1. SIGNAL TRANSDUCTION: INSULIN
BIOC DR. TISCHLER
LECTURE 23
SIGNAL TRANSDUCTION: INSULIN

2. OBJECTIVES
1. Structures of proinsulin and insulin; significance of C-peptide.
2. Mechanism for stimulation of insulin secretion and synthesis by glucose by increasing intracellular calcium.
Insulin receptor
a) key structural features of the
b) steps for activation of tyrosine kinase of insulin receptor; the
role of interchain autophosphorylation of tyrosine residues
c) three intracellular proteins phosphorylated by tyrosine kinase.
4. Mechanism by which insulin mobilizes GLUT-4 transporter to
muscle/fat cell plasma membrane via IRS, p85 and PI-3K.
5. Compare causes of type I and type II diabetes; what is meant by
insulin resistance in the type II form.

3. C-peptide secreted with insulin and cleared into the urine
PROINSULIN
COO- -S S-
NH3+
C-peptide
C-peptide secreted with insulin and cleared into the urine
INSULIN
COO- -S S-
NH3+
In the pancreatic -cell preproinsulin is processed to proinsulin
and then to insulin that is secreted
Figure 1. The structural features of proinsulin and insulin

4. Figure 2. Control of insulin synthesis and secretion by glucose.
Secreted insulin + C-peptide
Protein kinase C
DAG
IMMEDIATE
SECRETION 6
INSULIN
BIOSYNTHESIS
AND PROCESSING 5
Ca2+
Glucose 1
Calmodulin G L U T 2
METABOLISM 2
ATP 3 
CaM-kinase 4 
Ca2+
Figure 2. Control of insulin synthesis and secretion by glucose.
CaM kinase: calmodulin-dependent protein kinase; DAG: diacylglycerol

5. -OOC +3HN NH3+ S Insulin -S-S- -subunits
Insulin binding: negative cooperativity
EXTRACELLULAR
COO -
-OOC S S
NH3+
+3HN
Plasma
membrane
Transmembrane
domain
Tyrosine
kinase
domain
CYTOPLASM
-OOC
COO-
-subunits
Figure 2. The insulin receptor. Insulin binding to the -chains transmits a signal through the transmembrane domain of the -chains to activate the tyrosine kinase activity

6. Extracellular 3
IRTK (R)
phosphorylated/
activated 1
insulin
binds L R 2
IRTK (L)
activated OP P P P
Cytoplasm P
ATPs P
Phosphorylation
catalyzed by IRTK (L)
ADPs
Figure 4. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation

7. Extracellular 3
IRTK (R)
phosphorylated/
activated 1
insulin
binds L R 2
IRTK (L)
activated 4
IRTK (L)
phosphorylated OP PO OP P
ATPs
ADPs
Phosphorylation
catalyzed by IRTK (L)
ATPs
ADPs P P P P P
Cytoplasm
Phosphorylation
catalyzed by
IRTK (R)
Figure 4. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation

8. Control of the Insulin Receptor
Insulin binding and subsequent dissociation
Autophosphorylation to activate
Serine phosphorylation to inactivate

9. Figure 5. Intracellular action of insulin
Activated IRTK PO OP
Figure 5. Intracellular action of insulin
Glucose
Extracellular
Cytoplasm
GLUT-4
Glucose transport
(muscle/adipose)
Signal transduction (e.g., IRS,
SHC, PLC phosphorylation)
metabolic
responses
Activation of protein
phosphatase leads to
dephosphorylation of
enzymes in glycolysis,
glycogen metabolism,
lipogenesis,
cholesterol synthesis
KINASE CASCADE
(protein phosphorylation)
Cell growth
and replication
DNA synthesis
Mitogenic
response
NUCLEUS
mRNA synthesis
Protein
synthesis

10. IRS, insulin-receptor substrate; PO OP
Extracellular
space
Cytoplasm
= GLUT-4
Active IRTK 
tyr-OH
IRS
ATP
ADP
[1] IRTK
catalyzed 
tyr-OP
IRS
p85
[2] activated
by docking
active IRS 
tyr-OP
IRS
PI-3K 
tyr-OP
IRS 
tyr-OP
IRS 
tyr-OP
IRS
active
IRS
PIP2
PIP3
Figure 6. Hypothetical mechanism for insulin to mobilize GLUT-4 transporter to the plasma membrane in muscle and adipose tissue.
IRS, insulin-receptor substrate;
IRTK, insulin receptor tyrosine kinase;
PI-3K, phosphatidyl-inositol kinase;
PDK; phospholipid-dependent kinase
PKB, protein kinase B +
[4] signals Golgi to traffic GLUT-4 to
membrane
PDK
PKB
GOLGI

11. Figure 7. Insulin stimulated glucose transport (GLUT-4)
Step 5
Receptor
inactivation
Step 6
translocation back to Golgi
Glucose
Step 2
translocation
From Golgi
Step 4
Glucose
transport
Golgi
(signal)
glucose
Step 3
Binding and fusion
transporter P - - P
Step1 -
insulin binding
and signal transduction
Figure 7. Insulin stimulated glucose transport (GLUT-4)
in adipose or muscle cells

12. Type I versus Type II Diabetes
Autoimmune destruction of pancreas -cells
Lost ability to produce insulin
Requires life-long insulin injection
Lack of treatment leads to hyperglycemia
Generally begins in children but may not appear until 20’s
Type 2
Initiated by reduced ability to respond to insulin
Loss of ability to produce insulin
Hyperglycemia despite high blood insulin =
insulin resistance
Generally begins in adulthood but is increasingly seen in
teen and pre-teen years
Potential to be a major epidemic