Download Regulation of Glucose metabolism

Regulation of Glucose
metabolism
Lippincott’s illustrated reviews: Biochemistry
(latest edition)
Mahmoud A. Alfaqih BDS PhD
Jordan University of Science and Technology
• Regulation of glucose metabolism is primarily mediated
by the action of insulin and glucagon.
• Catecholeamines (Epinephrine and Nor-epinephrine play
a supporting role)
• Herein we will discuss; structure, function, regulation and
mechanism of action of Insulin and Glucagon
Insulin
• A polypeptide hormone
• Produced by β cells of islets of langerhans
• Islets of langerhans make only (1 to 2%) of the
total cells of the pancreas
• Anabolic hormone that favors synthesis of
Glycogen, triglycerides and protein
Structure of Insulin
• 51 amino acids arranged in two polypeptide
chains (A and B)
• Two disulfide bridges between A and B, and
intra-molecular disulfide bridge in chain A
Structure of Insulin
Synthesis and Secretion of Insulin
• Insulin is first made as a precursor chain called
preproinsulin (in the cytoplasm) (inactive).
• N-terminal signal sequence (AKA leader
sequence) is cleaved from preproinsulin
during transport to endoplasmic reticulum
• The resulting chain (called proinsulin) is
transported to Golgi complex
• Inside Golgi complex proinsulin is cleaved into
mature insulin and C-peptide
• Both insulin and C peptide are stored in
secretory granules and are released together
by exocytosis
Synthesis and secretion on insulin
Regulation of insulin secretion
• Tightly coordinated with the release of
Glucagon
• Secretion is stimulated by:
Glucose (most important stimulus)
Amino acids (particularly Arginine)
Gastrointestinal hormones (Example: Secretin)
Regulation of insulin secretion
• Inhibition of insulin secretion
 Scarce dietary fuel
 Stress (fever or infection)
• These effects are mediated by epinephrine (from
adrenal medulla) stimulated by nervous system
• Epinephrine causes rapid mobilization of glucose
(from liver) and fatty acids (from adipose tissue)
• Nervous system overrides plasma glucose as
primary regulator of insulin secretion
Regulation of insulin secretion
Metabolic effects of insulin
1. Effect on carbohydrate metabolism:
• Liver
 Inhibits breakdown of glycogen
(Glycogenolysis) and synthesis of glucose
(Gluconeogenesis)
 Stimulates synthesis of glycogen
• Adipose tissue
 Increases glucose uptake
Metabolic effects of insulin
1.
•


Effect on carbohydrate metabolism:
Muscle
Activates glycogen synthesis
Enhance glucose uptake
Metabolic effects of insulin
2. Effect on lipid metabolism:
• Affects adipose tissue and causes a reduction
in plasma fatty acids
 A decrease in triglyceride degradation
(inhibits hormone sensitive lipase)
 An increase in triglyceride synthesis by:
 Increased glucose uptake which is converted
into glycerol 3 phosphate
 Activation of lipoprotein lipase which
provides fatty acids for esterification
Metabolic effects of insulin
3. Effect on protein metabolism:
 Increases protein synthesis by increasing
entry of amino acids
Mechanism of insulin action
• Insulin binds to specific high affinity cell
membrane receptors
• Receptors are located on the cell membranes
of liver, muscle and adipose
Structure of Insulin receptor
• Synthesized as a single polypeptide that is
glycosylated and cleaved into two subunits
• The two subunits termed (α and β) are
assembled as a tetramer.
• There is a disulfide bridge that connects α
subunits together.
• A disulfide bridge connects α with β subunit
• β subunit spans plasma membrane.
• α subunit is extra-cellular, contains insulin
binding site.
Signal transduction of insulin receptor signaling
• Binding of insulin to α subunits induces a
conformational change
• Conformational change is transduced to β subunit
• This allows for auto-phosphorylation of specific
tyrosine residues on β subunit
• Auto-phosphorylation induces phosphorylation
of a group of proteins called Insulin Receptor
Substartes (IRS)
• Phosphorylated IRS activate multiple biological
pathways
Tissue specific requirement of insulin for glucose
transport
Insulin promotes the recruitment of
insulin sensitive glucose transporters
GLUT-4
Time course of insulin action
Hours to days
Minutes to hours
Immediate
•Changes in enzymatic
activity
•Changes in
phosphorylation state
Increase in glucose uptake
by adipose tissue and
skeletal muscles
An increase in the
amount of many
enzymes
(Glucokinase,
pyruvate kinase,
Phosphofructokinase)
Glucagon
• Glucagon is a polypeptide hormone secreted
by α cells of pancreatic islets of Langerhans
• Glucagon maintains blood glucose levels by:
 Activation of hepatic glycogenolysis.
 Activation of gluconeogenesis.
• Glucagon is made of 29 amino acids arranged
in a single polypeptide chain
Counter-regulatory hormones
• Glucagon, epinephrine, cortisol, and growth hormone
oppose the actions of insulin
Regulation of Glucagon secretion
• Stimulation of glucagon secretion:
Low blood glucose (Primary stimulus to
prevent hypoglycemia)
Amino acids
Epinephrine from adrenal medulla
Norepinephrine from sympathetic
innervation
N.B: During periods of stress and trauma,
glucagon levels increase regardless of
blood glucose levels
Regulation of glucagon secretion
• Inhibition of glucagon secretion:
 Elevated blood glucose
 Insulin
Metabolic effects of Glucagon
• Effects on carbohydrate metabolism:
Increase in breakdown of liver glycogen
Increase in gluconeogenesis
• Effects on lipid metabolim:
Hepatic oxidation of fatty acids and
subsequent formation of ketone bodies from
acetyl CoA
Effect on adipose tissue is minimal in humans
Metabolic effects of Glucagon
• Effects on protein metabolism:
Increase in uptake of amino acids by liver.
Increase in availability of carbon skeletons for
gluconeogenesis.
Mechanism of action of Glucagon
• Glucagon binds to high affinity hepatic
glucagon receptors.
• Binding of glucagon leads to activation of
Adenylate cyclase
• Adenylate cyclase converts ATP to cAMP
(second messenger)
• cAMP activates cAMP dependent protein
kinase
• This results in phosphorylation dependent
activation or inhibition of key enzymes
Metabolic changes during
fasting
Mahmoud A. Alfaqih BDS PhD
Jordan University of Science and Technology
Fasting
Overview
• Result from an inability to obtain food, the desire to lose
weight, or in clinical situations (trauma, surgery,
neoplasms, or burns)
• Plasma levels of glucose, amino acids, and TAG fall
• A decline in insulin secretion and an increase in
glucagon release
• Catabolic period characterized by degradation of TAG,
glycogen, and protein
Fasting
Overview
• Metabolic changes that take place are guided by:
1. The need to maintain plasma levels of glucose to sustain the brain,
RBCs.
2. The need to mobilize fatty acids from adipose tissue, and the
synthesis and release of ketone bodies from the liver.
Liver during fasting
Adipose tissue during fasting
Resting skeletal muscle during fasting
Brain during fasting
Kidney in prolonged fasting
 In early starvation and beyond, the kidneys play an
important role.
 Kidney expresses the enzymes of gluconeogenesis,
including glucose 6-phosphatase.
 In late fasting about 50% of gluconeogenesis occurs in
the kidney.
Role of ammonia produced by the kidneys in
acid base balance
 The glutamine released from muscle's metabolism of branchedchain amino acids is taken up by the kidney
 Glutamine is converted into α-ketoglutarate and ammonia by the
action of renal glutaminase and glutamate dehydrogenase.
 α-ketoglutarate can enter the TCA cycle.
 The ammonia picks up H+ from ketone body dissociation, and is
excreted in the urine as NH4+, decreasing acidity.
 In long-term fasting, there is a switch from nitrogen disposal in the
form of urea to disposal in the form of ammonia.