ENDOCRINE SYSTEM: FALL2003
MARTIN G. LOW, DEPT. PHYSIOLOGY
Q: WHY DO VERTEBRATES HAVE AN ENDOCRINE SYSTEM?
Q: WHY DO VERTEBRATES HAVE AN ENDOCRINE SYSTEM?
A: ALTHOUGH IT ALLOWS EXTREMELY RAPID COMMUNICATION THE “HARD
WIRING” OF THE NERVOUS SYSTEM IS TOO “EXPENSIVE”, INEFFICIENT (AND
UNNECCESARY) FOR THE DELIVERY OF MOLECULAR SIGNALS TO EVERY
CELL IN THE BODY.
THE CARDIOVASCULAR SYSTEM, WHICH IS MOSTLY DEVOTED TO
TRANSPORTING OXYGEN AND NUTRIENTS, CAN ALSO PROVIDE A HIGHLY
EFFICIENT, BUT RELATIVELY SLOW SYSTEM FOR DELIVERING “SOLUBLE”
MESSENGER MOLECULES TO ESSENTIALLY EVERY CELL IN THE BODY.
HOWEVER TO ENSURE FIDELITY AND SPECIFICITY OF THE SIGNALLING
PROCESS THESE “SOLUBLE MESSENGERS” MUST BE GUIDED TO THE
CORRECT DESTINATION BY A “MOLECULAR ADDRESS”
1
ENDOCRINE
STIMULUS
CELL A
TRANSPORT VIA BLOODSTREAM TO
DISTANT PARTS OF THE BODY
CELL B
HORMONE
SECRETION
2
RESPONSE
NEUROCRINE
CELL A
NEURON
CELL B
TRANSPORT VIA BLOODSTREAM TO DISTANT TARGET TISSUES
HORMONE
HORMONE
3
CELL
TYPE A
PARACRINE
SIGNALLING BETWEEN
“NEIGHBORING” BUT
DIFFERENT
CELLS VIA ECF
4
CELL
TYPE B
CELL
TYPE X
AUTOCRINE
CELL
TYPE X
CELL
TYPE X
SIGNALLING
BETWEEN
“NEIGHBORING”
IDENTICAL
CELLS OF SAME
TYPE
SUMMARY OF THE MAJOR COMPONENTS OF THE
ENDOCRINE SYSTEM
BRAIN
ANTERIOR LOBE
OF PITUITARY
GnRH
PRL
BREAST
GHRH
LH/FSH
GH
LIVER
GONADS
IGF-1
MILK
VASOPRESSIN
POSTERIOR LOBE
OF PITUITARY
TRH
DIET
CRH
TSH
ACTH
GLUCOSE
THYROID
ADRENAL
CORTEX
PANCREAS
T3 +T4
TARGET TISSUES
CALCIUM
PARATHYROID
PTH
STEROIDS
STEROIDS
ADRENAL
CORTEX
OXYTOCIN
GLUCAGON
INSULIN
FEEDBACK LOOPS
BRAIN
RH = RELEASING
HORMONE
HYPOTHALAMUS
IH
ULTRA
SHORT
L0OP
SHORT
LOOP
RH
IH = INHIBITORY
HORMONE
LONG LOOP
PITUITARY
LONG LOOP
TROPIC HORMONE
PERIPHERAL ENDOCRINE
GLAND
HORMONE
TARGET TISSUES
THREE DIFFERENT
SECRETION
MECHANISMS
*PEPTIDE
*STEROID
*THYROID
FEEDBACK REGULATION
OF PITUITARY HORMONE
SECRETION
STRUCTURE & FUNCTION OF MAJOR HORMONES
CHEMICAL STRUCTURE
HORMONE
M.W.
TRIIODOTHYRONINE (T3)
<1000
THYROXINE (T4)
<1000
STEROIDS
<1000
ARG-VASOPRESSIN (ADH)
~1000
OXYTOCIN
~1000
GLUCAGON
~3,500
29-RESIDUE PEPTIDE
CALCITONIN
~ 4,000
32-RESIDUE PEPTIDE
ADRENOCORICOTROPHIC
HORMONE (ACTH)
4,500
INSULIN
6,000
PARATHYROID HORMONE
9,500
PROLACTIN (PRL)
23,000
GROWTH HORMONE (GH)
22,000
THYROID-STIMULATING
HORMONE (TSH)
28,000
IODINATED TYROSINE DERIVATIVES
CHOLESTEROL DERIVATIVES
CHORIONIC
GONADOTROPHIN (hCG)
GROWTH, METABOLISM &
DEVELOPMENT
''
ANTI-DIURETIC HORMONE
(S-S) LINKED CYCLIC NONAPEPTIDES
39-RESIDUE PEPTIDE DERIVED
FROM 31K POMC PRECURSOR
51-RESIDUE PEPTIDE WITH
(S-S)-LINKED A AND B CHAINS
84-RESIDUE PEPTIDE
198 /191 RESIDUE GLYCOPROTEINS WITH
~ 80% HOMOLOGY
GLYCOPROTEINS WITH:
LUTEINZING HORMONE (LH) 30,000
FOLLICLE-STIMULATING
HORMONE (FSH)
MAJOR FUNCTION
SUCKLING RESPONSE
PLASMA GLUCOSE
PLASMA Ca
STIMULATES RELEASE
OF CORTICAL STEROIDS
PLASMA GLUCOSE
LIPOLYSIS
PLASMA CALCIUM
LACTOGENESIS
GROWTH / METABOLISM
STIMULATES RELEASE
OF T3 AND T4
COMMON ALPHA SUBUNIT
REGULATION OF
30,000
AND VARIABLE BETA SUBUNIT
SPERMATOGENESIS
AND OOGENESIS
57,000
LEPTIN: 16kDa 139-RESIDUE PEPTIDE
MAINTENANCE OF
CORPUS LUTEUM
CELL SURFACE RECEPTORS AND THEIR TRANSDUCERS: GROUP I
RECEPTOR
/ HORMONE
β1, β2, β3 - ADRENERGIC
MAJOR TRANSDUCERS
G PROTEIN : CYCLASE
α1- ADRENERGIC
G PROTEIN : PLC-β
α2- ADRENERGIC
G PROTEIN : PLC-β AND CYCLASE
M1- MUSCARINIC
G PROTEIN : PLC-β
D2-DOPAMINERGIC
G PROTEIN : PLC-β AND CYCLASE
HISTAMINE
G PROTEIN : PLC-β
BRADYKININ
G PROTEIN : PLC-β
ANGIOTENSIN
G PROTEIN : PLC-β
VASOPRESSIN
G PROTEIN : PLC-β
GLUCAGON
G PROTEIN : AND CYCLASE
CALCITONIN
G PROTEIN : AND CYCLASE
PARATHYROID HORMONE
G PROTEIN : AND CYCLASE
PROSTAGLANDIN E2
G PROTEIN : AND CYCLASE
LEUKOTRIENES
G PROTEIN : PLC-β
CELL SURFACE RECEPTORS TRANSDUCERS AND MESSENGERS?: GROUP II
RECEPTOR
/ HORMONE
MAJOR TRANSDUCERS
THROMBOXANE A2
G PROTEIN : PLC-β
THYROTROPIN-RELEASING HORMONE (TRH)
G PROTEIN : PLC-β
THYROID-STIMULATING HORMONE (TSH)
G PROTEIN : CYCLASE
FOLLICLE-STIMULATING HORMONE (FSH)
G PROTEIN : CYCLASE
LUTEINIZING HORMONE (LH)
G PROTEIN : CYCLASE
EPIDERMAL GROWTH FACTOR (EGF)
RECEPTOR TYROSINE KINASE: PLC-γ
PLATELET-DERIVED GROWTH FACTOR (PDGF)
RECEPTOR TYROSINE KINASE; PLC-γ
INSULIN
RECEPTOR TYROSINE KINASE; IRS-1
INSULIN -LIKE GROWTH FACTOR 1 ( IGF-1)
RECEPTOR TYROSINE KINASE; IRS-1
GROWTH HORMONE (GH)
NON-RECEPTOR TYROSINE KINASE; JAK/Stat
PROLACTIN (PRL)
NON-RECEPTOR TYROSINE KINASE; JAK/Stat
ACTIVIN/INHIBIN (TGF-β FAMILY)
RECEPTOR Ser/Thr KINASE:Smad
NEUROHYPOPHYSIS
(POSTERIOR PITUITARY)
ADENOHYPOPHYSIS
(ANTERIOR PITUITARY)
HYPOTHALAMUS
NEUROCRINE CELLS
RELEASING
AND
INHIBITING
HORMONES
MEDIAN EMINENCE
AND NEURAL STALK
ADH
OXYTOCIN
LONG
PORTAL VEIN
2
1
SUPERIOR
HYPOPHYSEAL
ARTERY
4
3
ENDOCRINE CELLS
INFERIOR
HYPOPHYSEAL
ARTERY
ANTERIOR PITUITARY HORMONES
ACTH GH
EFFERENT VEINS
PRL
LH
TSH FSH/LH
GH CONCENTRATION
CONTROL
AFTER 2 DAY FAST
GH SECRETION IS
TIGHTLY COUPLED
TO SLEEP PERIOD
FASTING INCREASES
GH SECRETION
AND UNCOUPLES IT
FROM SLEEP PERIOD
MAGNITUDE GREATER
DURING PUBERTY
2pm
8pm
2am
8am
8am
2pm
8pm
2am
8am
8am
2pm
8pm
2am
8am
8am
2pm
8pm
2am
8am
GH SECRETORY RATE
8am
PREPROOPIOMELANOCORTIN
26
265
+
146
76
+
+
ACTH
+
-LIPOTROPIN (91)
 -LIPOTROPIN (58)
-ENDORPHIN (31)
STRUCTURAL ORGANIZATION OF MAMMALIAN PREPROGLUCAGON
31
1
GRPP
69
64
GLUCAGON
IP-1
107/8
GLP-1
GLP-2
IP-2
MPGF
GLICENTIN
OXYNTOMODULIN
158
126
GLUCAGON
MPGF
GLP-2 (1-33) -
GLP-2 (3-33) -
bioactive
bioinactive
GLICENTIN
PANCREAS
GLUCAGON
MPGF
INTESTINE*
GLP-1
BRAIN
“ENTEROGLUCAGONS”
OXYNTOMODULIN-1
GLP-2
*
IP-2
HORMONES HAVE VARIABLE IN VIVO “STABILITY”
t½
HORMONE
FSH
3h
CORTISOL
70 min
ALDOSTERONE
70 min
LH
60 min
ACTH
I5 min
ADH
8 min
INSULIN
5-8 min
OXYTOCIN
3-5 min
POTENTIAL REASONS
FOR VARIABLE STABILITY
STEROIDS ARE HYDROPHOBIC
AND MAY PARTITION INTO
MEMBRANES AND ADIPOSE TISSUE
HORMONE CLEAVED BY SPECIFIC
PEPTIDASES IN PLASMA
HORMONE FORMS COMPLEX WITH
BINDING PROTEIN WHICH PROTECTS
IT FROM DEGRADATION
SHORT PEPTIDES ARE PARTICULARLY
VULNERABLE TO DEGRADATION
BECAUSE THERE ARE
FEW CONSTRAINTS ON THEIR
CONFORMATION
PERIPHERAL CONCENTRATION (ng/ml)
GnRH PULSE FREQUENCY REGULATES
SECRETION OF LH AND FSH
LH
LH
PLASMA LH
FSH
0
FSH
10
20
30
40
DAYS
HOURS
INTRACELLULAR RECEPTORS:“LIGAND-ACTIVATED
TRANSCRIPTION FACTORS”
HORMONES WITH INTRACELLULAR RECEPTORS ARE HYDROPHOBIC ALLOWING
DIFFUSION ACROSS PLASMA MEMBRANE
HIGHLY VARIABLE
TRANSCRIPTION-ACTIVATION
DOMAIN
HIGHLY CONSERVED (66 AMINO ACID)
DNA-BINDING DOMAIN CONTAINING
TWO “ZINC FINGERS”
N
“CONSERVED”
240 AMINO ACID
HORMONE-BINDING
DOMAIN
(STEROIDS ONLY)
C
CELL SURFACE RECEPTORS REQUIRE TRANSMEMBRANE SIGNALLING
POLYPEPTIDE HORMONES ARE
HYDROPHILIC AND CANNOT DIFFUSE
ACROSS THE PLASMA MEMBRANE
THIS PROBLEM IS SOLVED BY UTILISING THE
ENERGY OF HORMONE BINDING AT THE CELL
SURFACE TO ALTER CONFORMATION OF
TRANSMEMBRANE PROTEINS AND THEIR
INTERACTIONS WITH INTRACELLULAR
PROTEINS
OTHER STEROID HORMONES
GLUCOCORTICOIDS (GR)
PROGESTERONE (PR)
TESTOSTERONE (AR)
ESTROGEN (ER)
1
STEROID HORMONES DIFFUSE ACROSS PLASMA MEMBRANE
STEROID HORMONES BIND TO SPECIFIC, SOLUBLE
INTRACELLULAR RECEPTORS
2
GLUCOCORTICOSTEROID
HORMONES BIND TO A
SOLUBLE INTRACELLULAR
GR RECEPTOR: hsp90
COMPLEX
release of inhibitory
hsp90 proteins reveals
nuclear localization signal on
GR receptor
NUCLEUS
+
3
GRE: GLUCOCORTICOID
RESPONSE ELEMENT
HRE: HORMONE RESPONSE
ELEMENT
+ve HRE
- ve HRE
STEROID-RESPONSIVE
TARGET GENES
STEROID RECEPTORS TRANSLOCATE
INTO THE NUCLEUS AND INTERACT WITH
GRE’S, OTHER HRE’s AND COACTIVATOR
MOLECULES
REGULATION OF TRANSCRIPTION BY NON-STEROIDAL HORMONES
-
NUCLEUS
RX R
N
HRE
NO HORMONES
NO TRANSCRIPTION
HORMONE-RESPONSIVE
HORMONE-RESPONSIVE
TARGET
GENES
TARGET
GENES
C
RETINOID X RECEPTOR SUBUNIT
(RX)
REPRESSES TRANSCRIPTIONAL
ACTIVATION BY HORMONE
RECEPTOR (R)
PLUS HORMONES
NUCLEUS
+
VITAMIN D
RETINOIC ACID
THYROID HORMONE
HRE
TRANSCRIPTION
HORMONE-RESPONSIVE
TARGET GENES
HORMONE BINDING
RELIEVES REPRESSION
BY RETINOID X
RECEPTOR
TRANSDUCER
COMPLEX
MESSENGER CASCADE
TRANSCRIPTION
PERMEABILITY
ONE SIGNAL - MANY EFFECTS
SAME HORMONE MAY HAVE
DISTINCT EFFECTS IN DIFFERENT
TISSUES OR CELL TYPES
TRANSCRIPTION
PERMEABILITY
MANY SIGNALS - ONE EFFECT
EFFECTS ON CELL FUNCTION MAY ONLY
OCCUR IF CORRECT COMBINATION OF
HORMONES ACT SIMULTANEOUSLY ON SAME
,
CELL
TRANSDUCER COMPLEXES
METABOLISM
TRANSDUCER
COMPLEXES
MESSENGER
CASCADES
SECRETION
EFFECTS ON
CELLULAR
FUNCTION
TRANSCRIPTION
G PROTEIN: ADENYLYL CYCLASE
G PROTEIN: PLC
RECEPTOR TYROSINE KINASE: PLCγ
RECEPTOR TYROSINE KINASE: IRS-1
RECEPTOR TYROSINE KINASE: Grb2-SoS
non-RECEPTOR TYROSINE KINASE (JAK)
“2ND MESSENGER” CASCADES
cAMP
PROTEIN KINASE A
1,2- DAG
PROTEIN KINASE C
1P3
Ca2+
CALMODULIN
Ras:
MAP KINASE
OTHER IMPORTANT FEATURES
1. AMPLIFICATION BY ENZYMES OR ION
CHANNELS
2.“CROSS-TALK” BETWEEN PATHWAYS
3. RAPID DEGRADATION/ DEACTIVATION
OF 2ND MESSENGERS
STIMULUS INDUCED DIMERIZATION
EGF/ PDGF
G-PROTEIN COUPLED
EGF/PDGF
TSH BINDING SITE
PDGF
SH2 DOMAINS
PDGF
CELL
MEMBRANE
CELL
MEMBRANE
SMALL LIGAND
BINDING SITE
ACCOMODATES
CATECHOLAMINES
P
G-PROTEIN
P
P
P
DESENSITIZATION BY
-ark or pkc
Autophosphorylation
by intrinsic tyrosine kinase
THE INSULIN RECEPTOR IS A
STABLE S-S LINKED DIMER
GROWTH HORMONE AND PROLACTIN
RECEPTORS ARE LIGAND-INDUCED DIMERS
S-S
-S-S-
-S-S-
IRS-1
TYROSINE KINASE
(JAK2)
Stat
IGF-1 USES A SIMILAR MECHANISM
Stat 5A DEFICIENT MICE DO NOT LACTATE
GROWTH FACTOR
RECPTOR
SIGNAL TRANSDUCTION FROM CELL
SURFACE RECEPTORS TO THE NUCLEUS
TYROSINE PHOSPHORYLATION OF
RECEPTOR RECRUITS Grb2-Sos TO
PLASMA MEMBRANE
PROTEIN
KINASE C
GTP
Ras
ATP
MAPKKK
ADP
ATP
MAPKK
ADP
GDP
ACTIVATION OF Ras BY GUANINE
NUCLEOTIDE EXCHANGE FACTOR
Raf/MAPKKK ACTIVATED
BY RAS OR PROTEIN KINASE C
ACTIVATION OF MAP- KINASE
REQUIRES BOTH THREONINE AND
TYROSINE PHOSPHORYLATION
MAPK
NUCLEUS
PHOSPHORYLATION OF TRANSCRIPTION
FACTORS IN NUCLEUS
RECEPTOR
ACTIVATION
HETEROTRIMERIC G PROTEINS
CYCLASE
ACTIVATION

γ

γ


GTP
GDP
GTP
Pi
NUCLEOTIDE
EXCHANGE
GDP
HIGH INTRINSIC GTPase
= RAPID DEACTIVATION
ATP
cAMP
Ras AND OTHER SMALL G PROTEINS
SIGNAL IN
GTP
Sos
GDP
NUCLEOTIDE EXCHANGE
GTP
Ras
(inactive)
Ras
GDP
(active)
LOW INTRINSIC
GTPase
GAP
GTPase Activating Protein
SIGNAL OUT
MULTIPLE ROLES OF INTRACELLULAR CALCIUM IONS
LIGAND-GATED
PI-LINKED
CALCIUM CHANNEL
RECEPTOR
VOLTAGE-SENSITIVE
CALCIUM CHANNEL
G PROTEIN
PLC
Ca2+
Ca2+
IP3
CALCIUM IS “STORED”
PIP2
IN THE ENDOPLASMIC
RETICULUM
2+
Ca /CALMODULIN
MYOSIN LIGHT
CHAIN KINASE
(MLCK)
PHOSPHORYLASE
KINASE
MYOSIN LIGHT
CHAIN
PHOSPHORYLASE
EUKARYOTIC
ELONGATION FACTOR II
CAM KINASE 3
MULTIFUNCTIONAL
CAM KINASES
HO
HO
PLC
4
3
5
2
6
1
P
OH
4
3
2
5
P
INOSITOL
1,4,5-TRISPHOSPHATE
IP3
6
1
HYDROLYSIS
HO
PHOSPHATIDYLINOSITOLS
ARE HYDROLYSED BY
PHOSPHOLIPASE C INTO TWO
SECOND MESSENGERS
1,2-DIACYLGLYCEROL
PHOSPHATIDYLINOSITOL
PI-4P
PI
PI-4,5P2
4
4-KINASE
3
5
3
5
2
6
2
6
1
1
P
P
P
4
PI-3,4,5P3
5-KINASE
4
3
5
2
1
P
P
4
3
5
2
6
PI-3KINASE
6
1
P
1,2-DAG
PI 3,4 -P2
PHOSPHATIDYLINOSITOL
CYCLE
PROTEIN KINASE C
ACTIVATION
PHOSPHOLIPASE C
(PLC) MEDIATED
PI HYDROLYSIS
IS STIMULATED BY
MANY HORMONES
PI 3,4,5-P3
PI 3-KINASE
INSULIN ACTION
PI
PI 4-P
PLC
PI 4,5-P2
PHOSPHORYLATION
RESYNTHESIS
DEGRADATION
I
Li +
Li + BLOCKS
RESYNTHESIS
IP
IP2
CALCIUM RELEASE
FROM ER VIA LIGAND
GATED CHANNEL
IP3
PHOSPHOLIPASE C ISOFORMS
PLC
N
PH
X
EF
Y
C
CATALYTIC SITES
REGULATED
BY Gq
PLC
N
PH
EF
X
SH2
SH2
SH3
Y
C
REGULATED BY
TYROSINE
PHOSPHORYLATION
PLC
N
PH
EF
X
Y
C
CATALYTIC SITES
REGULATED
BY Gq
SEQUENCE MOTIFS INVOLVED IN SIGNAL TRANSDUCTION
DOMAIN
NAME
MOTIF RECOGNIZED
src homology 2
SH2
pY-X-X-X
“phosphotyrosine-binding”
PTB
- ψ -N-P-X-pY-
src homology 3
SH3
“proline-rich region”
Pleckstrin Homology
PH
PI-Px headgroups
Ψ =Hydrophobic residue
PROTEIN
ARRANGEMENT OF BINDING DOMAINS
AND CATALYTIC SITES
src kinase
--Myr----SH3----SH3----SH2----Tyr kinase---
Btk
Shc
--PH----Pro----SH3----SH2----Tyr kinase-----PTB----SH2- (‘Collagen-like’)
Grb-2
--SH3----SH2----SH3
Shp-2 (Syp)
--SH2----SH2----PTPase
PLC
PLC
?
--PH----PLC----PLC--
PLC
--PH----PLC----SH2----SH2----SH3----PLC
PLC
--PH----PLC----PLC
PKB
--PH---- Ser/Thr kinase
p120Ras-GAP
--SH2----SH3----SH2----PH----GAP
LECTURE 3
INSULIN RECEPTOR SIGNALING PATHWAY
GLUCOSE
UPTAKE
INSULIN
PDK
GLUT4
TRANSLOCATION
IRS-1
PY
PI 3-KINASE
INHIBITORS
e.g. WORTMANNIN
BLOCK GLUCOSE
UPTAKE
PY
GSK3
SH2
PI 3-KINASE
INHIBITION OF LIPOLYSIS
FATTY ACID
SYNTHESIS
GLYCOGEN
GENE
EXPRESSION SYNTHESIS
SYNTHESIS AND SECRETION OF PEPTIDE HORMONES
9. INCREASED HORMONE SYNTHESIS
1.TRANSCRIPTION
AFTER CHRONIC STIMULATION
AGONIST
2. ALTERNATIVE SPLICING
NUCLEUS
mRNA
Ca2+
ENDOPLASMIC RETICULUM
3. TRANSLATION
4. TRANSLOCATION
5. TISSUE-DEPENDENT
PROTEOLYTIC PROCESSING.
6. PACKAGING (200X
CONDENSATION) INTO
SECRETORY VESICLES
7. SECRETORY VESICLES
ACCUMULATE CLOSE TO
PLASMA MEMBRANE
REGULATION OF PLASMA GLUCOSE BY INSULIN AND GLUCAGON
Pglucose
Pglucose
GLUCOSE:
PANCREAS
 cell
- SYNTHESIS
INSULIN
SECRETION
INSULIN
t½ approx 5 min
- MOBILIZATION
PARACRINE INHIBITION OF ISLETS OF
LANGERHANS BY INSULIN
GLUCOSE:
- UPTAKE
GLUCAGON
t½ approx 10 min
GLUCAGON
SECRETION
PANCREAS
 cell
TARGET TISSUES
(liver, muscle, adipose, etc.)
- UTILIZATION
- STORAGE
1 MILLION ISLETS EACH
CONTAINING 2500 CELLS
BLOOD FLOWS RADIALLY FROM CENTER OF ISLET
TO THE PERIPHERY FACILITATING PARACRINE
INHIBITION OF GLUCAGON SECRETION BY INSULIN
CORE FORMED BY BETA CELLS
SECRETING INSULIN
(60-70 % OF TOTAL)
MANTLE FORMED BY  CELLS
SECRETING GLUCAGON (20-25%)
ARTERIAL BLOOD
 CELL
Canaliculus
ISLETS OF LANGERHANS
 CELL
SECRETORY
GRANULES
VENOUS BLOOD
BLOOD
VENOUS
PHYSIOLOGICAL ROLE OF INSULIN
MAINTENANCE OF NORMAL PLASMA GLUCOSE LEVELS IN
SPITE OF LARGE CHANGES DUE TO FOOD INTAKE
RAPID UPTAKE OF DIETARY GLUCOSE
STIMULATION OF GLUCOSE TRANSPORT
STIMULATION OF GLUCOSE UTILIZATION
UTILIZATION OF DIETARY GLUCOSE
STIMULATION OF GLYCOGEN SYNTHESIS
STIMULATION OF GLUCOSE OXIDATION
STIMULATION OF LIPID SYNTHESIS
PRESERVATION OF ENERGY STORES
INHIBITION OF GLYCOGEN DEGRADATION
INHIBITION OF GLUCONEOGENESIS
INHIBITION OF LIPOLYSIS
INHIBITION OF PROTEOLYSIS
K+
REGULATION OF
INSULIN SECRETION
BY GLUCOSE
THESE CHANNELS ARE ALSO
SENSITIVE TO OTHER STIMULI
SUCH AS ACETYLCHOLINE AND
CATECHOLAMINES
-
Ca2+
K+
ATP/ADP
GLUCOSE
OXIDATION
Ca2+
Ca2+
INSULIN
SECRETION
GLYCOLYSIS
GLUCOSE
ATP
GLUT2
KM >15mM
UNLIKE HEXOKINASE, GLUCOKINASE
IS NOT INHIBITED BY GLUCOSE-6-P
GLUCOSE
RESPONSE OF PLASMA GLUCOSE, GLUCAGON, ACTH AND GROWTH
LEVELS TO INSULIN INJECTION
100
80
Pglucose
ACTH
60
40
GROWTH
HORMONE
20
0
30
INSULIN INJECTION
60
MINUTES
90
120
RESPONSE OF PLASMA INSULIN AND GLUCAGON
TO ORAL GLUCOSE
180
POOR GLUCOSE
TOLERANCE
150
120
90
Plasma
glucose
NORMAL GLUCOSE
TOLERANCE
AVERAGE
VALUE
plasma
insulin
60
30
0
Plasma
glucagon
BELOW 60 mg/dl METABOLISM
IS LIMITED BY GLUCOSE
AVAILABILITY
1h
2h
3h
4h
5h
TISSUE/PLASMA DISTRIBUTION OF GLUCOSE AFTER A
MEAL
PLASMA/ECF
10g/h
11g
GLUT- 2
LIVER
FOOD
75g
GLYCOGEN
75-100g
6g/h
GLUT- 1
7g/h
14g/h
KIDNEY
0g/h
GLUT- 4
URINE
MUSCLE
300-400g
GLUT- 4
ADIPOSE
LIVER
GLYCOGEN
75-100 g
FED
7g/h
GLUT- 2
BRAIN
RBC’s
10g/h
INSULIN
LIVER
INSULIN
MUSCLE
GLYCOGEN
GLYCOGEN
+
+
AFTER
MEAL
PROTEIN
GLUCOSE
GLUCOSE
GLUT4
GLUCAGON
GLUCOSE
AMINO ACIDS
GLUCOSE
GLYCOGEN
GLYCOGEN
DURIN
G
FAST
+
GLUCOSE
+
ATP
MUSCLE
PROTEIN
GLUCOSE-6-P
PROTEOLYSIS
GLUCONEOGENESIS
LATE IN FAST~12-15h
GLUT4
AMINO ACIDS
GLUCOSE
AMINO ACIDS
CORTISOL HELPS TO MAINTAIN PLASMA
GLUCOSE LEVELS DURING A FAST BY
STIMULATING GLUCONEOGENESIS/LIPOLYSIS
AND INHIBITING LIPID SYNTHESIS
MUSCLE
PROTEIN
GLUT4
AMINO ACIDS
FATTY ACIDS PROVIDE AN ABUNDANT
SOURCE OF ENERGY BUT IN VERTEBRATES,
(UNLIKE PLANTS),THEY CANNOT BE
CONVERTED BACK TO GLUCOSE
IN DIABETES THERE IS NO
INSULIN TO INHIBIT THIS
PROCESS
PGLUCOSE
FATTY ACIDS
AMINO ACIDS
GLUCONEOGENESIS
LIPOLYSIS
GLUCOSE
LIVER
GLYCOGEN
FAT DROPLET
FATTY ACIDS
ADIPOSE
DURING A FAST THE LIVER MOBILISES
GLUCOSE
STORED FAT IN ADIPOSE TISSUE AND
CONVERTS IT TO KETOACIDS FOR EXPORT TO
OTHER TISSUES
LIVER
KETONE BODY SYNTHESIS
CAPILLARY ENDOTHELIUM
HYDROLYSIS OF TRIGLYCERIDES
TG
FFA
FFA
FFA
ACETYL CoA
“KETONE
FFA
BODIES”
MUSCLE HEART etc.
ß-OXIDATION OF FATTY ACIDS
TO ACETYL CoA
FFA
FFA
FREE FATTY ACIDS (FFA) HAVE
ADIPOSE TISSUE
HYDROLYSIS OF STORED
TRIGLYCERIDES (TG) BY LIPASE
LOW SOLUBILITY AND ARE
TRANSPORTED IN THE BLOOD
BOUND TO ALBUMIN OR
LIPOPROTEINS
SMALL INTESTINE
DIETARY
GLUCOSE
DIGESTION, ABSORPTION AND
DIETARY FAT
RESYNTHESIS OF TRIGLYCERIDES (TG)
FFA
TG
AFTER A MEAL THE LIVER
SYNTHESIZES FREE FATTY ACIDS
(FFA) FROM GLUCOSE AND
EXPORTS IT TO THE TISSUES AS
TRIGLYCERIDES
FFA
GLUCOSE CAN BE CONVERTED
TO FAT, BUT FAT CANNOT BE CONVERTED
BACK TO GLUCOSE
CAPILLARY ENDOTHELIUM
HYDROLYSIS OF TRIGLYCERIDES
LIVER
FATTY ACID SYNTHESIS
ACETYL CoA
MUSCLE, HEART etc.
ß OXIDATION OF FATTY ACIDS
ADIPOSE TISSUE
RESYNTHESIS AND STORAGE OF
FFA
ACETYL CoA
TRIGLYCERIDES
FFA
REM Sleep
Arginine
exercise
STRESS
preREM Sleep
REGULATION OF GROWTH
HORMONE SECRETION
PGLUCOSE
+
+
-
+
-
HYPOTHALAMUS
THERE ARE 6 DISTINCT
IGF BINDING PROTEINS
IGFBP(1-6) . ONE OF THEM IS
THE EXTRACELLULAR PORTION
OF THE GH RECEPTOR
SOMATOSTATIN / GHIH
-
+
TRANSPORT IN BLOOD
GHRH
“SOMATOMEDIN”
PITUITARY
FREE IGF’s
BOUND IGF’s
GROWTH HORMONE
BASAL GH  10-10M
TOO LOW TO MEASURE
ACCURATELY
MANY TISSUES
METABOLIC EFFECTS:
INCREASED LIPOLYSIS
AND PROTEIN SYNTHESIS
DECREASED GLUCOSE USE
“SOMATOMEDIN”
GROWTH HORMONE
IS SPECIES-SPECIFIC
LIVER AND FIBROBLASTS
IGF-1 AND IGF-2 SECRETION
BONE AND CARTILAGE
SKELETAL
GROWTH EFFECTS
HORMONAL REGULATION OF METABOLISM
LIPOLYSIS
PROTEIN
DEGRADATION
GLUCOSE
SYNTHESIS
LIVER
GLYCOGEN
PLASMA
GLUCOSE
(-1)
( )
( )
INSULIN
CORTISOL
GLUCAGON
GROWTH
HORMONE
CATECHOLAMINES
LEPTIN
?
REM Sleep
STRESS
+
PGLUCOSE
REGULATION OF ADRENAL
HORMONE SECRETION
+
HYPOTHALAMUS
“ADDISON’S DISEASE”
DESTRUCTION OF THE
ADRENAL GLAND BY DISEASE
OR BY SURGICAL REMOVAL OF
THE GLAND. THIS DISEASE IS
LETHAL IF NOT TREATED BY
HORMONE REPLACEMENT
THERAPY
-
CORTISOL
CRH
+
-
PITUITARY
ACTH
TRANSPORT IN BLOOD
BOUND STEROIDS (90%)
FREE STEROIDS (10%)
CORTISOL IS NOT STORED
+
CHOLESTEROL *
ADRENAL CORTEX
“ZONA FASCICULATA”
ACTH STIMULATES STEROID SYNTHESIS WITHIN
MINUTES DUE TO CHOLESTEROL ALREADY PRESENT
IN MITOCHONDRIAL INNER MEMBRANE
ALDOSTERONE
STEROIDS
ANDROGEN
PRECURSORS
LECTURE 4
CAPSULE
MEDULLA
RETICULARIS
MEDULLA
SECRETION OF INDIVIDUAL
STEROID HORMONES IS
RESTRICTED TO SPECIFIC
REGIONS OF THE ADRENAL
CORTEX
ALL STEROIDOGENIC TISSUES
STEROID SYNTHESIS
CHOLESTEROL (C27)
minus side
chain
+ 20-keto
GONADS
PREGNENOLONE (C21)
DEHYDROEPIANDROSTERONE
SULFATE (C19 :“DHEA-S”)
+ 17-OH
+ 3-keto
desmolase
17-OH PREGNENOLONE
PROGESTERONE
+ 21-OH
sulfotransferase
DEHYDROEPIANDROSTERONE”
’’DHEA”
+ 17-OH
+ 3-keto
+ 3-keto
desmolase
+ 11-OH
CORTICOSTERONE
+ 18-ALDEHYDE
17-OH PROGESTERONE
+ 21-OH
ANDROSTENEDIONE (C19)
TESTOSTERONE
aromatase
+ 11-OH
+3-keto
ALDOSTERONE (C21)
ADRENAL CORTEX
CORTISOL (C21)
DIHYDROTESTOSTERONE (C19)
ESTRONE
aromatase
ESTRADIOL (C19)
SYNTHESIS AND “SECRETION” OF STEROID HORMONES BY ADRENAL CORTEX
1
UPTAKE OF CHOLESTEROL
ESTER FROM LDL AND HDL
IN PLASMA
2
CHOLESTEROL IS TAKEN UP INTO MITOCHONDRIA
EITHER DIRECTLY FROM PLASMA LDL/HDL OR FROM
INTRACELLULAR CHOLESTEROL ESTERS “STORED”
IN LIPID DROPLETS
StAR facilitates transfer of
cholesterol molecules between
inner and outer membranes
KIDNEY
ALDOSTERONE
Cholesterol in
Intracellular
Lipid droplets
DIFFUSION OF STEROIDS
OUT OF CELL
CORTISOL
4
P450c11
11-HYDROXYLASE
REMOVAL OF
SIDE CHAIN
17-OH PROGESTERONE
ENDOPLASMIC RETICULUM
3
OXIDATION OF STEROID NUCLEUS
BY SPECIFIC P-450 HYDROXYLASES
ANDROGEN
PRECURSORS
GONADS
20
CHOLESTEROL
12
18
2
16
C
15
14
9
C H3
13
C
19
10
 5-PREGNENOLONE
17
11
1
21
12
8
7
5
4
1
2
13
C
19
6
15
14
9
10
17
16
11
B
3
18
O
8
B
C H3
17-OH PROGESTERONE
12
C
18
11
1
2
C
19
9
10
10
13
14
3
C H3
7
5
6
4
C
O
12
OH
16
2
15
8
5
O
4
6
16
9
10
10
13
C
19
14
15
8
B
B
7
18
11
1
O
O
7
5
6
PROGESTERONE
ANDROSTENEDIONE
ESTRONE
O
12
18
11
1
2
O
12
17
16
13
11
10
15
14
9
1
2
8
17 14
8 17
9
Aromatase
7
HO
6
7
5
6
4
OH
OH
12
18
11
1
2
12
17
C
9
1
14
15
2
8
O
TESTOSTERONE
C
9
10
14
8
B
7
6
13
19
B
5
18
11
13
19
10
15
B
5
4
C
19
10
B
OH
13
C
19
18
Aromatase
HO
7
5
4
6
ESTRADIOL
DIHYDROTESTOSTERONE
15
“PRE-RECEPTOR REGULATION” OF STEROID HORMONE ACTION
11ß-HYDROXYSTEROID DEHYDROGENASE - (11ß-HSD)
11ß- HSD TYPE 1 (LIVER)
CORTISOL ACTIVE
12
OH
2
C
10
10
16
13
1
14
15
2
8
O
7
5
4
6
19
11
40 C
9
10
10
13
14
8
B
B
B
3
18
OH
19
9
OH
O
12
18
11
11
1
CORTISONE INACTIVE
CH20H
C
11ß- HSD TYPE 2 (KIDNEY)
333
O
7
5
4
6
O
OH
16
15
LOCAL DEHYDROGENATION OF THE C11 HYDROXYL GROUP ON
CORTISOL PROTECTS MINERALOCORTICOID RECEPTORS (MR)
FROM INAPPROPRIATE ACTIVATION
ALDOSTERONE:MR
CORTISOL or CORTISONE : MR
CORTISOL or CORTISONE : GR
Kd~1nM
Kd~1nM
Kd~10nM
IN SPITE OF THE HIGH AFFINITY OF CORTISOL / CORTISONE FOR THE MR IN
VITRO, GLUCOCORTICOIDS DO NOT BIND TO MR IN TARGET TISSUES. THIS IS
DUE TO THE “PRE-RECEPTOR INACTIVATION” OF CORTISOL BY 11ß-HSD2
LIVER
ADIPOSE
GONADS
CORTISOL
CORTISOL
11ß-HSD1
11ß-HSD2
OXIDATION OF
C11 HYDROXYL
CORTISOL
CORTISONE
GR
RESPONSE
nucleus
MR
NO RESPONSE
nucleus
KIDNEY,COLON
SALIVARY
GLAND, HEART
BINDING AFFINITIES OF STEROIDS TO PLASMA PROTEINS
HORMONE
CORTISOL
CORTISOL BINDING
PROTEIN (CBP)
76
CORTISONE
7.8
ESTRADIOL
0.06
PREGNENOLONE
PROGESTERONE
17α -OH-PROGESTERONE
TESTOSTERONE
SEX HORMONE
BINDING GLOBULIN
(SHBG)
0.18
24
55
5.3
1.6
2.7
ALBUMIN
0.003
0.005
680
0.06
14
0.06
8.8
0.06
9.9
0.4
1600
0.04
SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION
TYROSINE
TYROSINE
IODINATION
MONOIODOTYROSINE (MIT)
THYROGLOBULIN
I
THYROGLOBULIN
Tyr
Approximately 10% of the tyrosine residues on the
550 amino acid residue Thyroglobulin molecule may
become iodinated by the enzyme - thyroid
peroxidase acting on the colloid at the luminal
surface of the thyroid follicle. These reactions only
occur in the thyroid at specific residues in
“Hormonogenic” sites located at the extreme ends of
the Thyroglobulin molecule.
TYROSINE
IODINATION
I
DIIODOTYROSINE (DIT)
-
Tyr
NH2
I
THYROGLOBULIN
SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES
I
HO
I
CH2CHCOOH
Tyr
I
HO
5’
+ HO
Tyr
CH2CHCOOH
HO
I
Tyr
O
Tyr
3
T4
I
Thyroglobulin
Thyroglobulin
5
3’
NH2
NH2
I
II
I
3,5,3’5’-tetraiodothyronine
I
Coupling of iodotyrosine moities results in the loss
of the peptide linkage to thyroglobulin allowing thyroid
hormones to diffuse across the cell membrane
3,5,3’-Triiodothyronine
I
Tyr
HO
CH2CHCOOH
+
Tyr
CH2CHCOOH
NH2
NH2
HO
Tyr
O
Tyr
I
I
Thyroglobulin
Thyroglobulin
I
T3
I
3,5,3’5’-tetraiodothyronine
STEP 3
DEIODINATION
I
I
O
Tyr
CH2CHCOOH
Tyr
NH2
“DEACTIVATION” PATHWAY
I
T4
I
5’- deiodination
5-deiodination
rT3
I
Tyr
O
“ACTIVATION” PATHWAY
SELENODEIODINASES
I
T3
I
Tyr
CH2CHCOOH
Tyr
I
O
Tyr
NH2
I
3,3’,5’-Triiodothyronine (reverse T3)
CH2CHCOOH
NH2
I
3,5,3’-Triiodothyronine (T3)
SECRETION OF THYROID HORMONE
4
IODINATION OF THYROGLOBULIN
BY THYROID PEROXIDASE
TG
3
TG
TG
I
ENDOCYTOSIS OF
‘COLLOID’ IN FOLLICLE BY
PSEUDOPOD
5
FUSION OF PHAGOSOME
WITH LYSOSOMES
TG
DEGRADATION
AND
RECYCLING
OF MIT/DIT
BY DEIODINASES
6
TG
DEGRADATION OF
THYROGLOBULIN
7
T4
2
FREE THYROXINE RELEASED FROM
PROTEIN INTO CYTOPLASM
8
IODIDE UPTAKE
BY Na/I
SYMPORTER
“DIFFUSION” OF THYROXINE
THROUGH CELL MEMBRANE
T4> > > T3
1
IODIDE IN
ECF~20nM
Additional metabolism??
THYROID HORMONES
HORMONE
T4
T3
rT3
*
RELATIVE
POTENCY
+
++++
-
PRODUCTION
PLASMA
CONCENTRATION
(µg/day)
(µg/dL)
80- 90
8
4-8 (24)*
2-3 (27) *
BOUND TO
PLASMA
PROTEINS
(%)
99.95
t½
(days)
6-7
0.3
99.7
1-3
0.04
99.8
0.1
VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION
EFFECTS OF THYROID HORMONE ON TARGET TISSUES
MOST EFFECTS OF THYROID HORMONE ARE “PERMISSIVE”:
THYROID HORMONE PROMOTES SYNTHESIS OF PROTEINS WHICH ARE THEN
REGULATED ACUTELY BY OTHER HORMONES.
THYROID DISEASES
METABOLISM
THYROID HORMONE INCREASES:
BASAL METABOLIC RATE
BODY TEMPERATURE
CARDIAC OUTPUT/ TACHYCARDIA
MOBILIZATION OF ENERGY STORES
GROWTH AND DEVELOPMENT
THYROID HORMONE REQUIRED IN
PERINATAL PERIOD FOR:
NEURAL DEVELOPMENT
BONE GROWTH (GH)
CONGENITAL HYPOTHYROIDISM
DUE TO “METABOLIC” DEFECT IN
THYROID HORMONE SYNTHESIS
RESULTING IN MENTAL RETARDATION
UNCOMMON IN DEVELOPED COUNTRIES
DUE TO EARLY POST- NATAL TESTING
“ENDEMIC”
HYPOTHYROIDISM
DUE TO IODIDE DEFICENCY
OR GOITROGENS.
READILY PREVENTED BY
IODIDE SUPPLEMENTATION
OF FOOD
HYPERTHYROIDISM
AUTOIMMUNE “GRAVES
DISEASE”
PITUITARY TUMOR
THYROID TUMOR
WEIGHT LOSS
THYROID DISEASES
DISEASE
TYPE
CONGENITAL
IODIDE
DEFICIENCY
AUTOIMMUNE:
THYROIDITIS
AUTOIMMUNE:
GRAVES DISEASE
THYROID SERUM
STATUS
HYPO
HYPO
HYPO
T3 +T4
LOW
LOW
LOW
SERUM
TSH
HIGH
HIGH
HIGH
CAUSE OF DISEASE
DEFECT IN IODIDE TRAP OR
THYROID HORMONE
SYNTHESIS
DIET: (i) LOW IN IODIDE
OR (ii) GOITROGENS
PRESENT
DESTRUCTION OF THYROID
TISSUE DUE TO INFLAMMATION
AUTOANTIBODIES TO THE TSH
HYPER
HIGH
LOW
RECEPTOR PROVIDE CONTINUOUS
UNREGULATED STIMULUS
THYROID TUMOR
HYPER
HIGH
LOW
PITUITARY TUMOR
HYPER
HIGH
HIGH
UNREGULATED SYNTHESIS
AND SECRETION OF T3 AND T4
UNREGULATED SYNTHESIS
AND SECRETION OF TSH
CALCIUM IN DIET
PLASMA Ca2+
CALCIUM SENSOR
DECREASE IN PLASMA
CALCIUM STIMULATES
PARATHYROID
HORMONE (PTH) SECRETION
PTH
CHOLESTEROL
PARATHYROID
VITAMIN D3
PTH
25-(OH)-D3
PO4
BONE
KIDNEY
1,25-(OH)2-D3
Ca2+
CALCIUM REABSORPTION
PHOSPHATE EXCRETION
Ca2+
INCREASE IN PLASMA CALCIUM
STIMULATES CALCITONIN
SECRETION FROM THYROID
PARAFOLLICULAR CELLS
PLASMA Ca2+
URINE
PO4
GUT
100
% MAXIMAL PTH RESPONSE
PTH SECRETION EXHIBITS A STEEP INVERSE SIGMOIDAL
DEPENDENCE ON EXTRACELLULAR Ca2+
INCREASED Ca2+ SUPRESSES
PTH SECRETION VIA A G PROTEIN
COUPLED MECHANISM
50
0
1.0
1.25
IONIZED CALCIUM (mM)
1.5
CALCITONIN IS SECRETED FROM THE THYROID PARAFOLLICULAR CELLS
BUT IS CALCITONIN AN IMPORTANT PHYSIOLOGICAL SUBSTANCE?
The observation that calcitonin (CT) at supraphysiological doses is hypocalcemic, led to the mistaken
conclusion that it was important for calcium homeostasis and this idea has persisted to this day.
Despite these findings there is no readily apparent pathology due to CT excess or deficiency and there
is no evidence that circulating CT is of substantial benefit to any mammal. ……….. .
Mammalian CT at physiological doses is not essential and very likely the CT gene has survived
because of the gene’s alternate mRNA pathway to produce calcitonin-gene-related peptide found in
neural tissues.
HIRSCH,PF and BARUCH H, ENDOCRINE 2003, 201-208