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BioEd Online
Glucose Homeostasis
Counter Regulation
Dr.Sarma.R.V.S.NM.D., (Med) M.Sc., (Canada)
Consultant Physician
and Chest Specialist
www.drsarma.inwww.drsarma.in
22
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 ?
33
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 ?
Let us grasp some of the fascinating answers !!
44
Glucose Homeostasis Research Timeline
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.
1552BC 1st Century AD 1776 1869 188918th Century 1921-23 1983 2001
55
Cell growth and energy metabolism
TCA CycleKreb’s Cycle
CoA
Acetyl-CoA
Proteins
Amino acids
Fats
Fatty acids
Carbohydrates
GlucosePyruvat
e
ATP
66
Intermediary Metabolism of Fuels
77
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
88
Glucose-6-Phosphate – The Central Molecule
99
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
1010
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
1111
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
Clinical Pearl
INSULIN v/s GLUCAGON and Rd V/s Ra
1212
Normal, Hyper and Hypoglycemic states
Ra is the rate of appearance of Glucose
Rd is rate of disappearance of Glucose
When Ra = Rd; It is Euglycemic state
HYPERGLYCEMIA HYPOGLYCEMIA
Ra > Rd; Ra ↑or Rd↓
Ra < Rd; Ra ↓or Rd ↑
Rd
Ra50 mg
Ra
Rd
50 mg
Ra
Rd
200 mg
Ra
Rd
200 mg
Ra
Rd
100 mg
1313
Effect of CHO intake on Glucose Metabolism
Ra
Rd
Gluconeogenesis
Lipolysis
Glycogenolysis
GLUCAGON
INSULIN
Exogenous CHO
1414
Glucose Homeostasis
-cells release Glucagon stimulate glycogen breakdown and gluconeogenesis
-cells release insulin stimulate glucose uptake by peripheral tissues
Lower Blood Glucose
Higher Blood GlucoseFood
Between meals
1515
High blood glucose affects the size of beta cells
1616
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)
Pancreatic Hormones
1717
Glucose is the major source of energy for cells
Blood Glucose (BG) regulated by Insulin & Glucagon
Regulation of Blood Glucose levels
1818
Regulation of beta-cell size by the level of blood glucoseGlucose Homeostasis – Insulin and Glucagon
1919
Glucose Homeostasis Chart
Liver breaks down glycogen to glucose
Raises blood glucose
Glucose uptake by muscle/fat tissue
Lowers blood glucoseResult
GlucagonInsulinEffector
-cell of the pancreas-cell of the pancreasControl Center
Glucose transporterGlucose transporterReceptor
Low Blood Sugar Energy needs unmet
High Blood SugarToxic to the cells - AGP
Condition
2020
The Six Mechanisms of Transport - CM
1
3
6
5 4
2
2121
Membrane Transport Proteins
2222
Channel Proteins
2323
Cell Membrane - Transporters
2424
ATP Powered Receptors
2525
Glucose Transport
FIRST STEP
GLUCOSE ABSORPTION IN THE GI TRACT
2626
Intestinal Cell Transport
2727
Intestinal Cell Transport
Clinical Pearl
New approach in T2D, MS and Obesity - GLUT-2 Blockers
2828
The First Messengers from GI tract
THE MESSERGERS
INCRETINS – GLP1 and GIP_
2929
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.
Entero-Insular Axis of Secretion
3030
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.
Entero-Insular Axis of Secretion
Clinical Pearl
New Drugs for T2D- Incretin (GLP-1 and GIP) Function Enhancers
3131
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
Response to Elevated Blood Glucose
3232
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
Response to Elevated Blood Glucose
Clinical Pearl
1.Insulin secretion must be triggered – First Signal
2.Secreted Insulin must trigger Glucose uptake – Second signal
3.T2D may result from failure of either or both
3333
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
Glucose induced Insulin secretion
3434
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
Glucose induced Insulin secretion
Clinical Pearl
Closure of KATP Channels by Glucose is fundamental
Glucose is necessary to stimulate Insulin
Insulin is necessary to let in glucose
3535
K+ATP Channel Closed by ↑ BG and SU
3636
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
37
Intricacies in the Beta Cell
3838
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
3939
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
Clinical Pearl
1.Glibenclamide, Tolbutamide cause prolonged closer of the SUR
2.This causes prolonged and intense pressure on Beta cells
3.This is the cause of late hypoglycemia with these SUs
4.Beta cell apoptosis sets in fast after a few years of use
4040
(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)
4141
K+ATP Channel Opening is Cardio-
protective
4242
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
4343
Tyrosine Kinase Pathway - Insulin
4444
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
4545
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.
Insulin Receptor (IR)
46
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
CYTOPLASM
EXTRACELLULAR
NH3+
SS
SS
Insulin
-OOC
-S-S-
+3HN
COO-
-subunits
-subunits
TransmembranedomainTyrosine
kinasedomain
+3HN NH3
+
-OOC COO-
Plasmamembrane
SS
SS
47
Extracellular
Cytoplasm
1
insulinbinds
L R
2
IRTK (L)activated
OPOP
3IRTK (R)phosphorylated/activated
Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation
P
PP
P
ATPs ADPs
Phosphorylationcatalyzed by IRTK (L)
P
48
Extracellular
Cytoplasm
1
insulinbinds
L R
2
IRTK (L)activated
OPOP
3IRTK (R)phosphorylated/activated
PO
PO
4IRTK (L)phosphorylated
OP
OP
Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation
P P P P
ATPs ADPs
Phosphorylationcatalyzed by IRTK (L)
ATPsADPs
P
P
4949
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)
5050
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
5151
Receptor tyrosine kinases
The interaction of the external domain of a receptor tyrosine kinase with the ligand, often a growth factor, up-regulates the enzymatic activity of the intra cellular catalytic domain, which causes tyrosine phosphorylation of cytoplasmic signaling molecules.
Epidermal Growth Factor (EGF) Receptor Auto-phosphorylation of TK (Obesity)
5252
Receptor tyrosine kinases
The interaction of the external domain of a receptor tyrosine kinase with the ligand, often a growth factor, up-regulates the enzymatic activity of the intra cellular catalytic domain, which causes tyrosine phosphorylation of cytoplasmic signaling molecules.
Epidermal Growth Factor (EGF) Receptor Auto-phosphorylation of TK (Obesity)
Clinical Pearl
1.Up regulation of TK receptor (autophosphorylation) in obesity
2.Leads to Glucose entry into cells with out insulin signal
5353
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
5454
Insulin Signaling – PKB and MAPK pathways
5555
Insulin Signaling – PKB and MAPK pathways
Clinical Pearl
1.Ras independent signaling cascade – PI3P – PKB
2.Ras dependent signaling cascade – MAP Kinase
5656
Glucose Uniporter - GLUTs
5757
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
5858
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
Ras Independent – PI3K - PKB Signaling
5959
PIP Signaling Pathway
6060
Ras - Independent Insulin Signaling
6161
Insulin and PI3K Signaling
62
Extracellular Space
Cytoplasm
tyr-OH
IRS
[4] signals Golgi to traffic GLUT-4 tomembrane
PKB
GOLGI
= GLUT-4
Active IRTK POPO
OPOP
[1] IRTKcatalyzed
tyr-OP
IRS
ATP
ADP
activeIRS
tyr-OP
IRS
PI-3K
p85 [2] activated by dockingactive IRS
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 kinasePKB, protein kinase B
tyr-OP
IRS tyr-OP
IRS tyr-OP
IRS
PIP2PIP3
PDK
+
Ras Independe
nt
6363
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
6464
Ras - Dependent Insulin Signaling
6565
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)
Ras Dependent – MAPK Signaling
66
Activated IRTK
PO
PO
OP
OP
Extracellular
Cytoplasm
Glucose
Glucose transport(muscle/adipose)
Dephosphorylation of:glycogen synthaseglycogen phosphorylasephosphorylase kinaseacetyl CoA carboxylasehormone-sensitive lipasephosphofructokinase-2pyruvate kinaseHMG CoA reductaseregulatory kinases
Activation of proteinphosphatase
NUCLEUS
Cell growthand replication
DNA synthesis
KINASE CASCADE(protein phosphorylation)
Signal transduction(e.g., phosphorylation of IRS, SHC, PLC)
metabolic responses
GLUT-4
mitogenicresponse
mRNA synthesis Proteinsynthesis
Ras Dependent
6767
MAPK regulates the activity of transcription factors
Active MAPK translocates to the nucleus
It phosphorylates several transcription factors
And production of more GLUT4
Ras Dependent – MAPK Signaling
6868
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
Glucose Entry in to the Cell
6969
Fatty Acid Dysregulation impairs Insulin action
7070
Fatty Acid Dysregulation impairs Insulin action
Clinical Pearl
1.Excess FFA – cause dysregulation of IR
2.GLUT-4 function is impaired – Insulin Resistance
7171
Cyclic AMP Pathway - Glucagon
Off switch
PDE inactivates cAMP
PDE stops signal transduction.
Caffeine inhibits PDE!
7272
Glucose controls Insulin and Glucagon release
7373
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.
7474
Metabolic Effects of Insulin - in the Liver
7575
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.
7676
Metabolic Effects of Insulin - in the Muscle
7777
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.
7878
Effects of Insulin - in the Adipose tissue
7979
Metabolic Effects of Glucagon
8080
Insulin – Anabolic and Glucagon - Catabolic
Metabolic Action Insulin Glucagon
Glycogen synthesis ↑ ↓
Glycolysis (energy release)
↑ ↓
Lipogenesis ↑ ↓
Protein synthesis ↑ ↓
Glycogenolysis ↓ ↑
Gluconeogenesis ↓ ↑
Lipolysis ↓ ↑
Ketogenesis ↓ ↑
8181
Glucose Uniporters - GLUTs
Transport can work in both directions
8282
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.
8383
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.
Clinical Pearl
1.GLUT -1 DS – a genetic disorder of Glucose metabolism
2.Anti GLUT -11 drugs in breast & prostate Ca are underway
8484
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.
8585
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.
Clinical Pearl
1.The GLUT-3 Receptors are Insulin independent
2.In brain GLUT-3 mediate glucose uptake
3.In placenta also GLUT-3 mediate Glucose uptake
4.Foetal growth is not affected very much in IR
8686
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
8787
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
Clinical Pearl
1.GLUT-4 is main Glucose transporter in all tissues
2.It cannot function without TK signaling of Insulin
8888
Brain
Converts glucose to CO2 and H2O.
Can use ketones during starvation.
Is not capable of gluconeogenesis.
Has no glycogen stores.
8989
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
9090
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
Clinical Pearl
1.Brain does not need Insulin for glucose uptake
2.The GLUT-3 Receptors mediate it without Insulin
3.In hypoglycemia we need to give Glucose only
9191
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
9292
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
Insulin – C peptide
9393
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
Insulin – C peptide
Clinical Pearl
1.Insulin Analogs are substitutions of AA in α and ß chains
2.Insulin Glargine, Insulin aspart, Insulin lispro etc., RAIA, LAIA
9494
Preproinsulin – Proinsulin – Insulin
9595
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
9696
PPAR Family of Nuclear Receptors
Peroxisome Proliferator Activated Receptors
9797
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
9898
Insulin
Hypoglycemic hormone
Beta cells of pancreas
Two chain polypeptide – Anabolic in nature
Receptor interactions
Intracellular interactions
Transporters
Clinical correlation
The Role of Pancreas
9999
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
Insulin - Mechanism of action
100100
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.
Insulin
101101
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.
Control of Insulin Secretion
102102
Insulin secretion is also increased by
Growth hormone (acromegaly)
Glucocorticoids (Cushings’)
Prolactin (lactation)
Placental lactogen (pregnancy)
Sex steroids
Control of Insulin Secretion
103103
Summary of feedback mechanism for regulation
↑ blood glucose
↓
↑ insulin
↓
↑ transport of glucose into cells,
↓ gluconeogenesis, ↓ glycogenolysis
↓
↓ blood glucose
↓
↓ insulin
Regulation of Insulin Secretion
104104
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
Role of Insulin
105105
Carbohydrate metabolism
Increases uptake of glucose
Promotes glycogen storage
Stimulates glucokinase
Inhibits gluconeogenesis
Inhibits hepatic glycogenolysis
Inactivates liver phophorylase
Role of Insulin
106106
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
Sources of Glucose in to blood
107107
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.
Fasting State
108108
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.
Role of Insulin
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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
Role of Insulin
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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.
Role of the Pancreas
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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
112112
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.
113113
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.
Clinical Pearl
1.T2D is mostly a question of Insulin Resistance
2.Drugs which improve Insulin resistance are crucial
3.Quantitative deficiency is only a late feature in T2D
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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
The Role of Pancreas
115115
Early response Glucagon Epinephrine
Delayed response Cortisol Growth hormone
Counter Regulatory Hormones
116116
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
Counter Regulatory Hormones
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Metabolic Effects of Glucagon Increases hepatic glycogenolysis Increases gluconeogenesis Increases amino acid transport Increases fatty acid metabolism
(ketogenesis)
Role of Glucagon
118118
Metabolic Effects of Glucagon Increases hepatic glycogenolysis Increases gluconeogenesis Increases amino acid transport Increases fatty acid metabolism
(ketogenesis)
Role of Glucagon
Clinical Pearl
1.Glucagon is the treatment for hypoglycemia
2.Glucagon Kit – 1 mg s/c or IM or IV injection –
3.In 2 to 3 minutes recovery
4.Costs Rs. 400 per dose
119119
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
Glucagon Secretion
120120
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%
↑ RaPrimary
Second Defense
↑ Epinephrine 65 - 70 mg%
↑ Ra ↓
Rd
Critical Third Defense
↑ Cortisol, GH 65 - 70 mg%
↑ Ra ↓
Rd
Not Critical
↑ Food ingestion
50 - 55 mg%
↑ Exogenous
Glucose
< 50mg% no cognitive change
121121
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.
Role of Epinephrine
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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.
Role of Cortisol and GH
123123
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
Cortisol
124124
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%
Growth Hormone (GH)
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What is T2D or T1D ?
4
What is Diabetes?Body does not make or properly use insulin:
no insulin production insufficient insulin production resistance to insulin’s effects
No insulin to move glucose from blood into cells:
high blood glucose means: fuel loss. cells starve short and long-term complications
4
What is Diabetes?Body does not make or properly use insulin:
no insulin production
insufficient insulin production
resistance to insulin’s effects
No insulin to move glucose from blood into cells:
high blood glucose means: fuel loss. cells starve short and long-term complications
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Normal, T2D and T1D
High blood glucose
Detected by -cells
-cells release insulin
Peripheral cells respond to insulin &
take up glucose
Lower blood glucose
Normal Subject Type 2 Diabetes (T2D)
High blood glucose
Poor function of -cells
-cells release of insulin is inadequate
or inefficient
Peripheral cells poorly respond to
insulin and glucose up take is poor
Blood glucose remains high
Blood glucose remains high
-cells destroyed by autoimmune reaction
Type 1 Diabetes (T1D)
High blood glucose
No -cells to detect & respond
Insulin secretion is nil
Peripheral cells have no insulin to
respond and take up glucose
Blood glucose remains high
Blood glucose remains very high
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Type 2 Diabetes Mellitus
Time in years
Peripheral Tissue Insulin Resistance v. Time
Rel
ativ
e In
sulin
Res
ista
nce
Time in years
-ce
ll In
sulin
Pro
duct
ion
-cell InsulinProduction v. Time
Disease Progression
Age
Birth
Normal Glucose Homeostasis
Pre-Diabetic
Diabetic
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T2D – It is Question of Balance !
PERIPHERAL INSULIN
RESISTANCE
ß-CELL MASS
& FUNCTION
Non-Diabetic State
PERIPHERAL INSULIN
RESISTANCE
ß-CELL MASS
& FUNCTION
Diabetic State
129129
Pathology of Type 2 Diabetes
130130
Time Sequence of Events in T2D
131131
Insulin Kinetic Defect in T2D
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Years of T2D *IGT = impaired glucose tolerance
Obesity IGT* Diabetes Uncontrolled Hyperglycemia
Relative -Cell Function
100 (%)
-20 -10 0 10 20 30
PlasmaGlucose
Insulin Resistance
Insulin Level
120 (mg/dL)Fasting Glucose
Post-meal Glucose
Natural History of T2D
133
Net Beta Cell Mass
Neoformation Apoptosis
Replication
-cell mass
Neoformation
Apoptosis
134
Net Beta Cell Mass
Neoformation Apoptosis
Replication
-cell mass
Neoformation
Apoptosis
Clinical Pearl
1.Crucial determinant of the course of T2D patient
2.Beta cell apoptosis is the cause of secondary OHA failure
135
Net Beta Cell Mass
THE FORMULA FOR ß-CELL MASS -
(Mitogenesis + Size + Neogenesis) - Apoptosis = Growth
(Mitogenesis + Size + Neogenesis) > Apoptosis
Increased ß-mass (i.e. compensation for insulin resistance):
Apoptosis > (Mitogenesis + Size + Neogenesis)
Decreased ß-mass (i.e. Type-2 diabetes):
136136
Approaches to lower Blood Glucose
137137
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
138138
Evolution of the Modern Cardio-metabolic Man
Grotesque not in physical appearance alone !!
139139
Fatty Acid Oxidation - What is the Switch ?
Stearoyl CoA Desaturase (SCD)
Thrifty Gene Hypothesis
Glucose
140140
Fatty Acid Oxidation - What is the Switch ?
Stearoyl CoA Desaturase (SCD)
Thrifty Gene Hypothesis
Glucose
Clinical Pearl
SCD SWITCH MANIPULATION might be the answer
141141
The Web of Cardio-metabolic pathogenesis
142142
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
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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
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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
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WISH YOU ALL A HAPPY NEW YEAR