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Metabolic effects of insulin and glucagon

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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Learning objectives (contd)


On completion of the study of this topic the students should be able to;
Outline the nature of glucagon and locate its site of origin. Apply this knowledge to differentiate it
from insulin
Differentiate the factors that stimulate and inhibit glucagon secretion
Illustrate the mechanism of action of glucagon with emphasis on glucagon receptor, G protein,
cyclic AMP and protein kinase A
Evaluate the regulatory effect of glucagon on: Glycolysis, Glycogen metabolism,
Gluconeogenesis, Fatty acid biosynthesis, Lipolysis and Amino acid metabolism. Apply this
knowledge to predict the relevant metabolic derangements in glucagon deficiency
Relate hypoglycaemia to relevant clinical symptoms
Outline glucoregulatory responses for hypoglycemia
Explain different causes of hypoglycaemia
Correlate alcoholism with hypoglycaemia citing the reasons
Reference: Lippincotts Biochemistry (Chapter 23)
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Metabolic integration between major tissues


Metabolism in major tissues- does NOT
occur in isolation
Exchange of substrates between tissues
Insulin & glucagon play key roles

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

Regulation of insulin secretion


Stimulation of insulin secretion
a. Glucose: plasma glucose- primary stimulus
(ingestion of carbohydrate-rich meal)
b. Amino acids - plasma amino acids (eg:
arginine) after a protein-rich meal, enhance
glucose-stimulated insulin release
c. Gastrointestinal peptide hormones- incretins
glucagon-like protein-1 (GLP-1), gastric
inhibitory polypeptide (GIP), sensitivity of cells to glucose

GI hormones- released from small intestine after


ingestion of food

Cause an anticipatory rise in insulin levels

Glucose-stimulated secretion of insulin


GLP-1, GIP

GK

[Ca2+]

Sulfonylureas

McGrawHill Education:Integrative Medical Biochemistry Examination and Board Review, Michael King

Glucose in blood entry into


cells (GLUT-2) glycolysis
increase in ATP inhibition of
ATP dependent K+ channels
(channel is closed for efflux of K+)
depolarization activation of
voltage gated calcium channels
Entry of calcium into - cells
increase in intracellular calcium
Fusion of insulin containing
exocytotic vesicles with plasma
membrane Insulin secretion

Inhibition of insulin secretion


Insulin synthesis & release decreases due to
Scarcity of dietary fuels
Stress (eg: vigorous exercise, infections)
Mediated by epinephrine (released from adrenal medulla)
Causes mobilization of glucose from liver (glycogenolysis) &
fatty acids from adipose tissue (lipolysis)
Overrides the normal glucose-stimulated release of insulin

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Insulin receptor & mechanism of action


Membrane-bound
receptor
Two subunits
(extracellular), two
subunits span the
membrane; connected
by disulfide bridges
subunits bind
insulin
subunits have
intrinsic tyrosine
kinase activity, contain
autophosphorylation
sites
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Insulin receptor & mechanism of action


Binding of insulin to
subunits activates tyrosine
kinase activity
phosphorylation of tyrosine
residues of subunits
Initiates a cascade of cellsignaling responses
Phosphorylation of insulin
receptor substrates (IRS)
IRS interact with other
signaling molecules, bringing
about biological effects of
insulin
Insulin actions terminated by
dephosphorylation of receptor
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Metabolic effects of insulin


Insulin has anabolic effects on
1. Carbohydrate metabolism
2. Lipid metabolism
3. Protein metabolism
Insulin and cellular glucose uptake
.Insulin promotes glucose uptake by cells, its utilization and storage
.Increases transport of glucose into skeletal & cardiac muscle,
adipose tissue
.Increases the number of glucose transporters on the membrane of
these cells (GLUT-4)
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Insulin-mediated recruitment of glucose transporters (GLUT-4)


to the cell membrane

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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
_
+

Uptake of amino acids &


protein synthesis (most
tissues)

Glycogenolysis (liver)

Lipolysis (adipose)

_
Protein degradation (muscle)

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Insulin plasma half-life ~ 6 minutes


Insulin bound to receptor is internalized, insulin degraded by
insulin-degrading enzyme (liver, kidney)
Receptors may be degraded or recycled to the cell surface
Time course of insulin actions
glucose uptake (within seconds)
dephosphorylation of key enzymes (minutes to hrs)
increase in amount of key enzymes (induction; hrs to days)

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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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Metabolic effects of glucagon (hyperglycemic)


Glycolysis

Glycogenesis
(liver)

Fatty acid synthesis


(liver)

Gluconeogenesis (liver)

Glucagon

_
+

Uptake of amino acids by liver for


gluconeogenesis

Glycogenolysis (liver)

Lipolysis (adipose)- minor


effect

Beta oxidation of FA &


ketogenesis (liver)

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Insulin and glucagon response to changes in blood glucose

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Hormones involved in blood glucose regulation


Normal fasting blood glucose level: 60-100 mg/dl

Hypoglycemic hormone:
decreases blood glucose level
Insulin

Hyperglycemic hormones:
increase blood glucose level
Glucagon
Epinephrine
Cortisol
Growth hormone &
ACTH

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Influence of other hyperglycemic hormones on blood glucose


level
Epinephrine decreases glycogenesis & increases glycogenolysis
Cortisol increases gluconeogenesis & decreases glucose utilization in
extrahepatic tissues
Growth hormone decreases glucose uptake and utilization by muscle
ACTH increases cortisol synthesis & secretion
Net effect: raising of blood glucose level
Glucagon, catecholamines, cortisol & GH called counterregulatory
hormones

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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

Neuroglycopenia symptoms (caused


by impaired delivery of glucose to
the brain
headache
confusion
slurred speech
seizures
coma & death

Adrenergic symptoms occur when blood glucose drops abruptly


Neuroglycopenic symptoms result from a gradual decline in blood
glucose (below 40 mg/dL)

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Glucoregulatory systems activated by hypoglycemia


In response to hypoglycemia
Hypothalamic
glucoreceptors trigger
release of catecholamines
(by ANS) & ACTH & GH
by anterior pituitary
Pancreatic -cells
release glucagon
These hormones correct
the hypoglycemia

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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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Concept map for


metabolic effects
of insulin &
glucagon

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