Introduction to The Endocrine Control

on
Metabolism

M. Djauhari Widjajakusumah
Department of Physiology
Fakultas Kedokteran Universitas Indonesia

Food intake

Dietary protein Dietary carbohydrate

Dietary triglyceride fat

D I G E S T I O N
Absorbable
units

Amino acids

Glucose

Fatty acids Monoglycerides

A B S O R B T I O N
Metabolic pool
Body proteins
Glycogen storage
(liver & muscle)
Triglycerides
(adipose tissue)

Amino acids
Glucose
Fatty acids

Urea --> urinary excretion

Oxydation to CO2+H2O+ATP

Figure 673
Interconversions of the three
major monosaccharidesglucose,
fructose, and galactosein liver
cells.

Guyton & Hall: Textbook of Med ical Physiol

11th ed, 2006

Ganongs Review of
Medical Physiology
22nd ed, 2005

Figure 674
Chemical reactions of glycogenesis and glycogenolysis, showing also
interconversions between blood glucose and liver glycogen. (The phosphatase
required for the release of glucose from the cell is present in liver cells but not in
most other cells.)
Guyton & Hall: Textbook of Medical Physiol
11th ed, 2006

Figure 172. The pathway of glycolysis. ( P ,

PO3
PO3
2; Pi, HOPO3 2; , inhibition.) At asterisk:
Carbon atoms 13 of fructose bisphosphate
form dihydroxyacetone phosphate, whereas
carbons 46 form glyceraldehyde 3phosphate. The term bis-, as in
bisphosphate, indicates that the phosphate
groups are separated, whereas diphosphate,
as in adenosine diphosphate, indicates that
they are joined.

Harpers Illustrated Biochemistry 26th

ed, 2003

Fig. 22.6. A. The pyruvate produced by glycolysis enters mitochondria and

is oxidized to CO2 and H2O.The reducing equivalents in NADH enter
mitochondria via a shuttle system

Fig. 22.6. B. Pyruvate is reduced to lactate in the cytosol, thereby using the
reducing equivalents in NADH.

Figure 675
Sequence of chemical reactions
responsible for glycolysis.
Guyton & Hall: Textbook of Medical
Physiol 11th ed, 2006

Oxaloacetic
acid
H2O

Acetyl coenzyme A
CoA
Citric acid
H2O
cis-Aconitic acid

H2O
Isocitric acid
2H
Oxalosuccinic acid
CO2
a-Ketoglutaric
H2O acid
ADP
Succinic acid

CO2
2H
ATP

Fumaric acid
H2O
Guyton & Hall: Textbook
of Medical Physiol 11th
ed, 2006

Malic acid
2H
Oxaloacetic acid

Net reaction per molecule of

glucose:
2 Acetyl-CoA + 6H2O + 2ADP
4CO2 + 16H + 2CoA + 2ATP

Guyton & Hall: Textbook

of Medical Physiol 11th
ed, 2006

Figure 677
Mitochondrial chemiosmotic mechanism of oxidative phosphorylation for forming large
quantities of ATP. This figure shows the relationship of the oxidative and phosphorylation
steps at the outer and inner membranes of the mitochondrion.

Formation of ATP in the Citric Acid Cycle.

+
Formation of Large Quantities of ATP by
Oxidation of Hydrogen
(the Process of OxidativePhosphorylation)

Guyton & Hall: Textbook of Medical Physiol

11th ed, 2006
Chapter 67, pp 834-835

GLUCOSE TRANSPORTERS IN MAMMALS

Function

Major sites of expression

Secondary active transport

(Na+ - glucose cotransport)
SGLT-1
SGLT-2

Absorption of glucose
Absorption of glucose

Small intestine.
Renal tubules

GLUT 1

Basal glucose uptake

Placenta, blood-brain barrier,

brain, red cells, kidneys,
colon,many other organs

GLUT 2

B cell glucose sensor, transport out of intestinal & renal

epithelial cells

B cells of islets, liver, epithelial

cells of small intestine, kidneys

GLUT 3

Basal glucose uptake

Brain, placenta, kidneys, many

other organs

GLUT 4
GLUT 5

Insulin-stimulated glucose
uptake
Fructose transport

Skeletal and cardiac muscle,

adipose tissue, other tissues
Jejunum. Sperm

GLUT 6

None

Pseudogene

GLUT 7

Glucose 6-phosphate
Liver, ?other tissues
transporter in endoplasmic
reticulum

Facilitated difussion

Figure 214

Ganongs Review of Medical Physiology 23rd

ed, 2010

Cycling of GLUT 4 transporters through endosomes in insulin-sensitive

tissues. Activation of the insulin receptor causes activation of
phosphoinositide 3-kinase, which speeds translocation of the GLUT 4containing endosomes into the cell membrane. The GLUT 4 transporters
then mediate glucose transport into the cell.

Figure 1. Insulin signaling pathways involved in stimulating glucose transport. Insulin binding to the IR
results in phosphorylation of tyrosine residues (in green) on the receptor and substrates such as IRS-1.
Docking of the regulatory subunit of PI3-kinase to phosphotyrosine residues of IRS-1 activates its
serine/threonine kinase activity and the phosphorylation cascade involving PDKs and Akt. While these
steps are necessary for the recruitment of intracellular pools of insulin-responsive glucose transport to
the plasma membrane, the mechanism connecting Akt to cellular trafficking of GLUT4 is not known.

Figure 2. Potential mechanisms involved in the stimulation of glucose transport by acute exercise. Muscle contractile
activity induces a recruitment of a separate pool of intracellular GLUT4 to the plasma membrane and a subsequent
increase in glucose transport. This effect does not involve the components of the insulin signaling pathway. Muscle
contraction is initiated by a necessary release of calcium to permit cross bridge formation. Intracellular calcium activates
PKC serine kinases which have been hypothesized to stimulate GLUT4 recruitment by unknown mechanisms. Contractile
activity alters the AMP/ATP ratio leading to the stimulation of AMPK. AMPK activation leads to an increase in glucose
transport, possibly through several mechanisms. AMPK can phosphorylate and activate eNOS, and NO production by this
enzyme may contribute to exercise stimulated glucose transport. AMPK can also lead to the phosphorylation of p38 MAPK,
which may be involved in the GLUT4 translocation response.

Fig 21-11. Mean rates of insulin and glucagon delivery from an artificial pancreas at
various plasma glucose levels. The device was programmed to establish and
maintain various plasma glucose levels in insulin-requiring diabetic humans, and the
values for hormone output approximate the output of the normal human pancreas.
The shape of the insulin curve also resembles the insulin response of incubated B
cells to graded concentrations of glucose.

Figure 2110

Factors
Factors Affecting
Affecting Insulin,
Insulin, Glucagon
Glucagon
and
and Growth
Growth Hormone
Hormone Secretion
Secretion

COMPLEMENTARY INTERACTIONS OF GLUCAGON AND INSULIN

Blood glucose

Blood glucose

--

-Alpha cell
Glucagon
Insulin

+
Beta cell
Insulin

Blood glucose
to normal
Meals
Blood glucose increases
decreases
Insulin increases
Glucagon decreases

+
Alpha cell

Beta cell

Glucagon

Blood glucose
to normal
Between meals
Blood glucose
Insulin decreases
Glucagon increases

FACTORS CONTROLLING INSULIN SECRETION

Blood glucose
Concentration
Gastrointestinal

acid

hormones
+

Blood amino
concentratio n

Major control
Food intake
+
+
Parasympathetic
stimulation
+

--

+ +

Islet B cells
Sympathetic
(and epinephrine)

Insulin secretion
Blood glucose
Blood fatty acids
Blood amino acids
Protein synthesis
Fuel storage

Figure 1914. Insulin secretion. Glucose enters B cells by GLUT 2 transporters. It is

phosphorylated and metabolized to pyruvate (Pyr) in the cytoplasm. The Pyr enters the
mitochondria and is metabolized via the citric acid cycle. The ATP formed by oxidative
phosphorylation inhibits ATP-sensitive K+ channels, reducing K+ efflux. This depolarizes
the B cell, and Ca2+ influx is increased. The Ca2+ stimulates release of insulin by
exocytosis. Glutamate (Glu) is also formed, and this primes secretory granules,
preparing them for exocytosis.

Factors Affecting Glucagon Secretion (Islets A Cells)

Stimulators

Inhibitors

Amino acids
Glucose (hyperglycemia)
(particularly
Somatostatin
the glucogenic AA)
Secretin
CCK, gastrin
FFA
Cortisol
Ketones
Exercise
Insulin
Stresses
2-adrenergic
stimulators
2-adrenergic stimulators
GABA
Effect of beta-receptors
hyperglycemia GABA
predominates
released from B cells
inhibits glucagon
secretion
Acetylcholine
Theophylline

Control of Growth Hormone Secretion

Stimuli that increase GH secretion

Deficiency of energy substrate
o Hypoglycemia
o Exercise
o Fasting
Stressful stimuli
Increase in circulating certain amino acids
o Protein meal
o Arginine
Glucagon

Effects of Insulin
Increases glucose uptake and storage in the liver
1. Activates glucokinase decreases free liver
glucose
increases glucose uptake
2. Inhibits glucose 6-phosphatase decreases free
liver
glucose increases glucose uptake
3. Inactivates liver phosphorilation prevents
glycogenolysis
4. Activates glycogen synthase increases
glycogenesis

Insulin

Marks Basic Medical

Biochemistry 2nd ed 2005

Effects of Insulin
Liver
1. Decreased ketogenesis
2. Increased protein synthesis
3. Increased lipid synthesis
4. Decreased hepatic glucose output, due to:
decreased gluconeogenesis
increased glycogen synthesis
increased glycolisis

Effects of Insulin
Adipose Tissue
1. Increased glucose entry
2. Increased fatty acid synthesis
3. Increased glycerol phosphate synthesis
4. Increased triglyceride deposition
5. Activation of lipoprotein lipase
6. Inhibition of hormone-sensitive lipase

Effects of Insulin
Muscle
1. Increased glucose entry
2. Increased glycogen synthesis
3. Increased amino acid uptake
4. Increased protein synthesis
5. Decreased protein catabolism
6. Decreased release of gluconeogenic amino acids

EFFECTS OF GLUCAGON
Glycogenolytic
Only in liver cells, not in muscle cells.
No glucagon receptor on muscle cells.
Via c-AMP, and IP3 & DAG Ca++
Decreases the metabolism of glucose 6-phosphate
Inhibits phospho-enolpyruvate pyruvate
Inhibits fructose 6-phosphate fructose 1,6
diphosphate
Results: build up of glucose 6-phosphate
increases free glucose (through glucose 6phosphatase activation by GH & cortisol)

Figure 19-16. Mechanisms by which glucagon increases glucose output

from the liver. Solid arrows indicate facilitation, and dashed arrows
indicate inhibition.

EFFECTS OF GLUCAGON
Gluconeogenic
Lipolytic
Ketogenic
Inotropic
Increases myocardial c-AMP
Stimulates secretions of:
GH, insulin and pancreatic somatostatin

Fed State

Ganongs Review of
Medical Physiology
22nd ed, 2005

Role of Insulin in Lowering Blood Glucose Level

C.J. Coffee 1998: Metabolism; Integrated Medical Sciences 1st ed

Glycogen Is Stored in Liver and Muscle

o After absorption into a cell, glucose can be used
immediately for release of energy to the cell, or it
can be stored in the form of glycogen, which is a
large polymer of glucose.
o All cells of the body are capable of storing at least
some glycogen, but certain cells can store large
amounts, especially liver cells, which can store up to
5 to 8 per cent of their weight as glycogen, and
muscle cells, which can store up to 1 to 3 per cent
glycogen.
Guyton & Hall: Textbook of Medical Physiol
11th ed, 2006

C.J. Coffee 1998: Metabolism;

Integrated Medical Sciences 1st ed

Marks Basic Medical

Biochemistry: A Clinical
Approach, 2nd Edition, 2005

Fig. 33.11. Regulation of acetyl CoA carboxylase.

Insulin

Fatty Acyl CoA

Triacylglycerols

Marks Basic Medical

Biochemistry: A Clinical
Approach, 2nd Edition, 2005

Fig. 33.11. Regulation of acetyl CoA carboxylase.

insul
in

insul
in

+ insul

in

insul
in

Fig. 33.24. Conversion of the fatty acid (FA) from the triacylglycerols (TG) of
chylomicrons and VLDL to the TG stored in adipose cells. Note that insulin
stimulates both the transport of glucose into adipose cells and the secretion
of LPL from the cells. Glucose provides the glycerol 3-phosphate for TG
synthesis. Insulin also stimulates the synthesis and secretion of lipoprotein

Marks Basic Medical Biochemistry 2nd ed, 2005

Fasting State

Role of Glucagon in Increasing Blood Glucose Level

C.J. Coffee 1998: Metabolism; Integrated Medical Sciences 1st ed

Hormones
affecting
glycogenolysis
in liver cells

Glucagon receptor

Fasting
state

Marks Basic Medical Biochemistry 2nd ed, 2005

Fig 28.8

Fed
state

Insulin
+

Insulin

Insulin

Insulin

Marks Basic Medical Biochemistry 2nd ed, 2005

Fig 28.8

Harpers Illustrated Biochemistry 26th ed,

2003
Insulin

Insulin

Figure 186. Control of phosphorylase in muscle. The sequence of reactions

arranged as a cascade allows amplification of the hormonal signal at each step. (n =
number of glucose residues; G6P, glucose 6-phosphate.)

Marks Basic Medical Biochemistry 2005

Marks Basic Medical

Biochemistry, 2nd ed, 2005

GLUCAGON

Hormones affecting hepatic

glucose output in liver cells

Figure 19-16. Mechanisms by which glucagon increases glucose output

from the liver. Solid arrows indicate facilitation, and dashed arrows
indicate inhibition.

adrenergic receptors, which increase intracellular cAMP, and adrenergic

receptors, which increase intracellular Ca2+. Hepatic glucose
output is
increased, producing hyperglycemia.

In muscle, the phosphorylase is also activated via cAMP and

presumably
via Ca2+, but the glucose 6-phosphate formed can be catabolized
only to
pyruvate because of the absence of glucose 6-phosphatase. For
reasons that
are not entirely clear, large amounts of pyruvate are converted
to lactate,
which diffuses from the muscle into the circulation (Figure 21
17).

The lactate is oxidized in the liver to pyruvate and converted to

glycogen.

Therefore, the response to an injection of epinephrine is an initial

glycogenolysis followed by a rise in hepatic glycogen content.

Lactate oxidation may be responsible for the calorigenic effect of

epinephrine (see Chapter 22).

beta-3

Hormones affecting lipolysis

in fat cells

Figure 191. Major pathways and regulation

of gluconeogenesis and glycolysis in the
liver. Entry points of glucogenic amino acids
after transamination are indicated by arrows
extended from circles. The key
gluconeogenic enzymes are enclosed in
double-bordered boxes. The ATP required for
gluconeogenesis is supplied by the oxidation
of long-chain fatty acids. Propionate is of
quantitative importance only in ruminants.
Arrows with wavy shafts signify allosteric
effects; dashshafted arrows, covalent
modification by reversible phosphorylation.
High concentrations of alanine act as a
gluconeogenic signal by inhibiting
glycolysis at the pyruvate kinase step.

Harpers Illustrated Biochemistry 26th

ed, 2003, page 154

Fig. 22.12. Major sites of regulation in the

glycolytic pathway. Hexokinase and
phosphofructokinase-1 are the major
regulatory enzymes in skeletal muscle.
The activity of
pyruvate dehydrogenase in the
mitochondrion determines whether
pyruvate is converted
to lactate or to acetyl CoA. The regulation
shown for pyruvate kinase only occurs for
the
liver (L) isoenzyme.

Marks Basic Medical

Biochemistry 2nd ed
2005

Fig. 36.1. Regulation of

glucokinase, PFK-1, and pyruvate
kinase in the liver.
nd

Marks Basic Medical Biochemistry 2

ed 2005

Insulin

Marks Basic Medical

Biochemistry 2nd ed 2005

1 Allosteric., 2 In adipose tissue but not in

Harpers Illustrated Biochemistry 26th ed,

1 Allosteric., 2 In adipose tissue but not in

Harpers Illustrated Biochemistry 26th ed,

Triacylglycerol
Fatty acids

Marks Basic Medical Biochemistry: A Clinical

Approach, 2nd Edition, 2005

Figure 1718.

Ganongs Review of Medical Physiology

22nd ed, 2005

Involvement of the citric acid cycle in transamination and gluconeogenesis. The bold arrows
indicate the main pathway of gluconeogenesis. (Reproduced, with permission, from Murray RK
et al: Harper's Illustrated Biochemistry, 26th ed. McGraw-Hill, 2003.)

Marks Basic Medical Biochemistry: A Clinical Approach, 2nd

Edition, 2005

Fig. 31.20. Sources of blood glucose in fed, fasting, and starved states.
Note that the scale changes from hours to days. From Ruderman NB, et al. In:
Hanson RW, Mehlman MA, eds. Gluconeogenesis: Its Regulation in
Mammalian Species. 1976:518. 1976 Marks
John Wiley
& Sons.
Basic Medical
Biochemistry 2nd ed, 2005

Marks Basic Medical Biochemistry: A Clinical

Approach, 2004

Terima
Kasih