LECTURE NOTES ON : BCM 202

REGULATION OF BLOOD
GLUCOSE

AJILORE B.S. (MBChB, PhD)

Dept. of Biochemistry, College of Health Sciences, Osun
State University, Osogbo
REGULATION OF BLOOD GLUCOSE (Homeostasis)
• Blood glucose level is maintained within physiological limits 60 to 100 mg%
(“true” glucose) in fasting state and 100 to 140 mg% following ingestion of a
carbohydrate containing meal, by a balance between two sets of factors:
A. Rate of glucose entrance into the blood stream, and
B. Rate of its removal from the blood stream.

Rate of supply of glucose to blood:

- Except for a possible minor contribution by the kidney, which probably does not
occur under physiological conditions, the blood glucose may be derived directly
from the following sources:

i. By absorption from the intestine

ii. Breakdown of glycogen of Liver (Hepatic glycogenolysis)
iii. By gluconeogenesis in Liver, source being glucogenic amino acids, lactate and
pyruvate, glycerol and propionyl-CoA
iv. Glucose obtained from other carbohydrates, e.g. fructose, galactose, etc.
Rate of removal of glucose from blood

i. Oxidation of glucose by the tissues to supply energy

ii. Glycogen formation from glucose in Liver (Hepatic glycogenesis)

iii. Glycogen formation from glucose in muscles (Muscle glycogenesis)

iv. Conversion of glucose to fats (lipogenesis) especially in adipose tissue

v. Formation of ribose sugars from glucose required for nucleic acid synthesis.

vi. Excretion of glucose in urine (glycosuria), when blood glucose level exceeds
the renal threshold.
Fasting (Post absorptive) State:

- Approx. 12 to 14 hours after last meal.

- There is practically no intestinal absorption.

- It is the condition of a subject between 8 to 10 A.M, if he had his dinner previous

evening about 8 P.M and had taken nothing thereafter.

- Under such a situation only source of glucose is liver glycogen.

- Muscle glycogen cannot provide blood glucose by glycogenolysis due to lack of

the enzyme Glucose-6-phosphatase.
Post-prandial State:

- Condition following ingestion of food

- Absorbed monosaccharides are utilised for oxidation to provide energy.

- Remaining in excess is stored as glycogen in liver and muscles.

- When load of glucose is very high renal mechanisms operate.

- When blood glucose rises more than 160 to 180 mg% i.e. the renal threshold,
glucose appears in urine (glycosuria). This is an abnormal state.

- In normal intestinal absorption such situation does not occur.

- It can take place with an IV load or disease processes

AUTOREGULATION (Fundamental/ Central Regulatory Mechanisms)
• Process of hepatic glycogenesis, glycogenolysis and tissue utilisation of glucose
are sensitive to relatively slight deviation from the normal blood sugar
concentration.
1. As blood sugar tends to increase ↑:
• Glycogenesis is accelerated, and
• Utilisation of glucose by tissues is increased, resulting to fall in blood glucose
level.

- The reverse occurs as the blood glucose level tends to fall↓.

- Circulating blood glucose is approximately 80 mg % (4.4 mmol/L).

- Balance between production and utilization of blood glucose depends on insulin

in one hand, and hormones of adrenal cortex and anterior pituitary on the other
hand.

- Overall effect of Insulin is to lower the blood glucose level while adrenocortical/
and growth hormone to raise it.
• Therefore, as blood sugar tends to rise, there is simultaneous increase in insulin
secretion which leads to increase in ratio of insulin/glucocorticoids and GH.
• This results in:
i. Increased hepatic glycogenesis↑
ii. Decreased gluconeogenesis↓
iii. Decreased output of glucose from Liver↓ and
iv. Increased utilisation of glucose↑.

• As a result of above, the blood glucose concentration tends to fall.

2. As blood sugar tends to decrease ↓:

- A drop in blood glucose concentration below the normal resting level causes:
• Decrease in secretion of insulin, ↓
• Resulting to decrease in ratio of insulin/glucocorticoids and GH, ↓
• Increased production of blood glucose mainly by gluconeogenesis ↑, and
• Decreased glucose utilisation ↓.

- Due to the above actions, blood glucose tends to rise.

• If the blood glucose falls below to hypoglycaemic levels, additional emergency
mechanisms come into play:

a. Stimulation of secretion of catecholamines by

• hypoglycaemia resulting in hepatic glycogenolysis and rise in blood glucose.
- The increase in catecholamines may also

b. Stimulate production of ACTH, hence of adrenocortical hormones

• causing increased gluconeogenesis.

• The blood glucose concentration in normal health regulates itself by the normal
responsiveness of the pancreas to variation in blood glucose concentrations.This
constitutes the “autoregulation” or central regulatory mechanism.
 HORMONAL / ENDOCRINE INFLUENCES ON CARBOHYDRATE METABOLISM
- There are 2 categories of endocrine influences:

A. Those which influence carbohydrate metabolism and exert a fundamental

regulatory influence. Examples are insulin and hormones of adrenal cortex and
anterior pituitary.

B. Those which influence carbohydrate metabolism, but are not essential for its
autoregulation under normal physiological conditions, e.g. hormones of
adrenal medulla and hormones of thyroid gland.

1. Insulin
• Administration of insulin is followed by a fall ↓ in blood glucose concentration to
hypoglycaemic levels.

2. Adrenocortical hormones
- The predominant glucocorticoids in man is cortisol.
- Increases blood glucose level by gluconeogenesis
3. Anterior Pituitary Gland
• Secretes hormones that tend to elevate the blood glucose level and therefore,
antagonise the effect of insulin. These are growth hormone and ACTH
(corticotropin)

4. Catecholamines
• These are hormones produced by adrenal medulla: Epinephrine & Non
epinephrine
• Produce an increase in blood glucose level and also blood Lactic acid level↑.
• It stimulates glycogen breakdown (glycogenolysis) in Liver as well as in muscle
and is accompanied by a decrease in glycogen content.

5. Glucagon
- In response to hypoglycaemia, α-cells produce glucagon which produces rapid
glycogenolysis in Liver.
- Glucagon cannot produce glycogenolysis in muscle as it lacks the receptor
- Glucagon also enhances “gluconeogenesis” from amino acids, pyruvates and
lactates.
• Thyroid Hormones: Thyroxine accelerates hepatic glycogenolysis, with
• consequent rise in blood glucose.
BLOOD SUGAR LEVEL AND ITS CLINICAL SIGNIFICANCE

I. Normal values: The range for normal fasting or Postabsorptive blood glucose
taken at least three hours after the last meal is 60 to 100 mg%

II. Abnormal values

- Hyperglycemia: increase above normal value
- Hypoglycemia: decrease below normal value

Causes of Hyperglycemia
i. Diabetes
ii. Hyperactivity of the thyroids (Hyperthyroidism), pituitary (Hyperpituitarism) and
adrenal
iii. Emotional stress
iv. Disease of the pancreas: pancreatitis and carcinoma
v. Sepsis
vi. Brain diseases: meningitis, encephalitis, intracranial tumors and hemorrhage
vii. Asphysia
viii. Anaesthesia
Causes of Hypoglycemia

i. Overdose of insulin in treatment of DM

ii. Insulin-secreting tumor (Insulinoma) of pancreas
iii. Hypoactivity of thyroids (Hypothyroidism): e.g. in cretinism
iv. Hypopituitarism: e.g. in Simmond’s disease
v. Hypoadrenalism: e.g. in Addisson’s disease
vi. Severe liver diseases
vii. Deficincy of of glucagon production in children: spontaneous hypoglycemia
viii. Severe exercise: due to depletion of liver glycogen
ix. Glycogen storage diseases: e.g. Von Gierke’s disease
x. Alcohol ingestion
Glycosuria
- Under ordinary dietary conditions, glucose is the only sugar present in the free
state in blood plasma in demonstrable amounts.

- Although normal urine contains virtually no sugar

- Under certain conditions, glucose and other sugars may be excreted in the urine.
This condition is called melituria (excretion of sugar in urine)

- The terms glycosuria, fructosuria, galactosuria, lactosuria and pentosuria are

applied specially to the urinary excretion of glucose, fructose, galactose, lactose,
and pentose respectively.

- Glucose is present in the glomerular filtrate in the same concentration as in the

blood plasma.

- Under normal conditions, it undergoes practically complete reabsorption by the

renal tubular epithelial cells and is returned to the blood stream.
- In normal subjects, a very small amount less than 0.5 gm of glucose may escape
reabsorption by tubules and be excreted by urine.

- But this amount is not detected by Benedict’s qualitative test.

- Rate of glucose absorption is expressed as TmG (tubular maximum for glucose)

which is 350 mg/mt.

- When the blood levels of glucose are elevated, the glomerular filtrate may
contain more glucose than can be reabsorbed, the excess passes in urine to
produce “glycosuria”.

- In normal individuals, glycosuria occurs when the venous blood glucose exceeds
170 to 180 mg/100 ml. This level of the venous blood glucose is termed as the
renal threshold for glucose.

Glycosuria is defined as the excretion of glucose in urine which is detectable by

Benedict’s Qualitative test.
DIABETES MELLITUS
- DM is a chronic endocrine disorder characterized by elevated levels of glucose in
the blood as a result of absolute or relative insulin deficiency.

- In DM insulin may be insufficient or not properly utilized.

CLINICAL TYPES AND CAUSES

- These are two main groups:
(a) Primary : constitute major group.
- Exact cause is not known
- metabolic defect is insufficient insulin which may be absolute or relative.

(b) Secondary: constitute minor group

- it can be secondary to some disease process.
Primary
• Two clinical types:
i. “Juvenile”-onset diabetes: Now called as Type-I DM(Insulin dependent) IDDM.

ii. “Maturity” onset diabetes: Type-II DM :NIDDM— (Non- Insulin Dependent).

CAUSES:
I. Hereditary
II. Autoimmunity: Type I
III. Infections
IV. Obesity: Type II
V. Diet
VI. Insulin resistance: Type II
Secondary
- This forms a minor group. Diabetes is secondary to some other diseases:
I. Pancreatic diabetes:
• Pancreatitis
• Haemochromatosis
• Malignancy of Pancreas.

II. Abnormal concentrations of insulin-antagonistic hormones:

• Hyperthyroidism
• Hypercorticism: like Cushing’s disease

III. Iatrogenic:
- In genetically susceptibles, DM may be precipitated by therapy like
- corticosteroids, thiazide, diuretics.

In experimental animals, DM is induced by chemicals like streptozotocin, alloxan

CLINICAL FEATURES AND BIOCHEMICAL CORRELATIONS
1. Polyuria
- Large amounts of glucose may be excreted in urine (may be 90 to 100 G/day in
some cases). Loss of solute produces osmotic diuresis thus large volume of
urine.
2. Loss of fluid leads to thirst and polydypsia.

3. Polyphagia: Eats more frequently.

4. Tissues including muscles received liberal supply of glucose but cannot use
glucose due to absolute or relative deficiency of insulin/ or transport defect to
cells. This causes weakness and tiredness.

5. As glucose cannot be used for fuel, fat is mobilised leading to increase FFA- in
blood and liver.
6. Increased acetyl-CoA is diverted for cholesterol synthesis:
Hypercholesterolaemia and atherosclerosis.

7. Increased ketone bodies leads to acidosis, which leads to hyperventilation

(“air-hunger”).
8. If ketosis is severe, acetone will be breathed out, giving characteristic “fruity”
smell in breath (due to acetone).

9. Along with above, there may be excessive breakdown of tissue proteins.

Deaminated amino acids are catabolised to provide energy, which accounts for
Loss of weight.

10. Due to ketosis, develops anorexia, nausea, and vomiting. Continued loss of
water and electrolytes increases dehydration.

11. Ketoacidosis produces increasing drowsiness, leading to diabetic coma in

untreated cases
METABOLIC CHANGES IN DIABETES MELLITUS

1. Hyperglycaemia: Occurs as a result of:

i. Decreased and impaired transport and uptake of glucose into muscles and
adipose tissues.

ii. Repression of key glycolytic enzymes like Glucokinase, phosphofructokinase

and pyruvate kinase takes place.

iii. Derepression of key gluconeogenic enzymes like Pyruvate carboxylase,

phosphoenol pyruvate carboxykinase, fructose biphosphatase and glucose-6-
phosphatase occur, promoting gluconeogenesis in Liver. This further
contributes to hyperglycaemia.

iv. Elevated amino acid level in the blood particularly alanine provides fuel for
gluconeogenesis in Liver.
2. Amino Acids Level
i. Transport and uptake of amino acids in peripheral tissues is also depressed
causing an elevated circulating level of amino acids, particularly alanine.
Glucocorticoid activity predominate having catabolic action on peripheral
tissue proteins, releasing more amino acids in blood.

ii. Amino acids breakdown in Liver results in increased production of urea N ↑.

3. Protein synthesis: Protein synthesis is decreased in all tissues due to:

iii. Decreased production of ATP↓
iv. Absolute or relative deficiency of Insulin.

4. Fat Metabolism
v. Decrease extramitochondrial de Novo synthesis of FA and also TG synthesis
due to decrease in acetyl-CoA from carbohydrates, ATP, NADPH and α-glycero-
(p) in all tissues.
vi. Stored lipids are hydrolysed by increased Lipolysis liberating free fatty acids
(FFA)↑. Increased FFA interferes at several steps of carbohydrate
phosphorylation in muscles, further contributing to hyperglycaemia.