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

109109

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

110110

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

111111

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

114114

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

117117

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

122122

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)

125125

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

127127

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

128

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

132132

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

143143

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

144144

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

145145

WISH YOU ALL A HAPPY NEW YEAR