REGULATION OF

BLOOD SUGAR
Regulation of blood sugar is one of the finest
homeostatic mechanisms of the body
Maintenance of blood glucose is very important
because organs like brain, kidney and RBC are
dependent on glucose for functioning
Normal plasma glucose level
in fasting or post absorptive (12
hours after last meal) glucose in
plasma ranges 70 – 110 mg/dl
When blood glucose level is within
normal level it is called
normoglycemia
Above normal range is
hyperglycemia and below normal
range is hypoglycemia
Blood sugar level is always
maintained at a constant level by
various homeostatic mechanisms of
the body
Concentration of sugar in the blood
depends upon the balance between
two sets of factors
1. Rate of glucose enters into the
blood stream

2. Rate of removal of glucose from

blood stream
Entry of glucose Removal of glucose

Absorption from glycolysis

GIT
Glycogenolysis Glycogenesis

Gluconeogenesis lipogenesis
Blood
glucose Synthesis of compounds
Glucose absorbed
from other containing
carbohydrates like carbohydrates like
galactose, fructose lactose, glycoproteins,
etc glycolipids etc
Balance between entry and
depletion of glucose is brought
about by insulin and other
hypoglycemic hormones
 Oohhhh…

GLUCOCORTICOIDS
GLUCAGON

NORADRENALIN
ADRENALIN

INSULIN

GROWTH HORMONE THYROXINE

 I C S
Y C EM
INSULIN RG L
Y P E
H
ROLE OF VARIOUS ORGANS IN BLOOD SUGAR
REGULATION

This include liver and other

extrahepatic tissues
Liver glucose uptake is
insulin independent
 SKELETAL MUSCLES

EXTRA
HEPATIC ADIPOSE
KIDNEY TISSUE TISSUE

GLUCOSE UPTAKE IS INSULIN DEPENDANT

ROLE OF LIVER
Role of liver in post absorptive or
fasting state

This state represents 12 hours after last meal.

So practically no sugar present in intestine for
absorption
Under such situation main source of blood
glucose is liver glycogen. Here glycogen
undergoes glycogenolysis
GLYCOGEN

GLUCOSE 6
PHOSPHATE

GLUCOSE
Liver can also provide glucose to blood in
fasting state by gluconeogenesis from

Lactate,
pyruvate,
glycerol,
propionyl Co A ,
glucogenic aminoacids.
Role of liver in post prandial state
Condition following the ingestion of food is called post
prandial state
Liver is the first organ which gets glucose after a
carbohydrate rich meal.
Glucose from the intestine reaches the liver through
the portal circulation.
Liver cells are unique in that they are freely permeable
to glucose. (because uptake of glucose by liver cells is
insulin independent)
In the post prandial or well fed state liver converts
excess glucose to glycogen (storage form)
 ROLE OF KIDNEY
Kidney excert a regulatory role when blood sugar
level increases to a relatively high level
Glucose is continuously filtered by the glomeruli. But
normally it is completely reabsorbed by renal tubules
The capacity of renal tubular system to reabsorb glucose
is limited to a rate of 375 mg/ minute
This value is called tubular maximum of glucose (Tm G)
When the blood level of glucose is still elevated the
glomerular filtrate may contain more glucose than its
ability to reabsorb
The excess glucose passes into urine to produce
glycosuria
Glycosuria occurs when blood glucose exceeds 180mg%
This value is the renal threshold for glucose
Kidney can also maintain the blood sugar level in fasting
state by gluconeogenesis. But this capacity is only 1/10
when compared to liver
 ROLE OF SKELETAL
MUSCLE
Increased blood glucose promotes muscle glycogenesis
During fasting state muscle glycogen does not directly
contribute to blood glucose level by glycogenolysis
Why? Because glucose 6 phosphatase enzyme is
absent in muscles
But skeletal muscles can supply glucose to blood
indirectly by cori’s cycle
 ROLE OF ADIPOSE
TISSUE

This is the main site for storage of fat as

triglycerides (TG)
During prolonged starvation TG is hydrolyzed to
glycerol and fatty acids
This glycerol diffuses into the circulation, reaches
the liver and gets converted to glucose by
gluconeogenesis
Glucose is released to blood for normal
maintenance of its level
 ROLE OF HORMONES

Blood sugar level is maintained at a normal level by

the balanced action of two groups of hormones

1. Hormones which decrease the blood sugar

level i.e. insulin

Hormones which increase the blood sugar level

i.e. gluagon, catacholamines, growth hormone,
glucocorticoides, thyroxine
 ROLE OF INSULIN

It is produced by the beta cells of islets of

langerhans in pancreas.
It is secreted to blood as a direct
response to hyperglycemia
Glucose is the major stimulant for insulin
secretion
By multiple actions it brings down the
blood sugar to normal
Insulin lowers blood glucose by
stimulating
• Glycogenesis
• Glycolysis
• Increase the rate of uptake of
glucose by tissues
• Stimulating HMP shunt pathway
by activating glucose 6
phosphate dehydrogenase
enzyme
Insulin lowers blood glucose by
inhibiting
• Glycogenolysis
• gluconeogenesis
 ROLE OF GLUCAGON

It is secreted by the alpha cells of

islets of langerhans of pancreas

Its secretion is stimulated by

hypoglycemia
It raises the blood sugar level to
normal by activating hepatic
glycogenolysis (main effect) and
gluconeogenesis
 ROLE OF
GLUCOCORTICOIDS

These secreted by adrenal cortex, its action is

antiinsulin

It raises blood sugar by stimulating

gluconeogenesis

a. It stimulate the activity of gluconeogenic

enzymes
b. Inhibits glycolysis by supressing glycolytic
enzymes
c. It decreases peripheral utilization of glucose
 ROLE OF
CATACHOLAMINES

They are epinephrine and nor

epinephrine, secreated by adrenal
medulla in response to stressful
stimuli
Like Fear,
Excitement,Hypoxia ,
hypoglycemia,
Hemorrhage etc…..
Catacholamines raise the blood sugar
level in hypoglycemic state, by
activating breakdown of glycogen
(activating glycogenolysis)
They also activate glycogen
phosphorylase enzyme by the cyclic
AMP dependant cascade
 ROLE OF GROWTH
HORMONE

Glycolysis is inhibited
Gluconeogenesis is stimulated
Glycogenolysis stimulated
Uptake of glucose by muscles
inhibited
 ROLE OF THYROID
HORMONES

Thyroxin increases the rate of

glucose absorption from intestine
It causes hyperglycemia
It stimulate gluconeogenesis and
glycogenolysis
Diabetes mellitus is a clinical syndrome
due to relative or absolute lack of insulin
or decreased effectiveness of insulin
It is associated with elevation of blood
sugar, glycosuria and wide spread
derangement in the metabolisms of
carbohydrates,proteins,lipids,water
and mineral metabolisms
 CLASSIFICATION As per WHO recommendation

1.Type 1.IDDM circulating insulin level is deficient

2. Type 2. NIDDM insulin resistant. Here
circulating insulin level is normal or nearly normal
3. Diabetic prone states
gestational diabetes mellitus
impaired glucose tolerance
impaired fasting glycemia
4. Secondary to other diseases
cushing’s disease, thyrotoxicosis, steroid
therapy, chronic pancreatitis pancreatic calculi
 Features of Type 1 DM
•It is due to decreased insulin production
•Juvenile diabetes comes under this group
•These patients are insulin dependant
•They are more prone to ketosis
•Autoimmune basis is attributed to most of these cases
Features of type 2 DM
•This is most common type
•Thers is only decreased response to insulin
•This is called insulin resistance
•So there is relative insulin deficiency
•It is seen in individuals above 40 years of age
•It is less prone to develop ketosis
•These patients have high plasma insulin levels
•Insulin receptor gene is defective
•60% of type 2 patients are obese 40% nonobese
 C L I N I CAL
MANIFESTATIONS
 The classical symptoms

urea phagia

dypsia
Patients complaints of extreme fatigue
and weight loss
When blood sugar level shoots above the
renal threshold glucose appears in urine.
This is known as glycosuria
The mechanisms of polyuria,
polydypsia and poly phagia
Poly uria
Glucose is osmotically active. It
draws large amount of water along
with it when excreted. This causes
poly uria or osmotic diuresis
 polydipsia
Loss of urine in large quantities
leads to thirst and poly dypsia
 Poly phagia
Loss of nutrients and electrlytes
stimulate hunger leading to
polyphagia
As the tissues cannot utilize glucose
there is extreme weakness and
tiredness.
There is loss of weight due to
excessive breakdown of tissue fat and
proteins
Continued loss of water and
electrolytes leads to dehydration
 METABOLIC CHANGES IN DIABETES

Changes in carbohydrate metabolism

There is decreased uptake of glucose by

peripheral tissues

Rate of glycolysis decreased

Glycogenesis is inhibited

Glycogenolysis is stimulated

Gluconeogenesis is stimulated

All these leads to increased blood sugar

glycolysis inhibited

Glycogenolysis
and
gluconeogenesis
Glycogenesis are stimulated
inhibited
Changes in lipid metabolism
There is increased mobilization of fat from adipose
tissue

Fat is oxidised in large amounts for energy

production. Plasma free fatty acid is increased

Increased fat oxidation results in accumulation of

acetyl CoA

Acetyl CoA is diverted to ketone body formation and

cholesterol biosynthesis

This leads to ketosis, hypercholesterolemia and

atherosclerosis in DM
Changes in protein metabolism

There is increased catabolism of

tissue proteins

Protein synthesis is decreased

There is negative nitrogen balance

Changes in water and electrolyte
metabolism

Dehydration and electrolyte imbalance

is common
Ketone bodies formed are acidic in
nature. This leads to decrease in pH of
blood and acidosis

These acidic substances are buffered

by plasma HCO3, which will lead to
depletion of plasma HCO3
Complications of DM

Diabetic ketoacidosis
Ketosis is more common in type 1
diabetes mellitus
Deficiency of insulin promotes
lipolysis, which results in over
production of acetyl CoA
Acetyl CoA is converted to ketone
bodies
Increased ketone bodies in blood
leads to ketosis, ketonemia and
Ketone bodies are acidic, so the pH of
blood is lowered, this results in diabetic
keto acidosis
In diabetic ketoacidosis, as a part of
compensatory pH regulation mechanism the
respiratory rate increases
This is called kussmaul respiration which is
associated with fruity odor of breath and
dehydration. The fruity odor is from the
volatile acetone.
Diabetic ketosis if untreated leads to coma
and finally death
 Vascular
complications
The basement membrane of vessels
are thickened due to atherosclerosis,
which leads to intravascular
thrombosis
Thrombosis of small vessels are called
microangiopathy
RENAL COMPLICATIONS

It is characterized by proteinuria and renal failure,

this condition is called KIMMELSTEIL WILSON
SYNDROME OR DIABETIC NEPHROPATHY

Microalbuminuria (50 – 300 mg albumin per day in

urine) can occur in renal involvement of diabetes
mellitus
 Ophthalmic
complications
Diabetic cataract due to increased rate of sorbitol
formation

Glycation of retinal protein and retinal

microvascular involvement leads to retinopathy
and blindness

Glycation of lens proteins also cause cataract

formation
NERVOUS TISSUE COMPLICATION
Diabetic neuropathy

Blood supply to peripheral nerves

gets blocked
(diabetic polyneuritis)

Paraesthesia is common. Sensory

deficit leads to foot ulcers
LABORATORY INVESTIGATION IN DM

Detection of glycosuria
Urine benedicts test or glucose
oxidase test
Only when the blood sugar is
above the renal threshold glucose
appears in urine
LABORATORY INVESTIGATION IN DM

Detection of hyperglycemia
Concentration of blood sugar depends on the
dietary state of the subject
Normal fasting blood sugar level ranges from
70 – 110 mg%
Two hour post prandial blood sugar level is
normally less than 140mg%
By two and half hours blood sugar returns to
fasting level in normal subjects
3 types of samples are used to diagnose DM

Fasting……..FBS
Post prandial……..PPBS
Random…….. RBS
Fasting blood sugar level over 126mg% on more
than one occasion is diagnostic of DM

Two hour post prandial sample after carbohydrate

rich meal gives values over 200mg%, even at one
occasion is diagnostic of DM

If the random blood sugar level is more than

200mg% on more than one occasion is diagnostic of
DM
 It is a well standardized test highly
useful to diagnose diabetes mellitus
in doubtful cases
 INDICATIONS

Patients with symptoms of DM

Fasting plasma blood glucose level between 110- 126mg%

During pregnancy with past history of big baby, h/o

miscarriages

To ascertain renal threshold for glucose

 contraindications

Not to be done in patients with confirmed DM. It

has no role in follow up of DM

Not to be done in acutely ill patients

 Test procedure

Patient should take sufficient

CHO in diet for at least 3 days
prior to the test
A diet containing 30 – 50 grams of
CHO should be taken on the evening
prior to the test.
Test is carried out after 12 hours of
fast in the morning
Patient should be physically
and mentally at rest.
Smoking not permitted
throughout the test
Fasting venous blood sample and
fasting urine sample are collected,
this is the zero hour sample.
Patient is then given 75 grams of
anhydrous glucose in 250 ml of
water orally.
For children dose is 1.75 gms/kg
body weight
Sample collection
Blood and urine samples are
collected at half hourly intervals for
two and half hours, total six samples
are collected

0 1/2 1 1 1/2 2 2 1/2

Glucose is estimated in all the
blood samples.
Urine samples are tested for
glucose by benedicts test
A graff is plotted with time of collection
on X axis and plasma glucose level on
the Y axis
This graff is called glucose tolerance
curve
The present WHO recommendation is
to collect only the fasting and 2 hour
post glucose load samples of urine
and blood
This is called mini GTT, that is zero hour and 2 hour
samples
Normal response

In normal subjects fasting plasma sugar

level is 70 – 110 mg%.
Peak values are obtained within one hour
of glucose load. i.e. less than 160 mg%
Values return to fasting level by 2 – 2 ½
hours
This is due to secretion of insulin
Normal oral glucose t olerance test

300

250

200 Renal threshold 180mg%

150 Peak value is below 150mg%

100

50 0.5 1.0 1.5 2.0 2.5

T I M E I N H O U R S
 DM o r a l g l u c o s e t o l e r a n c e t e s t

300 Urine sugar will be +ve in a few samples

250

200

150

100

50 0.5 1.0 1.5 2.0 2.5

T I M E I N H O U R S
Impaired glucose tolerance (IGT)
This name is suggested by WHO.
Here blood sugar values are above normal
but below but below diabetic values.
Here fasting plasma glucose level is
between 110–126 mg%
Two hour post glucose load level between
140- 200 mg%
IGT can progress to frank DM , follow-up is
needed
Impaired fasting glycemia
Here fasting plasma glucose level is
between 110 and 126mg%. But the two
hour post glucose load level is normal.
i.e. less than 140mg%.
These patients will have increased risk
for development of DM
Gestational DM
Here CHO intolerance is noticed
for the first time in pregnancy.
Fasting values more than 126mg%
is taken as gestational DM.
Women with GDM are at a greater
risk to develop frank DM
Alimentary glycosuria
It is seen in patients with
hyperthyroidism, gastrectomy, where
there will be rapid absorption of
glucose.
Fasting and 2 hour samples shows
normal values. Peak blood sugar
exceeding 180mg% within half to one
hour post glucose load.
Urine sugar present in half hour and
one hour sample
 Urine sugar will be +ve in half hour and one
hour samples

300

250
Peak values within half to one hour
200

150

100

50 0.5 1.0 1.5 2.0 2.5

T I M E I N H O U R S
 Flat curve

There is increased tolerance to

glucose.
Blood sugar will not rise following
glucose load
It is seen in hypothyroidism,
malabsorption, addisons disease,
hypopituitarism
300

250

200

150

100

50 0.5 1.0 1.5 2.0 2.5

T I M E I N H O U R S
Renal glycosuria
Blood sugar level after glucose load is
normal. But glocose appears in urine due to
diminished renal threshold.
Renal glycosuria can occur physiologically
in pregnancy
Pathologically it can occur in conditions
associated with renal tubular transport
deffects.
Eg fancony syndrome. Here glucosuria is
seen along with aminoaciduria and
phophaturia
Intravenous GTT
It is done 12 hours after fasting. It is
done in malabsorption or oral glucose
administration not possible.
Dose 0.5gm/kg bodywt (maximum 35 gm)
dissolved in 100ml distilled water and
given as iv injectionwithin 3 minutes
mid injection time is taken as zero time.
Blood samples are taken at ten minute interval for
next one hour
Peak value is reached within a few minutes (200-
250mg%)
Values reaches 100mg% by one hour
The number of minutes taken to reduce the blood
sugar value to half the peak is denoted as t- half.
In normal subjects t- half is less than 45 minutes.
In frank diabetes it is more than60 minutes
Cortisone stressed GTT
It is to diagnose latent DM.
Small doses of cortisone
administered
It will induce hyperglycemia and
glycosuria in prediabetic subjects
It is seldom done nowadays
Effects of hyperglycemia
When there is hyperglycemia proteins in the body may
undergo glycation. This is non enzymatic process.
Eg. glycated hemoglobin
Normal level of glycated Hb is 4-8% of total Hb (Hb A1c)
Measurement of Hb A1c indicates the average glucose
concentration in plasma over a period of several weeks
An elevated glycated Hb indicates poor control of DM
Estimation of Hb A1 c
Estimation of glycated hemoglobin is not for
diagnosis of DM
Hb A1c level reflects the average blood glucose
concentration over the preceding 6 – 8 weeks
An elevated Hb A1c indicate poor control of
blood glucose level
It can guide the physician in selection of
appropriate treatment
i.e. to increase the dose of insulin
Rigorous diet control etc
Proteins other than hemoglobin eg
plasma albumin, lens, proteins etc
undergo glycation.
In addition to these glycated proteins
advanced glycation end products (AGEs)
are found in tissue proteins such as
collagen in diabetes patients
In diabetic vascular tissues, the
concentration of AGEs is very much
increased.
 Lipid profile studies
b. Serum cholesterol
c. LDL cholesterol
d. HDL cholesterol
e. Serum triglycerides

These may be done once in six months

Renal funtion tests
Kidney functions may be assessed
by estimation of
Blood urea
Serum creatinine
Urine microalbumin
All are done once in six months