Download Insulin - ISpatula

Integration of Metabolism
• Metabolic effects of Insulin and Glucagon
• Metabolism in the Well fed state
• Metabolism in the Starvation and Diabetes Mellitus
Metabolic Map
Integration of metabolism
Individual tissues don’t function in
isolation but form part of
community.
Communication between tissues is
mediated by
- Nervous system.
- Circulating substrates.
- Plasma hormones.
* The integration of energy
metabolism is controlled mainly by
action of hormones. (Insulin,
glucagon, epinephrine,
norepinephrine).
* Changes in hormone levels allow
the body to store energy when
food is available .
*Insulin : polypeptide hormone
- β-cells of islets of langerhans of pancreas.
- Important in coordinating the utilization of fuel by tissues.
Its metabolic effects are anabolic  favoring, for example, the
synthesis of glycogen, tricylglycerols, and protein.
1- Semisynthesis of insulin from porcine insulin.
2- Synthesis of human insulin by recombinant DNA technology
# 51 amino acid
Insulin Biosynthesis
Formation of Insulin from preproinsulin
* Regulation of insulin secretion
Insulin secretion of β- cells is coordinated with
the release of glucagon of α- cells.
So  Insulin/ Glucagon ratio is regulated
the rate of hepatic glucose production and glucose
utilization are balanced
Insulin secretion is affected by:
a)
Glucose
β- cells are most important glucose-sensing cells in
body.
Ingestion of CHO meal  increase level of
glucose which is a signal for increasing insulin
secretion and decrease glucagon.
Glucose is the most important stimulus for
insulin secretion.
b)
Amino acids
Ingestion of protein increase secretion of
insulin.
Mainly amino acid Arginine which is a potent insulin
stimulus.
c) Gastrointestinal Hormones
The intestinal hormone secretion with
other GIT hormones stimulate insulin
secretion. These hormones are released
after the ingestion of food. They cause
anticipatory rise in insulin level in the
portal vein before actual rise in blood
glucose.
* Inhibition of insulin secretion
The synthesis and release of insulin are
decreased when there is decrease in CHO
or food (dietary fuels) and also during
period of trauma, stress, extreme
exercises. Where Epinephrine plays direct
effect on energy metabolism. Causing
rapid mobilization of energy-yielding fuels
like glucose from liver, fatty acids from
TG
- In emergency situations
The sympathetic nervous system 
increases the release of the epinephrine.
*Metabolic effect of insulin
Effect on CHO metabolism
the effect of insulin on glucose metabolism is important in three tissues:
( liver, muscle, adipose tissue )
A) In liver
Insulin inhibits gluconeogenesis, and break down glycogen Decrease production of glucose.
also it increase glycogen synthesis.
B) In muscle and adipose tissue
Increase Glucose uptake increase synthesis of TG.
Effect on TG metabolism:
Insulin  decrease TG degradation  decrease fatty acid level in the circulation.
Insulin inhibits hormone sensitive lipase enzyme inhibits TG degradation
- Insulin increase the transport and metabolism of glucose into adipocyte providing
glycerol 3-P for TG synthesis  activate the TG synthesis in the adipocytes
- Also increase lipoprotein lipase activity  increase degradation of chylomicrones
to release fatty acid that will enter to the adipocytes and will be esterfied with glycerol
phosphate  increase TG synthesis.
Effect of insulin on protein metabolism:
- Insulin stimulates the energy of amino acid into the cells and increase protein synthesis.
Anabolic effect of Insulin
Insulin binding
site
α-subunit
β-subunit
Mechanism of insulin action
Insulin receptors: tetramer
protein linked by disulfide bonds
The systolic domain of β-subunit
is a tyrosine kinase
activated by insulin
Insulin
receptor
substrate
Time course of insulin action
- The most immediat response is an increase in glucose transport into cells which occurs within
seconds
- Insulin induce enzyme activity over minutes to hours phosphorylation starts.
- Insulin affects gene transcription that affect the enzyme synthesis
Insulin action over hours or days.
* Insulin sensitive and insulin insensitive glucose transport.
Glucagon
- Polypeptide hormone secreted by α-cells
of the pancreatic cells
- (29a.a of 1 chain)
- Glucagon, epinephrine, cortisol, growth
hormone have opposite action of insulin.
- α-cells respond to many stimuli that signal
of hypoglycemia
* Glucagon secretion increased by:
1) Low glucose level is the primary stimulus
for glucagon release.
2) a.a stimulate both insulin and glucagon
Glucagon prevents hypoglycemia that occurs
after a protein meal.
3) Epinephrin: released from adrenal
medulla increases the release of glucagon
regardless the concentration of glucose in
the blood.
Glucagon Mechanism
of action
The action of glucagon is
mediated by the activation
of adenylate cyclase 
cAMP activates cascade
of enzyme reactions.
Inhibition of glucagon secretion:
Glucagon secretion is decreased by elevated blood sugar and by insulin
ingestion of CHO rich meal
*Metabolic effects of glucagon:
A) Effect on CHO metabolism
Increases breakdown of liver (not muscle) glycogen and increases
gluconeogenesis.
B) Effect on Lipids metabolism
Glucagon favors hepatic oxidation of fatty acids and also formation of
keton bodies.
C) Effect on protein metabolism
Glucagon increases uptake of a.a by liver resulting in increased availability
of carbon skeleton for gluconeogenesis plasma level of a.a will decrease.
Hypoglycemia
The CNS has an absolute requirement for a continuous supply of blood-glucose to
serve as fuel for energy.
- Transient hypoglycemia  causes cerebral dysfunction.
- Prolonged hypoglycemia  causes brain death.
* The body has multiple overlapping mechanisms to prevent or correct
hypoglycemia.
- Hormonal changes in reversing hypoglycemia are increase glucagon and
epinephrine with decrease release of insulin.
*Symptoms of hypoglycemia:
Appear when glucose level of 45mg/dl or less
The symptoms are divided into:
Adrenergic symptoms: anxiety, palpitation, tremor, sweating are mediated by
epinephrine release which is regulated by hypothalamas. (sudden decline of
glucose  increases epinephrine)
Neuroglycopenic symptoms: neuroglycopenia (decrease delivery of glucose to
brain) results of impairment of brain function  causing headache, confusion,
seizures, coma, death. Resulted from slow decline of glucose.
Glucoregulatory systems
- humans have two overlapping glucose-regulating systems that activated by
hypoglycemia.
A) The islets of langerhans that release glucagon.
B) receptors in hypothalamus that respond to low glucose level.
hypothalamic glucoreceptors  activate the release of ACTH and GH.
Glucagon, epinephrine, cortisol and GH have opposite action of insulin.
*Glucagon and epinephrine: hypoglycemia is combated by decrease release of
insulin and increase secretion of glucagon, epinephrine, cortisol and GH.
- glucagon and epinephrine are important in short term regulation of blood-glucose
level
Glucagon: Increases the hepatic glycogenolysis and increases gluconeogensis.
Epinephrine: Increases glycogenolysis, increases lipolysis, decreases Insulin
secretion decreases the uptake of glucose by peripheral cells.
*Cortisol and growth hormone
- play a role in long term management of glucose metabolism.
Types of hypoglycemia
A) Reactive hypoglycemia (postprandial hypoglycemia)
“excessive insulin release after meal” transient
hypoglycemia
B) Fasting hypoglycemia: neuroglycopenia symptoms
 hepato cellular damage, adrenal insufficiency,
- Fasting hypoglycemia may due to increase utilization of
glucose by peripheral tissues.
- High insulin level due to tumor of β-cells.
C) Fasting individuals who have consumed large amount of
ethanol
The End