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Learning objectives
On completion of the study of this topic the students should be able to;
Explain the structure of insulin in order to recognize the peptide chains, total number of amino
acids present and disulfide bridges
Outline the synthesis of pre-proinsulin, proinsulin and insulin in the pancreatic beta cells
Evaluate the clinical importance of estimation of C peptide to assess the insulin production
Differentiate the factors that stimulate and inhibit insulin secretion
Outline the sequence of mechanisms by which glucose stimulates insulin secretion
Illustrate the orientation of insulin receptor in the target cell membranes. Recognize the insulin
binding site and site of autophosphorylation in the insulin receptor
Outline the mechanism of action of insulin emphasizing the role of insulin receptor and Insulin
receptor substrates (IRS)
Relate the influence of insulin on transport of glucose into the muscle and adipose cells
Evaluate the regulatory effects of insulin on: Glycolysis, Glycogen metabolism, Gluconeogenesis,
Pentose phosphate pathway, Fatty acid biosynthesis, TAG synthesis, Lipolysis (breakdown of
TAG in adipose tissues and amino acid metabolism. Apply this knowledge to predict the relevant
metabolic derangements in insulin deficiency
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Structure of insulin
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1
1
2
0
A Chain
1
9
B Chain
Polypeptide hormone
Secreted by -cells of islets of Langerhans in the endocrine pancreas
Consists of two polypeptide chains A & B connected by disulfide
bridges
A chain- 21 amino acids, B chain- 30 amino acids
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Biosynthesis of
insulin
Biosynthesis of insulin
C-peptide
Essential for proper insulin folding
Released along with insulin into circulation
Half-life in plasma is longer than that of insulin
A good indicator of insulin production & secretion, can be measured in
plasma to assess endogenous insulin secretion
GK
[Ca2+]
Sulfonylureas
McGrawHill Education:Integrative Medical Biochemistry Examination and Board Review, Michael King
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Metabolic effects of
insulin (hypoglycemic)
Glycolysis
Glycogenesis
(liver, muscle)
Glucose uptake
(adipose, muscle)
HMP shunt +
(liver)
Lipogenesis +
(liver, adipose)
Gluconeogenesis (liver)
_
Insulin
_
+
Glycogenolysis (liver)
Lipolysis (adipose)
_
Protein degradation (muscle)
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Glucagon
29 a.a polypeptide secreted by -cells of
pancreas
Synthesized as preproglucagon, converted to
glucagon by proteolysis
Regulation of glucagon secretion
Stimulated by
Low plasma glucose (primary stimulus)
Amino acids (eg: arginine) from a protein meal
Epinephrine (from adrenal medulla),
norepinephrine (sympathetic nerve endings)
Glucagon secretion inhibited by
Elevated blood glucose and insulin (following a carbohydrate-rich
meal)
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Mechanism of action of
glucagon (through G-protein
coupled receptor)
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Glycogenesis
(liver)
Gluconeogenesis (liver)
Glucagon
_
+
Glycogenolysis (liver)
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Hypoglycemic hormone:
decreases blood glucose level
Insulin
Hyperglycemic hormones:
increase blood glucose level
Glucagon
Epinephrine
Cortisol
Growth hormone &
ACTH
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Hypoglycemia
Lower than normal blood glucose level
Very critical if blood glucose falls below 40 mg/dL
Is a medical emergency (brain requires glucose supply from blood
for its energy metabolism)
If transient, can cause cerebral dysfunction
If severe & prolonged, can cause brain death
Multiple mechanisms exist for prevention of or correction of
hypoglycemia
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Symptoms of hypoglycemia
Adrenergic symptoms (mediated
by release of catecholamines)
anxiety
palpitation
tremor
sweating
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Types of hypoglycemia
1. Insulin-induced hypoglycemia
In diabetic patients on insulin treatment
2. Post-prandial hypoglycemia
Caused by an exaggerated insulin release after a meal
3. Fasting hypoglycemia: symptoms appear at night or early morning
. Liver damage
. Adrenal insufficiency
. Alcohol-induced (refer gluconeogenesis)
. Insulinoma (insulin secreting tumors)
. Inborn errors of metabolism
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Hypoglycemia in infants
Convulsions, tremors, attacks of apnea
Infants born to diabetic mothers
Intrauterine malnutrition, prematurity
Glycogen storage disorders (Eg: Von Gierkes)
Hereditary fructose intolerance
Adrenal insufficiency, hypopituitarism
Disorders of -oxidation (Carnitine deficiency, CPT I
deficiency, MCAD deficiency)
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