Coordinated regulation of
glycolysis/gluconeogenesis
High blood glucose
Insulin secretion
Synthesis of
hexokinase II,
PFK-1, pyruvate
kinase
Movement
of GLUT4 to
plasma
membrane
of myocyte
Activation of
insulinsensitive
protein kinase
Activation of
protein
kinase B
p.903
p.887
Glucose
Glucose
p.903
GLUT2
Pancreatic b cell
Glucose
Glycolysis
pyruvate
Citric acid
cycle
NADH,FADH2
Oxidative
phosphorylation
ATP
K+
closed
ATP-gated
K+ channel
Ca2+
-+ -+ -+ -+ +- +- +-+ +- +- +- +- +- +-
Membrane depolarization
Open
Ca2+
Voltage-dep.
Ca2+ channel
Insulin
secretion
Movement of GLUT4 to plasma
membrane of myocyte
Glc
Insulin
Glc
Glc
Glc
Glc
Glc
p.396
Glc
Glc
Glc
Glc
Insulin receptor
GLUT4
Cytosol of myocyte
p. 588
Activation of insulin-sensitive kinase
Insulin
Insulin
receptor
Insulinsensitive
kinase
Insulinsensitive
kinase
GM
GM
Glycogen
phosphorylase
PP1
Glycogen
synthase b
a
Phosphorylase
kinase
Glycogen synthesis 
Glycogen degradation 
p.587
Activation of protein kinase B (PKB)
Insulin
Insulin
receptor
PIP2
PI3-K
PIP3
IRS-1
PDK-1
PKB
GSK-3
IRS-1
GSK-3
Glycogen
synthase b
Glycogen
synthase a
Glycogen synthesis
GSK3 inactivate glycogen
synthase by phosphorylation
p.587
Phosphorylation by
Casein kinase II
GSK3
P
P
GSK3
P
P
p.587
GSK3 can be inactivated by
phosphorylation
PKB
P
P
p.578
High blood glucose affect
hexokinase IV activity
Glc
nucleus
Glc
Glc
Glc
Glc
Glc
Glc
GLUT2
Hexokinase
IV
Regulator
protein
Hexokinase
IV
Regulator
protein
Glc
Fru
Fru
Regulator
protein
Fru
Glc
Glc
Hepatocyte
Insulin regulate PFK-1 activity
Insulin
Insulin
receptor
PFK-2
FBPase-2
PFK-2
Phosphoprotein
phosphatase
FBPase-2
Fru
Fru
F6P
F6P
PFK-2
Fru
FBPase-2
F2,6BP
Fru
PFK-1
F1,6BP
FBPase-1
Low blood glucose
Glucagon secretion
Inactivation of
pyruvate kinase L
(liver form)
Activation of
FBPase-2
and
inactivation
of PFK-2
Inactivation of
glycogen
synthase
Activation of
glycogen
phosphorylase
Regulation pathway initiated by p.436
glucagon secretion
glucagon
Glucagon
receptor
b GTP
GDP
g a
Adenylyl
cyclase
cAMP
ATP
GM
Pyruvate
Protein
A
kinase
L
Gkinase
M
PFK-2
FBPase-2
PFK-2
FBPase-2
Pyruvate
kinase L
Regulation of PFK-1 by glucagon
Protein
kinase A
Fru
F1,6BP
PFK-2
FBPase-2
PFK-2
Fru
FBPase-2
F6P
PFK-1
Fru
F2,6BP
FBPase-1
Fru
F6P Fru
F2,6BP
Regulation of glycogen synthesis
and breakdown by glucagon
Inhibitor-1
GM
Glycogen
phosphorylase
Protein
kinase A
PP1
Glycogen
synthase b
a
Phosphorylase
kinase
Glycogen synthesis 
Glycogen degradation 
Protein
kinase A
Inhibitor-1
p. 588
Hexokinase
• There are four isozymes (I, II, III and IV) of
hexokinase encoded by four different genes.
• Hexokinase I and II are allosterically
inhibited by their product, glucose 6phosphate. Hexokinase IV is not inhibited
by G-6-P.
Hexokinase
• Hexokinase I and II are
the predominant forms
existing in muscle.
Hexokinase IV is the
predominant form in liver.
• Hexokinase I and II will
be half-saturated at about
0.1mM, but hexokinase IV
will not be half-saturated
until 10mM.
Hexokinase
• Hexokinase has
different functions in
liver and muscle.
• Muscle consumes
glucose, using it for
energy production.
• Liver maintains blood
glucose homeostasis
by removing or
producing glucose.
Muscle hexokinase
• Because blood glucose
concentration is about
4 to 5 mM, hexokinase
in the muscle (which
will be half saturated
at 0.1mM) is always
working at or near its
maximal rate.
Liver hexokinase
• However, liver
hexokinase (halfsaturated at 10mM)
will not ever reach its
maximal rate even
after meal.
Phosphofructokinase-1
• PFK-1 catalyze the
committing step of
glycolysis.
• This enzyme is
regulated by ATP,
AMP, ADP, citrate and
fructose 2,6bisphosphate.
ATP regulate the affinity of PFK-1
towards its substrate F-6-P
• Not only as a substrate,
ATP is also one of the
end product of the
glycolytic pathway.
• ATP inhibit PFK-1 by
binding to an allosteric
site and lowering the
affinity of the enzyme
for F-6-P.
Molecules regulate PFK-1 and
FBPase-1 activity
PFK-1
ATP
citrate
ADP
AMP
F2.6BP
FBPase-1
• ADP and AMP relieve the inhibition by ATP.
• Citrate increases the inhibitory effect of ATP.
• F-2,6-BP is the strongest activator of PFK-1.
Regulation of gluconeogenesis
Pyruvate carboxylase
FBPase-1
Pyruvate carboxylase
• Pyruvate carboxylase is being
positively regulated by acetylCoA.
• The accumulation of acetylCoA signals that cell’s energy
demands are met.
• Acetyl-CoA also indirectly
inhibit pyruvate
dehydrogenase complex.