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Glucose Homeostasis
Counter Regulation
Dr.Sarma.R.V.S.N
M.D., (Med) M.Sc., (Canada)
Consultant Physician
and Chest Specialist
BioEd Online
Glucose Equilibrium – A Wonder !!

Normal Blood Glucose
 Fasting state : 60 to 100 mg%





Postprandial : 100 to 140 mg %
What keeps the blood glucose in such a narrow range?
Why are we not becoming hypoglycemic when we
fast?
Why is our blood sugar not shooting up to very high
levels after a rich meal ?
What are the regulatory and counter regulatory
hormones ?
2
Glucose Equilibrium – A Wonder !!

Normal Blood Glucose
 Fasting state : 60 to 100 mg%

Postprandial : 100 to 140 mg %
Let us grasp some of the fascinating
 What keeps the blood glucose in such a narrow range?
answers !!



Why are we not becoming hypoglycemic when we
fast?
Why is our blood sugar not shooting up to very high
levels after a rich meal ?
What are the regulatory and counter regulatory
hormones ?
3
Glucose Homeostasis Research Timeline
1552BC
1st Century AD
1776
18th Century
1869
1889
1921-23
1983
2001

1552 BC: Ebers Papyrus in ancient Egypt. First known written description of diabetes.

1st Century AD: Arateus — “Melting down of flesh and limbs into urine.”

1776: Matthew Dobson conducts experiments showing sugar in blood and urine of diabetics.


Mid 1800s: Claude Bernard studies the function of the pancreas and liver, and their roles in
homeostasis.
1869: Paul Langerhans identifies cells of unknown function in the pancreas. These cells later
are named “Islets of Langerhans.”

1889: Pancreatectomized dog develops fatal diabetes.

1921: Insulin “discovered” — effectively treated pancreatectomized dog.

1922: First human treated with insulin. Eli Lilly begins mass production.

1923: Banting and Macleod win Nobel Prize for work with insulin.

1983: Biosynthetic insulin produced.

2001: Human genome sequence completed.
4
Cell growth and energy metabolism
Carbohydrates
Glucose
Pyruvate
Fatty acids
Fats
Amino acids
TCA Cycle
Kreb’s Cycle
Proteins
ATP
5
Intermediary Metabolism of Fuels
6
Intermediary Metabolism of Fuels
Clinical Pearl
1. All the fuels are inter changeable in the body
2. It is the total calorie restriction that is important in Obesity
and T2D
7
Glucose-6-Phosphate – The Central Molecule
8
Glucose-6-Phosphate – The Central Molecule
Clinical Pearl
G-6-Phosphate is the Center Stage for CHO Metabolism
Glucose-6-Phosphate dehydrogenase (G6PD) is the crucial
enzyme
9
Homeostasis of Glucose
Counter Regulation Mechanisms

A steady maintenance of blood glucose with in a narrow range

Fasting state and fed states – their effects on BG

Rate of glucose appearance Ra

Rate of disappearance Rd must be in balance

Blood Glucose (BG) = Ra

- Rd
Control systems
 Glucose Receptors, GLUT 1-14
 Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,
 Insulin Signaling sequences, Glucagon signaling
 Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue
 Feedback loops
 Negative feedback
 Positive feedback
10
Homeostasis of Glucose
Counter Regulation Mechanisms

A steady maintenance of blood glucose with in a narrow range

Fasting state and fed states – their effects on BG

Rate of glucose appearance Ra

Clinical
Pearl
Rate of disappearance Rd must
be in balance

INSULIN
Blood Glucose
(BG) = v/s
Ra - GLUCAGON
Rd

and Rd V/s Ra
Control systems
 Glucose Receptors, GLUT 1-14
 Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,
 Insulin Signaling sequences, Glucagon signaling
 Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue
 Feedback loops
 Negative feedback
 Positive feedback
11
Normal, Hyper and Hypoglycemic states
Ra
Ra is the rate of appearance of
Glucose
100
mg
Rd
Ra
Ra
200
mg
Rd is rate of disappearance of
Glucose
When Ra = Rd; It is
Ra
Euglycemic
state Ra
200
mg
Rd
Rd
Ra > Rd; Ra ↑or Rd↓
HYPERGLYCEMIA
50
m
g
Rd
50
m
g
Rd
Ra < Rd; Ra ↓or Rd ↑
HYPOGLYCEMIA
12
Effect of CHO intake on Glucose Metabolism
Gluconeogen
esis
Lipolysis
Exogenous
CHO
Glycogenoly
sis
Ra
GLUCAG
ON
Rd
INSULIN
13
Glucose Homeostasis
Lower Blood
Glucose
-cells release
Glucagon
stimulate glycogen
breakdown and
gluconeogenesis
Food
Between meals
-cells release
insulin
stimulate glucose
uptake by
peripheral tissues
Higher Blood
Glucose
14
High blood glucose affects the size of beta cells
15
Pancreatic Hormones
Pancreas

Exocrine Pancreas – P Lipase, P amylase etc

Endocrine Pancreas – Islets of Langerhans

Hormones secreted are –

Alpha cells – Glucagon

Beta cells – Insulin

C cells - Somatostatin

D cells - Somatostatin

E cells - ?? Function

F cells - Pancreatic polypeptide (PPP)
16
Regulation of Blood Glucose levels

Glucose is the major source of energy for cells

Blood Glucose (BG) regulated by Insulin & Glucagon
17
Regulation
of beta-cell size
by the level
of blood
glucose
Glucose
Homeostasis
– Insulin
and
Glucagon
18
Glucose Homeostasis Chart
Condition
Receptor
High Blood Sugar
Low Blood Sugar
Toxic to the cells - AGP
Energy needs unmet
Glucose transporter
Glucose transporter
Control Center -cell of the pancreas
Effector
Result
-cell of the pancreas
Insulin
Glucagon
Glucose uptake by
muscle/fat tissue
Lowers blood glucose
Liver breaks down
glycogen to glucose
Raises blood glucose
19
The Six Mechanisms of Transport - CM
2
1
3
6
5
4
20
Membrane Transport Proteins
21
Channel Proteins
22
Cell Membrane - Transporters
23
ATP Powered Receptors
24
Glucose Transport
FIRST STEP
GLUCOSE ABSORPTION IN THE GI TRACT
25
Intestinal Cell Transport
26
Intestinal Cell Transport
Clinical Pearl
New approach in T2D, MS and Obesity - GLUT-2 Blockers
27
The First Messengers from GI tract
THE MESSERGERS
INCRETINS – GLP1 and GIP_
28
Entero-Insular Axis of Secretion
Insulin secretion is also increased

By intestinal polypeptide hormones

GLP-1 (glucagon like peptide) [exendin-4]

Glucose-dependent insulinotropic peptide(GIP)

GLP-1 and GIP are called Incretins

Cholecystokinin and by pancreatic Glucagon.

Insulin secretion is decreased by pancreatic
somatostatin.
29
Entero-Insular Axis of Secretion
Insulin secretion is also increased

By intestinal polypeptide hormones

GLP-1 (glucagonClinical
like peptide)
Pearl [exendin-4]
 Glucose-dependent
insulinotropic
peptide(GIP)
New
Drugs for T2D- Incretin
(GLP-1 and
GIP) Function
Enhancers
 GLP-1 and GIP are called Incretins


Cholecystokinin and by pancreatic Glucagon.
Insulin secretion is decreased by pancreatic
somatostatin.
30
Response to Elevated Blood Glucose
In the post prandial state (after a meal)

Remember there are two separate signaling events

First signal is from the ↑ Blood Glucose to pancreas

To stimulates insulin secretion in to the blood stream

The second signal from insulin to the target cells


Insulin signals to the muscle, adipose tissue and liver
to permit to glucose in and to utilize glucose
This effectively lowers Blood Glucose
31
Response to Elevated Blood Glucose
In the post prandial state (after a meal)

Pearl signaling events
Remember there are Clinical
two separate
1.First
Insulin
secretion
must
be triggered
First Signal
signal
is from the
↑ Blood
Glucose to–pancreas

2.To
Secreted
Insulin
must
trigger
Glucose
uptake
stimulates
insulin
secretion
in to
the blood
stream–
Second signal


The second signal from insulin to the target cells
3. T2D may result from failure of either or both


Insulin signals to the muscle, adipose tissue and liver
to permit to glucose in and to utilize glucose
This effectively lowers Blood Glucose
32
Glucose induced Insulin secretion






Glucose enters the beta cells
through uniporter GLUT 2
Oxidative phosphorylation
ATP closes the ATP gated K+
channel and depolarizes the
cell membrane
Depolarization opens the
voltage gated Ca+ channels
Ca+ enters the beta cells
This leads to exocytosis of
Insulin and secretion
33
Glucose induced Insulin secretion

Glucose enters the beta cells
through uniporter GLUT 2
Clinical Pearl

Oxidative phosphorylation
Closure of KATP Channels by Glucose is
+
 ATP closes the ATP gated K
fundamental
channel and depolarizes the
membrane
Glucose is necessary to cell
stimulate
Insulin
Insulin is necessary
Depolarization opens the
tovoltage
let ingated
glucose
Ca+ channels



Ca+ enters the beta cells
This leads to exocytosis of
Insulin and secretion
34
K+ATP Channel Closed by ↑ BG and SU
35
K+ATP Channel Closed by ↑ BG and SU
Clinical Pearl
1. SU Group close KATP Channels – Secrete
Insulin
2. Differences in action of SU are because of the
differences
in their action on KATP Channels
3. Gliclazide and Glimiperide just hit the SUR
closure and stop
36
Intricacies in the Beta Cell
37
K+ ATP – Sulfonylurea Receptor





K+ ATP channel has two sub
units – Kir6.2 and regulatory
sulfonylurea receptor(SUR)
ATP gated K+ channel is
coupled to SUR
K+ channel can be closed
independently of glucose
This leads to increased
insulin secretion
SUR1 are ATP binding
transporters superfamily
38
K+ ATP – Sulfonylurea Receptor
K+ ATP channel has two sub
Clinical Pearl
units – Kir6.2 and regulatory
sulfonylurea
receptor(SUR)
1. Glibenclamide, Tolbutamide
cause prolonged
+
closer of the SUR
 ATP gated K channel is
coupled to SUR

2. This causes prolonged and intense pressure on
+
 K channel can be closed
Beta cells
independently of glucose
3. This is the cause of late hypoglycemia with these
 This leads to increased
SUs
insulin secretion
4. Beta cell apoptosis sets inSUR1
fast are
after
a binding
few years of
ATP
use
transporters superfamily
39
(F)PHHI

(Familial) Persistent Hyperinsulinemic Hypoglycemia of Infancy

Unregulated insulin secretion

Profound hypoglycemia and brain damage

Manifests at birth or at first year of life

Under diagnosed

Probably the cause of undiagnosed postnatal deaths

Defect is KATP Channels mutation –

Persistent closure with continuous trigger for Insulin release

Treatment is pancreatectomy – (95% of pancreas)
40
K+ATP Channel Opening is Cardio-protective
41
K+ATP Channel Opening is Cardio-protective
Clinical Pearl
1. Glibenclamide, Tolbutamide close the SUR in myocardium
2. This effect is deleterious to heart in ischemia
42
Tyrosine Kinase Pathway - Insulin
43
Tyrosine Kinase Pathway - Insulin
Clinical Pearl
1. Tyrosine Kinase (TK) phosphorylation is the
fundamental step
2. Its failure stops further cascade of intracellular
signals
3. This is one of the possible mechanisms of Insulin
Resistance
4. PPAR- Gamma (Pioglitazone) enhances TK
signaling pathway
44
Insulin Receptor (IR)

Insulin Receptor is a tyrosine kinase.

Consists of 2 units -dimerize when bound with insulin.

Inside cell - auto phosphorylation occurs,

Increasing tyrosine kinase activity.

Insulin Receptor phosphorylates intracellular
signaling molecules.

Stimulates insertion of GLUT-4 proteins

which let in glucose

Stimulate glycogen, fat and protein synthesis.
45
+ HN
3
Insulin
NH3+
S S
S S -S-S-
-subunits
EXTRACELLULAR
-OOC
+ HN
3
S
S
S
S
Plasma
membrane
Tyrosine
kinase
domain -OOC
COONH3+
CYTOPLASM
Transmembrane
domain
COO-
-subunits
Figure 2. The insulin receptor. Insulin binding to the -chains transmits
a signal through the transmembrane domain of the -chains to activate
46
the tyrosine kinase activity
Extracellular
2
1
IRTK (L)
insulin
activated
binds
L
IRTK (R) 3
phosphorylated/
activated
OP
OP
R
P
P
Cytoplasm
P
P
P
ATPs
ADPs
Phosphorylation
catalyzed by IRTK (L)
Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by
47
insulin binding, followed by interchain autophosphorylation
Extracellular
2
1
IRTK (L)
insulin
activated
binds
L
IRTK (R) 3
phosphorylated/
activated
4
IRTK (L)
phosphorylated
PO
OP
OP
R
ATPs
P
Cytoplasm
P
P
PO
P
OP
OP
P P
ADPs
ATPs
ADPs
Phosphorylation
catalyzed by IRTK (L)
Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by
48
insulin binding, followed by interchain autophosphorylation
Insulin Signaling – TK Receptor phosphorylation
Binding of insulin to the TK Receptor causes

Transphosphorylation of tyrosines on the receptor

Phosphotyrosine residues bind to

IRS-1 (insulin receptor substrate – adopter protein)
49
Insulin Receptor (IR)
A key regulator of growth signaling



IR is hetero-tetramer
Insulin binding induces
conformation change and
stimulation of receptor
Tyrosine kinase activity
IR auto-phosphorylates and
phosphorylates downstream
second messengers, like IRS
(Insulin Receptor Substrate)

Obesity down regulation of IR

Diabetes up regulation of IR
50
Epidermal Growth Factor (EGF) Receptor
Auto-phosphorylation of TK (Obesity)
Receptor tyrosine kinases
The interaction of the
external domain of a
receptor tyrosine kinase
with the ligand, often a
growth factor, upregulates the enzymatic
activity of the intra
cellular catalytic
domain, which causes
tyrosine
phosphorylation of
cytoplasmic signaling
molecules.
51
Epidermal Growth Factor (EGF) Receptor
Auto-phosphorylation of TK (Obesity)
Receptor tyrosine kinases
The interaction of the
external domain of a
receptor tyrosine kinase
Clinical Pearl
with the ligand, often a
growth factor, up1. Up regulation of TK receptor
regulates the enzymatic
(autophosphorylation) in obesityactivity of the intra
cellular catalytic
2. Leads to Glucose entry into cells
with out insulin
domain, which causes
signal
tyrosine
phosphorylation of
cytoplasmic signaling
molecules.
52
Insulin Signaling – PKB and MAPK pathways

Ras independent signaling – The PKB Signaling and

Ras dependent – The MAPK Signaling

Ras independent through activation of Protein Kinase B

Responsible for immediate non-genomic effects

Ras dependent – Activation of

Mitogen Activated Protein Kinase (MAPK) pathway

Responsible for genomic effects
53
Insulin Signaling – PKB and MAPK pathways
54
Insulin Signaling – PKB and MAPK pathways
Clinical Pearl
1. Ras independent signaling cascade – PI3P – PKB
2. Ras dependent signaling cascade – MAP Kinase
55
Glucose Uniporter - GLUTs
56
Glucose Uniporter - GLUTs
Clinical Pearl
1. Translocation of GLUT-4 to cell surface is crucial for
Glu. uptake
2. Insulin resistance is usually due to failure of this step
57
Ras Independent – PI3K - PKB Signaling

IRS1 binds PI3 kinase through SH2 domain

This phosphorylates PIP2 to PIP3

Increased concentration of PIP3 recruits

PKB to the plasma membrane

PKB is phosphorylated by

two membrane associated kinases PKC λ and ξ

Active PKB is released into the cytosol

Where it translocates glucose transporter (GLUT-4)

GLUT-4 (uniporter) moves on to the membrane

GLUT-4 lets Glucose in and increases glucose uptake
58
PIP Signaling Pathway
59
Ras - Independent Insulin Signaling
60
Insulin and PI3K Signaling
61
Ras
Independent
Extracellular
Space
= GLUT-4
Active IRTK
Cytoplasm
IRS

PO
PO
OP
OP
tyr-OH
ATP [1] IRTK
Figure 5. Mechanism for insulin to
mobilize GLUT-4 transporter to the
plasma membrane in muscle & adipose
tissue.
IRS, insulin-receptor substrate;
IRTK, insulin receptor tyrosine kinase;
PI-3K, phosphatidyl-inositol kinase;
PDK; phospholipid-dependent kinase
PKB, protein kinase B
catalyzed
IRS
p85 [2] activated
by docking
IRS 
PIactive IRS
tyr-OP

IRS
3K
IRS IRSactive tyr-OP
PIP2


PIP
IRS
3

tyr-OP
tyr-OP
tyr-OP
+
[4] signals Golgi to
traffic GLUT-4 to
PDK
PKB
membrane
ADP
GOLGI
62
Ras Dependent – MAPK Signaling
At the same time…

Phosphorylated insulin receptor binds

to adapter protein SHC through GRB2

GRB2 also has SH3 domains that bind and activates Sos

Binding of Sos to inactive Ras causes a

conformational change that permits release of

GDP and binding of GTP (activation of Ras)

Sos is a GEF for monomeric G protein Ras

Sos dissociates from activated Ras

Linking insulin receptor to Ras
63
Ras - Dependent Insulin Signaling
64
Ras Dependent – MAPK Signaling

Activated Ras passes the signal to raf kinase

Raf activates a cascade of kinases (MAP Kinase cascade)

Mitogen Activated Protein Kinases (MAP Kinases)

Highly conserved kinase cascades

Last kinase in the cascade has to be double phosphorylated

It has high specificity (since it is double phosphorylation)
65
Ras
Dependent
Glucose
Extracellular
GLUT-4
PO
PO
Glucose transport
(muscle/adipose)
Activated IRTK
metabolic
responses
Activation of protein
phosphatase
OP
Cytoplasm
OP
Signal transduction
(e.g., phosphorylation of IRS, SHC, PLC)
Dephosphorylation of:
KINASE CASCADE
glycogen synthase
(protein phosphorylation)
glycogen phosphorylase
mitogenic
Cell growth
phosphorylase kinase
response
acetyl CoA carboxylase and replication
hormone-sensitive lipase
NUCLEUS
phosphofructokinase-2
pyruvate kinase
DNA synthesis
HMG CoA reductase
regulatory kinases
mRNA synthesis
Protein
synthesis
66
Ras Dependent – MAPK Signaling

MAPK regulates the activity of transcription factors

Active MAPK translocates to the nucleus

It phosphorylates several transcription factors

And production of more GLUT4
67
Glucose Entry in to the Cell



Insulin/GLUT4 is not the only pathway
Insulin-dependent, GLUT 4 - mediated
 Cellular uptake of glucose into muscle and
adipose tissue (40%)
Insulin-independent glucose disposal (60%)
 GLUT 1 – 3 in the Brain, Placenta, Kidney
 SGLT 1 and 2 (sodium glucose symporter)
 Intestinal epithelium, Kidney
68
Fatty Acid Dysregulation impairs Insulin action
69
Fatty Acid Dysregulation impairs Insulin action
Clinical Pearl
1.Excess FFA – cause dysregulation of
IR
2.GLUT-4 function is impaired – Insulin
Resistance
70
Cyclic AMP Pathway - Glucagon

Off switch

PDE inactivates cAMP

PDE stops signal transduction.

Caffeine inhibits PDE!
71
Glucose controls Insulin and Glucagon release
72
Liver and Kidney




Major source of net endogenous glucose production
Accomplished by gluconeogenesis and glycogenolysis
when glucose is low
And of glycogen synthesis when glucose is high.
Can oxidize glucose for energy and convert it to fat
which can be incorporated into VLDL for transport.
73
Metabolic Effects of Insulin - in the Liver
74
Muscle



Can convert glucose to glycogen.
Can convert glucose to pyruvate through glycolysis further metabolized to lactate or transaminated to
alanine or channeled into the TCA cycle.
In the fasting state, can utilize FA for fuel and
mobilize amino acids by proteolysis for transport
to the liver for gluconeogenesis.

Can break down glycogen

But cannot liberate free glucose into the circulation.
75
Metabolic Effects of Insulin - in the Muscle
76
Adipose Tissue (AKA fat)


Can store glucose by conversion to fatty
acids and combine these with VLDL to
make triglycerides.
In the fasting state can use fatty acids for
fuel by beta oxidation.
77
Effects of Insulin - in the Adipose tissue
78
Metabolic Effects of Glucagon
79
Insulin – Anabolic and Glucagon - Catabolic
Metabolic Action
Insulin
Glucagon
Glycogen synthesis
↑
↓
Glycolysis (energy release)
↑
↓
Lipogenesis
↑
↓
Protein synthesis
↑
↓
Glycogenolysis
↓
↑
Gluconeogenesis
↓
↑
Lipolysis
↓
↑
Ketogenesis
↓
↑
80
Glucose Uniporters - GLUTs
Transport can work in both directions
81
The GLUT – Glucose Transporters

14 transporters of Glucose are identified

Their genes are located and cloned

The function of some is yet under evaluation


Some genetic defects produce specific diseases like
GLUT-1-DS
In breast and prostate cancer GLUT- 11 is hyper
expressed and supplies the high needs of glucose
to the cancer cells. – Anti GLUT – 11 drugs might
be a therapeutic approach for these cancers.
82
The GLUT – Glucose Transporters

14 transporters of Glucose are identified
Their genes are located and cloned
Clinical Pearl
 The function of some is yet under evaluation
1. GLUT -1 DS – a genetic disorder of Glucose
 Some genetic defects produce specific diseases like
metabolism
GLUT-1-DS
2. Anti GLUT -11 drugs in breast & prostate Ca are
 In breast and prostate cancer GLUT- 11 is hyper
underway
expressed and supplies the high needs of glucose
to the cancer cells. – Anti GLUT – 11 drugs might
be a therapeutic approach for these cancers.

83
Glucose Transporter Proteins - GLUTs



GLUT - 1 - Responsible for feeding muscle during
exercise (that is how exercise lowers blood glucose)
Placenta, BB, RBC, Kidney and many tissues. Low in
liver. Mainly “house keeping”
GLUT – 2 – Uniporter of glucose into the beta cells and
stimulates insulin secretion. Beta cells of pancreas.
Liver, small intestinal epithelium, Kidney. Has high
Km (60 mM). Never saturates.
GLUT - 3 – Insulin independent glucose disposal in to
the tissues. Abundant in neuronal tissue, placenta and
kidney. It feeds the high glucose requirement with out
insulin.
84
Glucose Transporter Proteins - GLUTs



GLUT - 1 - Responsible for feeding muscle during
exercise (that is how
exercisePearl
lowers blood glucose)
Clinical
Placenta, BB, RBC, Kidney and many tissues. Low in
1. The
GLUT-3
liver.
Mainly
“houseReceptors
keeping” are Insulin
independent
GLUT – 2 – Uniporter of glucose into the beta cells and
stimulates
insulin
secretion.
Beta cells
of pancreas.
2. In brain
GLUT-3
mediate
glucose
uptake
Liver, small intestinal epithelium, Kidney. Has high
3. (60
In placenta
GLUT-3 mediate Glucose
Km
mM). Neveralso
saturates.
uptake
GLUT - 3 – Insulin independent glucose disposal in to
the
in neuronal
tissue,very
placenta
andin
4.tissues.
FoetalAbundant
growth is
not affected
much
kidney.
IR It feeds the high glucose requirement with out
insulin.
85
Glucose Transporter Proteins – GLUTs contd..





GLUT – 4 – Insulin dependent – It is the main channel
for glucose entry into cells. Muscle, Heart and adipose
tissues depend on GLUT –4 for glucose entry in to cells
GLUT – 5 – Rich in small intestine and conduct
absorption of dietary glucose and fructose transport.
Mediate glucose for spermatogenesis
GLUT – 6 – Pseudo gene – Mediates none so far
GLUT – 7 – Only in liver endoplasmic reticulum and it
conducts glucose back out – G6P transporter in ER
SGLT 1 and 2 - Sodium - Glucose symporter in the
intestinal epithelium and renal tubular epithelium
86
Glucose Transporter Proteins – GLUTs contd..

GLUT – 4 – Insulin dependent – It is the main channel
for glucose entry into cells. Muscle, Heart and adipose
tissues depend on GLUT –4 for glucose entry in to cells
Clinical Pearl




GLUT – 5 – Rich in small intestine and conduct
1. GLUT-4
is main
Glucose
transporter
in all
absorption
of dietary
glucose
and fructose
transport.
tissues
Mediate
glucose for spermatogenesis
GLUT
6 – Pseudo
gene – Mediates
so far
2. It –cannot
function
withoutnone
TK signaling
of
GLUT
– 7 – Only in liver endoplasmic reticulum and it
Insulin
conducts glucose back out – G6P transporter in ER
SGLT 1 and 2 - Sodium - Glucose symporter in the
intestinal epithelium and renal tubular epithelium
87
Brain

Converts glucose to CO2 and H2O.

Can use ketones during starvation.

Is not capable of gluconeogenesis.

Has no glycogen stores.
88
Know Our Brain !!

Brain is the major glucose consumer

Consumes 120 to 150 g of glucose per day

Glucose is virtually the sole fuel for brain

Brain does not have any fuel stores like glycogen

Can’t metabolize fatty acids as fuel

Requires oxygen always to burn its glucose

Can not live on anaerobic pathways

One of most fastidious and voracious of all organs

Oxygen and glucose supply can not be interrupted
89
Know Our Brain !!

Brain is the major glucose consumer

Consumes 120 to 150
g of glucose
Clinical
Pearl per day

Glucose
is virtually
theneed
sole fuel
for brain
1. Brain
does not
Insulin
for glucose

Brainuptake
does not have any fuel stores like glycogen


Can’t
metabolize
acids as fuel
2. The
GLUT-3fatty
Receptors
mediate it without
Insulin
Requires
oxygen always to burn its glucose

Can
live on anaerobicwe
pathways
3.not
In hypoglycemia
need to give Glucose
only
One of
most fastidious and voracious of all organs

Oxygen and glucose supply can not be interrupted

90
Second Signaling




Now Insulin that is secreted
in to the blood starts the
second signaling event
Insulin binds to the Insulin
Receptors (IR) on the muscle
and fat cells
Muscle and fat cells increase
glucose uptake
This leads to lowering of
blood glucose
91
Insulin – C peptide


Insulin is dimer of two
peptides
Each peptide consists of
A and B chains

A has 21 amino acids

B has 30 amino acids


2 chains are linked by
pair of S – S bonds
C peptide has 35 amino
acids and is cleaved
92
Insulin – C peptide

Clinical Pearl
Insulin is dimer of two
peptides
Each peptide consists of
1. Insulin Analogs are substitutions
ofBAA
in α and ß
A and
chains

chains

A has 21 amino acids
2. Insulin Glargine, Insulin aspart,
Insulin lispro etc.,
 B has 30 amino acids
RAIA, LAIA


2 chains are linked by
pair of S – S bonds
C peptide has 35 amino
acids and is cleaved
93
Preproinsulin – Proinsulin – Insulin
94
Preproinsulin – Proinsulin – Insulin
Clinical Pearl
1. C – Peptide assay is simpler, less costly than
Insulin assay
2. It is the surrogate for endogenous Insulin
secretion
3. It is not affected by exogenously administered
Insulin
4. It is not largely influenced by food intake
95
PPAR Family of Nuclear Receptors
Peroxisome Proliferator Activated
Receptors
96
PPAR Family of Nuclear Receptors
Peroxisome Proliferator Activated
Receptors
Clinical Pearl
1. PPAR alpha are essential regulators of serum
lipids
2. PPAR gamma are essential for Insulin
Sensitivity
3. In Insulin Resistance the PPAR Gamma are
inactivated
4. Glitazones enhance the PPAR Gamma activity
97
The Role of Pancreas
Insulin

Hypoglycemic hormone

Beta cells of pancreas

Two chain polypeptide – Anabolic in nature

Receptor interactions

Intracellular interactions

Transporters

Clinical correlation
98
Insulin - Mechanism of action

Insulin binds to its trans-membrane receptor.

β subunits of the receptor become phosphorylated

Receptor has intrinsic tyrosine kinase activity.

Intracellular proteins are activated/inactivated—

IRS-1, IRS-2 and seven PI-3-kinases

GLUT-4, Transferrin, LDL-R, IGF-2-R move to the cell
surface.

Cell membrane permeability increases:

Glucose, K+, amino acids, PO4 enter
99
Insulin
Insulin Release




In a 24 hour period, 50% of the insulin secreted is
basal and 50% is stimulated.
The main stimulator for secretion is glucose.
Amino acids also stimulate insulin release,
especially lysine, arginine and leucine.
This effect is augmented by glucose.
100
Control of Insulin Secretion

Glucose interacts with the GLUT-2 transporter on the
pancreatic beta cell.

Glucose enters the cell releases - hexokinase→ G-6-P

Increased metabolism of glucose → ATP →

Excess of ATP- blocks ATP dependent K channels →

Membrane depolarization →

↑ Cytosolic Ca++ →

This stimulates degranulation and

Releases ↑ insulin secretion.
101
Control of Insulin Secretion
Insulin secretion is also increased by

Growth hormone (acromegaly)

Glucocorticoids (Cushings’)

Prolactin (lactation)

Placental lactogen (pregnancy)

Sex steroids
102
Regulation of Insulin Secretion
Summary of feedback mechanism for regulation
↑ blood glucose
↓
↑ insulin
↓
↑ transport of glucose into cells,
↓ gluconeogenesis, ↓ glycogenolysis
↓
↓ blood glucose
↓
↓ insulin
103
Role of Insulin
Metabolic Effects of Insulin

Main effect is to promote storage of nutrients

Paracrine effects

Decreases Glucagon secretion

Carbohydrate metabolism

Lipid metabolism

Protein metabolism and growth
104
Role of Insulin
Carbohydrate metabolism

Increases uptake of glucose

Promotes glycogen storage

Stimulates glucokinase

Inhibits gluconeogenesis

Inhibits hepatic glycogenolysis

Inactivates liver phophorylase
105
Sources of Glucose in to blood

Glucose is derived from 3 sources

Intestinal absorption of dietary carbohydrates

Glycogen breakdown in liver and in the kidney.

Only liver and kidney have glucose-6-phosphatase.

Liver stores 25-138 grams of glycogen, a 3 to 8 hour supply.

Gluconeogenesis, the formation of glucose from precursors

These include lactate and pyruvate, amino acids (alanine
and glutamine), and to a lesser degree, from glycerol
106
Fasting State



Short fast

Utilizes free glucose (15-20%)

Break down of glycogen (75%)
Overnight fast

Glycogen breakdown (75%)

Gluconeogenesis (25%)
Prolonged fast

Only 10 grams or less of liver glycogen remains.

Gluconeogenesis becomes sole source of glucose

Muscle protein is degraded for amino acids.

Lipolysis generates ketones for additional fuel.
107
Role of Insulin
Lipid Metabolism

Insulin promotes fatty acid synthesis

Stimulates formation of α-glycerol phosphate

α-glycerol phosphate + FA CoA = TG

TG are incorporated into VLDL and transported to
adipose tissues for storage.

Insulin inhibits hormone-sensitive lipase,

Thus decreasing fat utilization.
108
Role of Insulin

Protein Metabolism and Growth

Increases transport of amino acids

increases mRNA translation and new Proteins,

A direct effect on ribosomes

Increases transcription of selected genes,

Especially enzymes for nutrient storage

Inhibits protein catabolism

Acts synergistically with growth hormone
109
Role of the Pancreas
Lack of insulin


Occurs between meals, and in diabetes.
Transport of glucose and amino acids into the cells
decreases, leading to hyperglycemia.

Hormone sensitive lipase is activated,

Causing TG hydrolysis and FFA release.

↑ FFA conversion in liver →

Phospholipids and cholesterol →

Lipoproteinemia,

FFA breakdown leads to ketosis and acidosis.
110
Insulin Resistance




Associated with obesity
Underlying metabolic defect in
 Type 2 diabetes
 Polycystic ovarian disease
Associated with
 Hypertension, gout, high triglyceride
30% of general population
111
What causes insulin resistance?

Decreases in receptor concentration

Decreases in tyrosine kinase activity,

Changes in concentration and phosphorylation of
IRS-1 and IRS-2,

Decreases in PI3-kinase activity,

Decreases in glucose transporter translocation,

Changes in the activity of intracellular enzymes.
112
What causes insulin resistance?



Decreases in receptor concentration
Clinical Pearl
Decreases in tyrosine kinase activity,
1. T2D is
a question
of Insulin of
Changes
in mostly
concentration
and phosphorylation
Resistance
IRS-1
and IRS-2,

Decreases
PI3-kinase
activity,
2. Drugsin
which
improve
Insulin resistance are

crucialin glucose transporter translocation,
Decreases

Changes
in the activity
of intracellular
3. Quantitative
deficiency
is onlyenzymes.
a late
feature in T2D
113
The Role of Pancreas
Other pancreatic hormones



Somatostatin
 14 amino acid paracrine factor
 Potent inhibitor of glucagon release
 Stimili: glucose, arginine, GI hormones
 It is anti GH (somatotrophin) in its actions
Pancreatic polypeptide
 36 amino acids, secreted in response to food
Glucagon
114
Counter Regulatory Hormones

Early response



Glucagon
Epinephrine
Delayed response
 Cortisol

Growth hormone
115
Counter Regulatory Hormones



Glucagon
 Acts to increase blood glucose
 Secreted by alpha cells of the pancreas
 Chemical structure 29 amino acids
 Derived from 160 aminoacid proglucagon
precursor
GLP-1 (Glucagon Like Peptide -1)
 The most potent known insulin Secretagogue
 It is made in the intestine by alternative
processing of the same precursor
Intracellular actions
116
Role of Glucagon

Metabolic Effects of Glucagon




Increases hepatic glycogenolysis
Increases gluconeogenesis
Increases amino acid transport
Increases fatty acid metabolism (ketogenesis)
117
Role of Glucagon

Metabolic Effects of Glucagon
Clinical Pearl
Increases hepatic glycogenolysis
1.
Glucagon
is
the
treatment
for
hypoglycemia
 Increases gluconeogenesis
2.Increases
Glucagon
Kit –acid
1 mg
s/c or IM or IV injection

amino
transport
–
 Increases
fatty acid metabolism (ketogenesis)

3. In 2 to 3 minutes recovery
4. Costs Rs. 400 per dose
118
Glucagon Secretion
Stimulation of Glucagon secretion

Blood glucose < 70 mg/dL

High levels of circulating amino acids

Especially arginine and alanine

Sympathetic and parasympathetic stimulation

Catecholamines

Cholecystokinin, Gastrin and GIP

Glucocorticoids
119
Responses to decreasing Glucose levels
Response
Glycemic
theshhold
Physiological
effects
Role in counter
regulation
↓ Insulin
80 - 85 mg%
↑ Ra (↓ Rd)
Primary
First Defense
↑ Glucagon
65 - 70 mg%
↑ Ra
↑ Epinephrine
65 - 70 mg%
↑ R a ↓ Rd
Critical
Third Defense
↑ Cortisol, GH
65 - 70 mg%
↑ R a ↓ Rd
Not Critical
↑ Food ingestion 50 - 55 mg%
Primary
Second Defense
↑ Exogenous
< 50mg% no
Glucose
cognitive change
120
Role of Epinephrine
Epinephrine




The second early response hyperglycemic hormone.
This effect is mediated through the hypothalamus in
response to low blood glucose
Stimulation of sympathetic neurons causes release of
epinephrine from adrenal medulla .
Epinephrine causes glycogen breakdown,
gluconeogenesis, and glucose release from the liver.

It also stimulates glycolysis in muscle

Lipolysis in adipose tissue,

Decreases insulin secretion and

Increases glucagon secretion.
121
Role of Cortisol and GH


These are long term hyperglycemic hormones
Activation takes hours to days.
 Cortisol and GH act to decrease glucose
utilization in most cells of the body
 Effects of these hormones are mediated
through the CNS.
122
Cortisol

Cortisol is a steroid hormone



It is synthesized in the adrenal cortex.
Synthesis is regulated via the hypothalamus
(CRF) and anterior pituitary (ACTH).
Clinical correlation: Cushing’s Disease
123
Growth Hormone (GH)

GH is a single chain polypeptide hormone.

Source is the anterior pituitary somatotrophs.

It is regulated by the hypothalamus.

GHRH has a stimulatory effect.

Somatostatin (GHIF) has an inhibitory effect.

Clinical correlation: Gigantism and Acromegaly
cause insulin resistance.

Glucose intolerance—50%

Hyperinsulinemia—70%
124
What is T2D or T1D ?
125
Normal, T2D and T1D
Normal Subject
High blood glucose
Type 2 Diabetes (T2D)
High blood glucose
Type 1 Diabetes (T1D)
High blood glucose
-cells destroyed by
autoimmune reaction
Detected by -cells
-cells release insulin
Peripheral cells respond to
insulin & take up glucose
Lower blood glucose
Blood glucose remains high
Blood glucose remains high
Poor function of -cells
No -cells to detect & respond
-cells release of insulin is
inadequate or inefficient
Peripheral cells poorly
respond to insulin and
glucose up take is poor
Blood glucose remains high
Insulin secretion is nil
Peripheral cells have no
insulin to respond and
take up glucose
Blood glucose remains very high
126
Peripheral Tissue Insulin
Resistance v. Time
-cell Insulin
Production v. Time
Relative Insulin Resistance
-cell Insulin Production
Type 2 Diabetes Mellitus
Time in years
Disease
Progression
Age
Diabetic
Pre-Diabetic
Normal Glucose
Homeostasis
Time in years
Birth
127
T2D – It is Question of Balance !
Non-Diabetic State
PERIPHERAL INSULIN
ß-CELL MASS
RESISTANCE
& FUNCTION
Diabetic State
128
Pathology of Type 2 Diabetes
129
Time Sequence of Events in T2D
130
Insulin Kinetic Defect in T2D
131
Natural History of T2D
Obesity
IGT*
Diabetes
Uncontrolled
Hyperglycemia
Post-meal
Glucose
Plasma
Glucose
Fasting Glucose
120 (mg/dL)
Relative -Cell
Function
Insulin Resistance
100 (%)
Insulin Level
-20
*IGT = impaired glucose tolerance
-10
0
10
20
Years of T2D
30
132
Net Beta Cell Mass
Replication
Neoformation
Apoptosis
Neoformation
Apoptosis
-cell mass
133
Net Beta Cell Mass
Replication
Clinical Pearl
1. Crucial determinant of the course of T2D
patient
2. Beta cell apoptosis is the causeApoptosis
of
Neoformation
Apoptosis
secondary OHA failure
Neoformation
-cell mass
134
Net Beta Cell Mass
THE FORMULA FOR ß-CELL MASS (Mitogenesis + Size + Neogenesis) - Apoptosis = Growth
Increased ß-mass (i.e. compensation for insulin resistance):
(Mitogenesis + Size + Neogenesis) > Apoptosis
Decreased ß-mass (i.e. Type-2 diabetes):
Apoptosis > (Mitogenesis + Size + Neogenesis)
135
Approaches to lower Blood Glucose
136
Approaches to lower Blood Glucose
Clinical Pearl
1. Various approaches to treat T2D and
T1D
2. To restore normoglycemia is the goal
3. These approaches have additive effect
137
Evolution of the Modern Cardio-metabolic Man
Grotesque not in physical appearance alone !!
138
Fatty Acid Oxidation - What is the Switch ?
Glucose
Stearoyl CoA Desaturase (SCD)
Thrifty Gene Hypothesis
139
Fatty Acid Oxidation - What is the Switch ?
Glucose
Clinical Pearl
SCD SWITCH MANIPULATION might be the answer
Stearoyl CoA Desaturase (SCD)
Thrifty Gene Hypothesis
140
The Web of Cardio-metabolic pathogenesis
141
Leptin

Produced almost exclusively by adipose tissues

Regulates appetite via ‘satiety signal’ to Hypothalamus



Has beneficial effects on muscle fat oxidation and
insulin resistance
These are compromised by Leptin insensitivity
Has a suggested role in the development of various
cardiac risk factors – including high blood pressure
142
Adipsin (ASP)

ASP – Acylation Stimulation Protein

Role in the uptake and esterification of Fatty Acids

Facilitates fatty acid storage through Triacylglycerols

Stimulates Triacylglycerol synthesis via Diacylglycerol
Acyl Transferase (DGAT)

Stimulates translocation of GLUT to cell surface

ASP release is induced by HDLc
143
Adiponectin

Significant homology to complement factor C1q

Accumulates in vessel walls in response to ET injury

Reduced in obesity

Weight loss causes increase in its levels

Reduced in patients with CAD

Beneficial effects on CAD may be through
 Inhibition of mature macrophage function
 Modulation of endothelial inflammatory response

Inhibition of TNFα induced release of adhesion
molecules
144
WISH YOU ALL A HAPPY NEW YEAR
145