DIABETES MELLITUS - BIOCHEMISTRY

 Diabetes mellitus is the 3rd leading cause of
death in many developed countries.
 Diabetes is a major cause of blindness, renal
failure, amputation, heart attacks and stroke.
 Diabetes mellitus is a characterized by
increased blood glucose level
(hyperglycemia) due to insufficient or
inefficient (incompetent) insulin.

 Insulin is a polypeptide hormone produced
by the β-cells of islets of Langerhans of
pancreas.
 It influences the metabolism of
carbohydrate, fat & protein.
 It is an anabolic hormone, promotes the
synthesis of glycogen, triacylglycerols &
proteins.

 Human insulin (mol. wt. 5,7341) contains 51
amino acids, arranged in 2 polypeptide chains.
 A chain – 21 amino acids & B chain – 30 amino
acids.
 Both are held together by 2 interchain disulfide
bridges, connecting A7 to B7 & A20 to B19.
 There is an intrachain disulfide link in chain A
between the amino acids 6 & 11.

 The gene for insulin synthesis is located on
chromosome 11.
 The synthesis of insulin involves two
precursors, namely preproinsulin with 108
amino acids (mol. wt. 11,500) & proinsulin with
86 amino acids (mol. wt. 9,000).

 They are sequentially degraded to form the
active hormone insulin & a connecting
peptide (C-peptide).
 Insulin & C-peptide are produced in
equimolar concentration.
 C-peptide is biologically inactive.
 Its estimation is useful index for the
endogenous production of insulin.

 In the β-cells, insulin (also proinsulin)
combines with zinc to form complexes.
 In this complex form, insulin is stored in the
granules of the cytosol which is released in
response to various stimuli by exocytosis.

 Factors stimulating insulin secretion:
 Glucose & amino acids
 Gastrointestinal hormones – secretin, gastrin,
pancreozymin increase the secretion.
 Factors inhibiting insulin secretion:
 Epinephrine from adrenal medulla is most
potent inhibitor of insulin secretion.

 Insulin has a half-life of 4-5 minutes.
 About 40-50 units of insulin is secreted daily
human pancreas.
 The normal range of insulin: 20-30 μU/ml.
 A protease enzyme – insulinase degrades
insulin.
 Insulinase is mainly present in liver & kidney.

 Effects on carbohydrate metabolism:
 Insulin lowers blood glucose level by
promoting its utilization & storage & by
inhibiting its production.
 Effect on glucose uptake by tissues:
 Insulin is required for uptake of glucose by
muscle (skeletal, cardiac & smooth), adipose
tissue, leukocytes & mammary glands.

 About 80% of glucose uptake in the body is
not dependent on insulin.
 Effect on glucose utilization:
 Insulin increases glycolysis in muscle & liver.
 Insulin activates key enzymes of glycolysis –
glucokinase, PFK & pyruvate kinase.
 Glycogen production is increased, due to
increased activity of glycogen synthase by
insulin.

 Effect on glucose production:
 Insulin decreases gluconeogenesis by
suppressing the enzymes pyruvate
carboxylase, phosphoenol pyruvate
carboxykinase & glucose 6- phosphatase.
 Insulin also inhibits glycogenolysis by
inactivating the enzyme glycogen
phosphorylase.

 Effects on lipid metabolism:
 The net effect of insulin on lipid metabolism
is to reduce the release of fatty acids from
the stored fat & decrease the production of
ketone bodies.
 Adipose tissue is the most sensitive to the
action of insulin.

 Effect on lipogenesis:
 Insulin favours the synthesis of
triacylglycerols from glucose by providing
more glycerol 3-phosphate & NADPH.
 Insulin increases the activity of acetyl CoA
carboxylase, a key enzyme in fatty acid
synthesis.

 Effect on lipolysis:
 Insulin decreases the activity of hormone-
sensitive lipase & reduces the release of fatty
acids from stored fat.
 The mobilization of fatty acids from liver is
also decreased by insulin.
 Effect on ketogenesis:
 Insulin reduces ketogenesis by decreasing
the activity of HMG CoA synthetase.

 Effects on protein metabolism:
 It stimulates the entry of amino acids into the
cells, increases protein synthesis & reduces
protein degradation.
 Insulin promotes cell growth & replication.
 This is mediated through certain factors such
as epidermal growth factor (EGF), platelet
derived growth factor & prostaglandins.

 Insulin receptor mediated signal transduction:
 Insulin receptor:
 It is a tetramer consisting of 4 subunits – α2β2.
 The subunits are in the glycosylated form.
 They are held together by disulfide linkages.
 α – subunit (mol. wt. 135,000) is extracellular &
it contains insulin binding site.

 β – subunit (mw. 95,000) is a transmembrane
protein which is activated by insulin.
 The cytoplasmic domain of β – subunit has
tyrosine kinase activity.
 The insulin receptor is synthesized as a single
polypeptide & cleaved to α & β subunits which
are then assembled.
 Insulin receptor has a half-life of 6-12 hours.
 About 20,000 receptors/cell in mammals.

 Signal transduction:
 Insulin binds to the receptor, a conformational
change is induced in the α-subunits of insulin
receptor.
 This results in the generation of signals which
are transduced to β-subunits.
 The net effect is that insulin binding activates
tyrosine kinase activity of intracellular β-
subunit of insulin receptor.

 This causes the autophosphorylation of
tyrosine residues on β-subunit.
 Receptor tyrosine kinase also phosphorylates
insulin receptor substrate (IRS).
 The phosphorylated IRS, in turn, promotes
activation of other protein kinases &
phosphatases, finally leading to biological
action.

 Insulin-mediated glucose transport:
 The binding of insulin to insulin receptor signals the
translocation of vesicles containing glucose
transporters from intracellular pool to the plasma
membrane.
 The vesicles fuse with the membrane recruiting the
glucose transporters.
 The glucose transporters are responsible for the
insulin-mediated uptake of glucose by the cells.

 As the insulin level falls, the glucose
transporters move away from the membrane
to the intracellular pool for storage & recycle.
 Insulin mediated enzyme synthesis:
 Insulin promotes the synthesis of enzymes
such as glucokinase, PFK & pyruvate kinase.
 This is brought about by increased
transcription & translation.

 Glucagon, secreted by α-cells of the pancreas.
 It is a polypeptide hormone composed of 29
amino acids (mol. wt. 3,500) in a single chain.
 It is synthesized as proglucagon, on sequential
degradation releases active glucagon.
 Its amino acid sequence is the same in all
mammalian species & half-life. i.e. about 5
minutes.

 The secretion of glucagon is stimulated by
low blood glucose concentration, amino
acids derived from dietary protein & low
levels of epinephrine.
 Increased blood glucose level markedly
inhibits glucagon secretion.

 Glucagon enhances the blood glucose level
(hyperglycemic).
 Primarily, glucagon acts on liver to cause
increased synthesis of glucose & enhanced
degradation of glycogen.

 Effects on lipid metabolism:
 Glucagon promotes fatty acid oxidation
resulting in energy production & ketone
body synthesis.
 Effects on protein metabolism:
 Glucagon increases the amino acid uptake
by liver & promotes gluconeogenesis.

 The maintenance of glucose level in blood
within narrow limits is a very finely &
efficiently regulated system.
 It is essential to have continuous supply of
glucose to the brain.

 Following a meal, glucose is absorbed from
the intestine and enters the blood.
 The rise in blood glucose level stimulates the
secretion of insulin.
 The uptake of glucose by most extrahepatic
tissues, except brain is dependent on insulin.
 Insulin helps in the storage of glucose as
glycogen or its conversion to fat.

 Normally, 2 to 2½ hours after a meal, blood
glucose level falls to near fasting levels.
 It may go down further; but this is prevented
by processes that contribute glucose to the
blood.
 For another 3 hours, hepatic glycogenolysis
will take care of the blood glucose level.

 Thereafter gluconeogenesis will take charge
of the situation.
 Liver is the major organ that supplies the
glucose for maintaining blood glucose level.
 Glucagon, epinephrine, glucocorticoids,
growth hormone, ACTH & thyroxine will keep
the blood glucose level from falling.
 They are referred to as antiinsulin hormones
or hyperglycemic hormones.

 Random blood sugar
 Fasting blood sugar
 Post-prandial blood sugar
 Hyperglycemia
 Hypogycemia
 Glucose is estimated by GOD/POD or
hexokinase method.

 Insulin:
 It is produced in response to hyperglycemia.
 Some amino acids, free fatty acids, ketone
bodies, drugs such as tolbutamide also cause
the secretion of insulin.
 It is hypoglycemic hormone that lowers in
blood glucose level.

 Glucagon:
 Hypoglycemia stimulates its production.
 It increases blood glucose concentration.
 It enhances gluconeogenesis & glycogenolysis.
 Epinephrine:
 It is secreted by adrenal medulla.
 It acts on muscle & liver to bring about
glycogenolysis by increasing phosphorylase
activity.

 Thyroxine:
 It is a hormone of thyroid gland.
 It elevates blood glucose level by stimulating
hepatic glycogenolysis & gluconeogenesis.
 Glucocorticoids:
 Glucocorticoids increases gluconeogenesis.
 The glucose utilization by extrahepatic tissues is
inhibited by glucocorticoids.
 The overall effect of glucocorticoids is to elevate
blood glucose concentration.
 GH & ACTH also increases blood glucose.

 A fall in plasma glucose less than 50 mg/dl is
called as hypoglycemia.
 Hypoglycemia is life-threatening.
 The manifestations include headache,
anxiety, confusion, sweating, slurred speech,
seizures & coma, and, if not corrected, death.

 Post-prandial hypoglycemia:
 This is also called reactive hypoglycemia & is
observed in subjects with an elevated insulin
secretion following a meal.
 This causes transient hypoglycemia & is
associated with mild symptoms.
 The patient is advised to eat frequently rather
than the 3 usual meals.

 Fasting hypoglycemia:
 Fasting hypoglycemia is not very common.
 It is observed in patients with pancreatic β-
cell tumor & hepatocellular damage.
 Hypoglycemia due to alcohol intake:
 Alcohol consumption causes hypoglycemia
 This is due to the accumulation of NADH,
which diverts pyruvate & oxaloacetate to
form lactate & malate.

 Finally gluconeogenesis is reduced due to
alcohol consumption.
 Hypoglycemia due to insulin overdose:
 The most common complication of insulin
therapy in diabetic patients is hypoglycemia.
 This is particularly observed in patients who
are on intensive treatment.

 Diabetes mellitus (DM) is a metabolic disease
due to absolute or relative insulin deficiency.
 DM is a common clinical condition.
 It is a major cause for morbidity & mortality.
 Mainly two types.
 Type 1 diabetes mellitus (T1DM).
 Type 2 diabetes mellitus (T2DM).

 Also known as IDDM or (less frequently)
juvenile onset diabetes, mainly occurs in
childhood (between 12 -15 years age).
 IDDM accounts for about 10 to 20% of the
known diabetics.
 Characterized by almost total deficiency of
insulin due to destruction of β-cells.

 The β-cell destruction may be caused by drugs,
viruses or autoimmunity.
 Due to certain genetic variation, the β-cells are
destroyed by immune mediated injury.
 Symptoms of diabetes appear when 80-90% of
the - β cells have been destroyed.
 The pancreas ultimately fails to secrete insulin
 The patients of IDDM require insulin therapy.

 Also called as non-insulin dependent diabetes
mellitus (NIDDM).
 Accounting for 80 to 90% of diabetic population.
 NIDDM occurs in adults (above 35 years) & is
less severe than IDDM.
 The causative factors of NIDDM include genetic
& environmental.
 NIDDM commonly occurs in obese individuals.

 Gestational diabetes mellitus (GDM):
 This term is used when carbohydrate intolerance is
noticed, for the first time, during a pregnancy.
 A known diabetic patient, who becomes pregnant, is
not included in this category.
 Glucose challenge test (GCT) is done between 22 & 24
weeks of pregnancy by giving an oral glucose load
of 50 g of glucose regardless of the time.
 If the 2-hour post-glucose value is >140 mg/dl, the test
is positive.

 Impaired glucose tolerance (IGT):
 Also called as Impaired Glucose Regulation (IGR).
 Plasma glucose values are above the normal level, but
below the diabetic levels.
 In IGT, the FBS value is 110 & 126 mg/dl & PPBS value is
between 140 & 200 mg/dl.
 Requires careful follow-up because IGT progresses to
frank diabetes at the rate of 2% patients per year.

 Impaired fasting glycemia (IFG):
 In this condition, fasting plasma glucose is
above normal (between 110 & 126 mg/dl); but
the 2 hour post-glucose value is within
normal limits (less than 140 mg/dl).
 These persons need no immediate treatment;
but are to be kept under constant check up.

 Secondary to other known causes:
 Endocrinopathies (Cushing's disease,
thyrotoxicosis, acromegaly)
 Drug induced (steroids, beta blockers, etc.)
 Pancreatic diseases (chronic pancreatitis,
fibrocalculus pancreatitis, hemochromatosis,
cystic fibrosis).

 The diagnosis of diabetes can be made on
the basis of individual's response to the oral
glucose load, commonly referred to as oral
glucose tolerance test (OGTT).
 Preparation of the subject:
 Carbohydrate-rich diet for at least 3 days
prior to the test.

 All drugs known to influence carbohydrate
metabolism should be discontinued (2 days).
 The subject should avoid strenuous exercise
on the previous day of the test.
 Person should be in an overnight fasting
state.
 During the course of GTT, the person should
be comfortably seated & should refrain from
smoking & exercise.

 Glucose tolerance test should be conducted
preferably in the morning (ideal 9 to 11 AM).
 A fasting blood sample is drawn and urine
collected.
 The subject is given 75 g glucose orally,
dissolved in about 300 ml of water, to be
drunk in about 5 minutes.

 Blood & urine samples are collected at 30
minute intervals for at least 2 hours.
 All blood samples are subjected to glucose
estimation while urine samples are
qualitatively tested for glucose.

 The fasting plasma glucose level is 75-110 mg/dl
in normal persons.
 On oral glucose load, concentration increases
& peak value (140 mg/dl) is reached in less
than an hour which returns to normal by 2
hours.
 Glucose is not detected in any of the urine
samples

 In individuals with impaired glucose
tolerance, the fasting (110-126 mg/dl) as well as
2 hour (140-200 mg/dl) plasma glucose levels
are elevated.
 These subjects slowly develop frank diabetes.
 Dietary restriction & exercise are advocated
for the treatment of impaired glucose
tolerance.

Condition Plasma glucose concentration as mmol/l (mg/dl)
Normal IGT Diabetes
Fasting
<6.1
(<110)
<7.0
(<126)
>7.0
(>126)
2 hours
after
glucose
<7.8
(<140)
<11.1
(<200)
>11.1
(>200)

 For conducting GTT in children, oral glucose is
given on the basis of weight (1.5 to 1.75 g/kg).
 In case of pregnant women, 100 g oral
glucose is recommended.
 Mini GTT carried out in some laboratories,
fasting and 2 hrs. sample (instead of 1/2 hr.
intervals) of blood & urine are collected.

 To evaluate the glucose handling of the body
under physiological conditions, fasting blood
sample is drawn, the subject is allowed to
take heavy breakfast, blood samples are
collected at 1 hour & 2 hrs (post-prandial-
meaning after food).
 Urine samples are also collected.
 This type of test is commonly employed in
established diabetic patients for monitoring
the control.

 For individuals with suspected malabsorption,
intravenous GTT is carried out.
 Corticosteroid stressed GTT is employed to detect
latent diabetes.
 Glycosuria:
 The commonest cause of glucose excretion in urine
(glycosuria) is diabetes mellitus.
 Glycosuria is the first line screening test for diabetes.
 Normally, glucose does not appear in urine until the
plasma glucose concentration exceeds renal
threshold (180 mg/dl).

 Renal glycosuria:
 Renal glycosuria is a benign condition due to
a reduced renal threshold for glucose.
 It is unrelated to diabetes & should not be
mistaken as diabetes.
 Further, it is not accompanied by the classical
symptoms of diabetes.

 Alimentary glycosuria:
 In certain individuals, blood glucose level rises
rapidly after meals resulting in its spill over
into urine.
 This condition is referred to as alimentary
glycosuria.
 It is observed in some normal people & in
patients of hepatic diseases, hyperthyroidism
& peptic ulcer.

 Hyperglycemia:
 Elevation of blood glucose concentration is the
hallmark of uncontrolled diabetes.
 Hyperglycemia is primarily due to reduced
glucose uptake by tissues & its increased
production via gluconeogenesis &
glycogenolys.
 Glucose is excreted into urine (glycosuria).

 Ketoacidosis:
 Increased mobilization of fatty acids results
in overproduction of ketone bodies which
often leads to ketoacidosis.
 Hypertriglyceridemia:
 Conversion of fatty acids to TAGs & secretion
of VLDL & chylomicrons is higher in diabetics.
 Plasma levels of VLDL, chylomicrans, TAGs &
cholesterol are increased.

 Glycosuria – glucose excretion in urine.
 Due to osmotic effect, more water
accompanies the glucose (polyuria).
 To compensate for this loss of water, thirst
center is activated & more water is taken
(polydypsia).
 To compensate the loss of glucose & protein,
patient will take more food (polyphagia).

 Diabetic keto acidosis (DKA):
 DKA more common in T1DM.
 Normally the blood level of ketone bodies is
<1 mg/dl & only traces are excreted in urine.
 Increased synthesis causes the accumulation
of ketone bodies in blood.
 It causes ketonemia, ketonuria & smell of
acetone in breath.
 Together constitute ketosis.

 Detected by Rothera's test.
 Supportive evidence may be derived from
estimation of serum electrolytes, acid–base
parameters & glucose estimation.

 The urine of a patient with diabetic keto
acidosis will give positive Benedict's test as
well as Rothera's test.
 But in starvation ketosis, Benedict's test is
negative, but Rothera's test will be positive.

 Diabetes Mellitus:
 The combination of hyperglycemia,
glucosuria, ketonuria & ketonemia is called
diabetic ketoacidosis (DKA).
 Untreated diabetes mellitus is the most
common cause for ketosis.
 Deficiency of insulin causes accelerated
lipolysis & more fatty acids are released into
circulation.

 Oxidation of these fatty acids increases the
acetyl CoA pool.
 Enhanced gluconeogenesis restricts the
oxidation of acetyl CoA by TCA cycle, since
availability of oxaloacetate is less.

 In starvation, dietary supply of glucose is
decreased.
 Available oxaloacetate is channelled to
gluconeogenesis.
 The increased rate of lipolysis provides
excess acetyl CoA which is channeled to
ketone bodies.
 The high glucagon favors ketogenesis.

 Hyperemesis (vomiting) in early pregnancy may
also lead to starvation-like condition & may lead to
ketosis.
 In both diabetes mellitus & starvation, the
oxaloacetate is channelled to gluconeogenesis.
 Acetyl CoA cannot be fully oxidized in TCA cycle.
 This excess acetyl CoA is channelled into ketogenic
pathway.

 Metabolic acidosis:
 Acetoacetate & β-hydroxy butyrate are
accumulated, causes metabolic acidosis.
 There will be increased anion gap.
 Reduced buffers:
 The plasma bicarbonate is used up for
buffering of these acids.

 Kussmaul's respiration:
 Patients will have typical acidotic breathing due to
compensatory hyperventilation.
 Smell of acetone in patient's breath.
 Osmotic diuresis induced by ketonuria may lead to
dehydration.
 Sodium loss:
 The ketone bodies are excreted in urine as their
sodium salt, leading to loss of cations from the body.

 High potassium:
 Due to lowered uptake of potassium by cells
in the absence of insulin.
 Dehydration:
 Sodium loss further aggravates dehydration.
 Coma:
 Hypokalemia, dehydration & acidosis
contribute to the lethal effect of ketosis.

 Parenteral administration of insulin & glucose.
 Intravenous bicarbonate to correct acidosis.
 Correction of water imbalance by normal
saline.
 Correction of electrolyte imbalance.

 Hyperglycemia is directly or indirectly
associated with several complications.
 These include
 Atherosclerosis
 Retinopathy
 Nephropathy
 Neuropathy.

 Dietary management:
 A diabetic patient is advised to consume low
calories (i.e. low carbohydrate & fat), high
protein & fiber rich diet.
 Diet control & exercise will help to a large
extent obese NIDDM patients.

 Hypoglycemic drugs:
 The oral hypoglycemic drugs are broadly of
two categories-sulfonylureas & biguanides.
 Sulfonylurea such as acetohexamide,
tolbutamide & gibenclamide are frequently
used.
 They promote the secretion of endogenous
insulin & help in reducing blood glucose level.

 Management with insulin:
 Two types of insulin preparations are
commercially available – short acting & long
acting.
 The short acting insulins are unmodified &
their action lasts for about 6 hours.
 The long acting insulins are modified ones &
act for several hours, which depends on the
type of preparation.

 Glycated hemoglobin:
 Refers to the glucose derived products of normal adult
hemoglobin (HbA).
 Glycation is a post-translational, non-enzymatic
addition of sugar residue to amino acids of proteins.
 Among the glycated hemoglobins, the most abundant
form is HbA1c.
 HbA1c is produced by the condensation of glucose
with N-terminal valine of each β-chain of HbA.

 The rate of synthesis of HbA1c is directly related to
the exposure of RBC to glucose.
 The concentration of HbA1c serves as an indication of
the blood glucose concentration over a period.
 HbA1c concentration is about 3-5%.
 In diabetic patients, HbA1c is elevated (15%).
 HbA1c reflects the mean blood glucose level over 2
months period prior to its measurement.

 Other proteins in the blood are glycated.
 Glycated serum proteins (fructosamine) can
also be measured in diabetics.
 Albumin is the most abundant plasma
protein, glycated albumin largely contributes
to plasma fructosamine measurements.
 Albumin has shorter half-life than Hb.
 Glycated albumin represents glucose status
over 3 weeks prior to its determination.

 Microalbuminuria is defined as the excretion of 30-
300 mg of albumin in urine per day.
 Microalbuminuria represents an intermediary stage
between normal albumin excretion (2.5-30 mg/d) &
macroalbuminuria (>300 mg/d).
 The small increase in albumin excretion predicts
impairment in renal function in diabetic patients.
 It indicates reversible renal damage.

 Textbook of Biochemistry – U Satyanarayana
 Textbook of Biochemistry – DM Vasudevan

DIABETES MELLITUS - BIOCHEMISTRY

DIABETES MELLITUS - BIOCHEMISTRY

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