs.
Complications of Diabetes
Both types of diabetes mellitus may develop complications which are broadly divided into 2
major groups:
I. Acute metabolic complications: These include diabetic ketoacidosis, hyperosmolar
nonketotic coma, and hypogiycaemia.
II. Late systemic complications: These are atherosclerosis, diabetic microangiopathy, diabetic
nephropathy, diabetic neuropathy, diabetic retinopathy and infections.
Diabetic coma is a very serious manifestation of diabetes. The cause of coma development can
be inadequate treatment of diabetes or some other concomitant diseases (trauma, operation, stress).
The main forms of diabetic coma are ketoacidotic, hyperosmolaric and lactoacidotic.
I. Ketoacidotic coma. It can develop in patients with severe insulin deficiency combined with
glucagon excess. Failure to take insulin and exposure to stress are the usual precipitating causes.
Once the rate of ketogenesis exceeds the rate at which the ketone bodies can be utilised by the
muscles and other tissues, ketonaemia and ketonuria occur. If urinary excretion of ketone bodies is
prevented due to dehydration, systemic metabolic ketoacidosis occurs. Clinically, the condition is
characterised by anorexia, nausea, vomitings, deep and fast breathing, mental confusion and coma.
Most patients of ketoacidosis recover.
II. Hyperosmolar Hyperglycemic Nonketotic Coma: Also called hyperosmolar non-acidotic
diabetes, hyperosmolar hyperglycemic nonketotic coma. Hyperosmolar nonketotic coma is usually
a complication of type II diabetes. It is caused by severe dehydration resulting from sustained
hyperglycaemic diuresis. The loss of glucose in urine is so intense that the patient is unable to drink
sufficient water to maintain urinary fluid loss. The usual clinical features of ketoacidosis are absent
but prominent central nervous signs represent. Blood sugar is extremely high and plasma osmolality
is high. Thrombotic and bleeding complications are frequent due to high viscosity of blood. The
mortality rate in hyperosmolar nonketotic coma is high.
III. Lactoacidotic Coma may develop at patient with diabetes accompanying diseases resulting
hypoxia e.g. cardiovascular diseases, diseases of the langs. In this case anaerobic pathway of
splitting of glucose will be prevalent and it result in accumulation of lactic acid.
IV. Hypoglycaemia, Hypoglycaemic Coma. Hypoglycaemic episode may develop in patients
of type I diabetes. It may result from excessive administration of insulin, missing a meal, or due to
stress. Hypoglycaemic episodes are harmful as they produce permanent brain damage and coma, or
may result in worsening of diabetic control and rebound hyperglycaemia, so called Somogyi's
Late systemic complications
A number of systemic complications may develop after a period of 15-20 years in either type
of diabetes. These late complications are largely responsible for morbidity and premature mortality
in diabetes mellitus.
1. Atherosclerosis. Diabetes mellitus of both type I and type II accelerates the development of
atherosclerosis so that consequent atherosclerotic lesions appear earlier than in the general
population, are more extensive, and are more often associated with complicated plaques such as
ulceration, calcification and thrombosis. The cause for this accelerated atherosclerotic process is not
known but possible contributory factors are hyperlipidaemia, reduced HDL levels, nonenzymatic
glycosylation, increased platelet adhesiveness, obesity and associated hypertension in diabetes.
The possible ill-effects of accelerated atherosclerosis in diabetes are early onset of coronary
artery disease, silent myocardial infarction, cerebral stroke and gangrene of the toes and feet.
Gangrene of the lower extremities is 100 times more common in diabetics than in non-diabetics.
2. Diabetic microangiopathy. Microangiopathy of diabetes is characterised by basement
membrane thickening of small blood vessels and capillaries of different organs and tissues such as
the skin, skeletal muscle, eye and kidney. Similar type of basement membrane-like material is also
deposited in nonvascular tissues such as peripheral nerves, renal tubules and Bowman's capsule.
The pathogenesis of diabetic microangiopathy as well as of peripheral neuropathy in diabetics is
believed to be due to recurrent hyperglycaemia that causes increased glycosylation of haemoglobin
and other proteins (e.g. collagen and basementmembrane material) resulting in thickening of
basement membrane.
3. Diabetic nephropathy. Renal involvementis a common complication and a leading cause of
death in diabetes. Four types of lesions are described in diabetic nephropathy:
i) Diabetic glomerulosclerosis which includes diffuse and nodular lesions of
ii) Vascular lesions that include hyaline arteriolosclerosis of afferent and efferent arterioles
and atheromas of renal arteries,
iii) Diabetic pyelonephritis and necrotising renal papillitis.
iv) Tubular lesions or Armanni-Ebstein lesion.
4. Diabetic neuropathy. Diabetic neuropathy may affect all parts of the nervous system but
symmetric peripheral neuropathy is most characteristic. The basic pathologic changes are segmental
demyelination, Schwann cell injury and axonal damage. The pathogenesis of neuropathy is not clear
but it may be related to diffuse microangiopathy as already explained, or may be due to
accumulation of sorbitol and fructose as a result of hyperglycaemia.
5. Diabetic retinopathy. Diabetic retinopathy is a leading cause of blindness. There are 2 types
of lesions involving retinal vessels: background and proliferative. Besides retinopathy, diabetes also
predisposes the patients to early development of cataract and glaucoma.
6. Infections. Diabetics have enhanced susceptibility to various infections such as tuberculosis,
pneumonias, pyelonephritis, otitis, carbuncles and diabetic ulcers. This could be due to various
factors such as impaired leucocyte functions, reduced cellular immunity, poor blood supply due to
vascular involvement and hyperglycaemia per se.
Metabolic Syndrome
Metabolic syndrome describes a combination of cardiovascular and metabolic characteristics
often associated with type 2 diabetes and macro- and microvascular pathology. According to the
World Health Organization (WHO), a diagnosis of the disorder is based on a combination of insulin
resistance plus two other factors that may include hypertension, high plasma triglycerides, low
levels of HDL cholesterol, central (or apple-shaped) obesity, microalbuminuria, or high urinary
albumin-to-creatinine ratio. The consequences of the syndrome are severe and include
atherosclerosis, cerebrovascular disease, myocardial infarction, renal failure, and other disorders
related to vascular impairment.
Diagnosis of Diabetes
Hyperglycaemia remains the fundamental basis for the diagnosis of diabetes mellitus. In
symptomatic cases, the diagnosis is not a problem and can be confirmed by finding glucosuria and a
random plasma glucose concentration above 250 mg/dl. The severity of clinical symptoms of
polyuria and polydipsia is directly related to the degree of hyperglycaemia. In asymptomatic cases,
when there is persistently elevated fasting plasma glucose level, diagnosis again poses no difficulty.
The problem arises in asymptomatic patients who have normal fasting glucose level in the plasma
but are suspected to have diabetes on other grounds and are thus subjected to oral glucose tolerance
test (GTT). If abnormal GTT values are found, these subjects are said to have 'chemical diabetes'.
The WHO has suggested definite diagnostic criteria for early diagnosis of diabetes mellitus.
The following investigations are helpful in establishing the diagnosis of diabetes mellitus:
I. URINE TESTING. Urine is tested for the presence of glucose and ketones.
1. Glucosuria.
The main disadvantage of relying on urinary glucose test alone is the individual variation in
renal threshold. Thus, a diabetic patient may have a negative urinary glucose test and a nondiabetic
individual with low renal threshold may have a positive urine test.
2. Ketonuria. Tests for ketone bodies in the urine are required for assessing the severity of
diabetes and not for diagnosis of diabetes. Uncontrolled diabetes, ketonuria may appear in
individuals with prolonged vomitings, fasting state or exercising for long periods. However, if both
glucosuria and ketonuria are present, diagnosis of diabetes is almost certain.
For diagnosis of diabetes, blood sugar determinations are absolutely necessary. A grossly
elevated single determination of plasma glucose may be sufficient to make the diagnosis of
diabetes. A fasting plasma glucose value above 250 mg/dl is certainly indicative of diabetes. In
other cases, oral GTT is performed.
The patient who is scheduled for oral GTT is instructed to eat a high carbohydrate diet for at
least 3 days prior to the test and comes after an overnight fast on the day of the test. A fasting blood
sugar sample is first drawn. Then 75 gm of glucose dissolved in 300 ml of water is given. Blood
and urine specimen are collected at half-hourly intervals for at least 2 hours. Blood or plasma
glucose content is measured and urine is tested for glucosuria to determine the approximate renal
threshold for glucose. Venous whole blood concentrations are 15% lower than plasma glucose
The previous criteria suggested by Fajans and Conn (1960) employing 4-5 test glucose
determinations have been revised upwards by the WHO in 1985, placing higher reliance on two test
glucose determinations. Individuals with fasting value of plasma glucose higher than 140 mg/dl and
2-hour value after 75 gm oral glucose higher than 200 mg/dl are labelled as diabetics, whereas those
with fasting and 2-hour plasma glucose value between 140 and 200 mg/dl are considered to have
'impaired glucose tolerance (IGT)' and are kept under observation for repeating the test later. During
pregnancy, however, a case of IGT is treated as a diabetic.