Glucose CO2 + H2O

ATP

NIMGU

Central Nervous System

NEFA = Non-Esteried Fatty Acids

Liver

G6P

GLUT-4

NIMGU

Glucose

Glycogen

Glycolysis Pyruvate Lactate

CO2 + ATPSkeletal Muscle

Insulin (+) (+)Catecholamines

Insulin (+)Insulin (+)

Glycerol

GLUT-4

NIMGU

Adipose Tissue

Glucose Triglyceride

NEFAInsulin (+)

(+)Insulin

(+)Insulin

Insulin (+)

Randal Cycle -Rate of Glucose & Fatty Acid utilization in Muscle are inversely related -Low Insulin State (fasting) Fatty Acid Oxidation is favored

Randal Cycle-Low blood Glucose= low insulin

Triglycerides+ NEFA

Lactate

ATP

GluconeogenesisGlucose

The Cori Cycle(anerobic metabolism)

Action of Insulin on CHO Metabolism -Increase Glucose transport into cells -Increase Glycolysis in Muscle + Fat -Increase Glycogenesis -Decrease Glycogenolysis in Liver + Muscle -Decreae rate of Gluconeogenesis in Liver

Actions of Insulin on Fat Metabolism -Decrease Lipolysis -Increase Fatty Acid + Triglyceride Synthesis -Decrease FA Oxidation -Increase Fatty Acid uptake by Adipocytes (hydrolysis of TAGs) -Increased disposal of VLDL

Actions of Insulin on Protein Metabolims -Increased Protein Synthesis -Decrease Protein Degredation -Increased AA transport into cells

Other Actions of Insulin -Increase inux of Potassium into Cells -Increase Na retention by Kidneys

D

B

A

Insulin

Somatostatin

Gluc

agon

To Portal Vein

Bloo

d Flo

w

Insu

lin

Glucagon

Somatostatin

Parasympathetic

Sympathetic

SUR-1*Inhibited by Sulfonyl-ureas*Activated by: Diazoxide, Mg-ATP, Mg-ADP Kir6.2 (Inward-recting potassium channel)*Inhibit: ATP + ADP*Activate: PIP2, Fatty Acid Metabolites

*LOF Mutations in SUR1 & Kir6.2 cause more K-ATP channels to remain closed thereby causing dysregulation of insulin secretion and leading to Neonatal Hyperinsulinemic Hypoglycemia *GOF Mutations in SUR1 & Kir6.2 cause more K-ATP channels to remain open thereby decreasing insulin secretion and leading to neonatal diabetis mellitus

Insulin Processing1) Insulin is Synthsized a Pre-Proinsulin

2) Pre-ProInsulin is processed to Pro-insulin before TGN (@ rER) (Pro-insulin = A~c~B) Endopeptidase cleave C @ Lys(64)~Arg(65) @ Arg(31)~Arg(32)

3) Mature Insulin is in Granules

Insulin Secretion1) Eat >>> blood [Glc]2) Glc enters B-Cell via GLUT-23) Glc metabolism increase ATP:ADP ratio4) (+) ATP:ADP ratio inhibits Kir6.2/SUR1 potassium channel5) Increase in intracellular K+ depolarizes cell6) depolarization opens V-gates Ca++ channels7) increase intacellular [Ca] activates PLC8) PLC > IP3 + DAG9) IP3 > ER > further increase in [Ca]10) increase in [Ca] >>> vesicle fusion + Insulin exocytosis

Pre-Pro-Insulin

Pro-Insulin

GLUT-2

G6PGlucose

+ ATPGlycolysis

(+) ATP : ADP ratio

++[K+]

(-)

X

exocytosis

Depolarization

Ca++

Glucokinase

Insulin +C-Peptide

Regulated Pathway> 95% Insulin > Proinsulin

Constitutive Pathway< 5%, Proinsulin > Insulin

Beta CellrER

TGN

50

25

008 12 16 20 24 04 08

8

7

6

5

4

Plas

ma

[insu

lin] (

mU

/L)

Plas

ma

[glu

cose

] (m

mol

/L)

Clock Time (h)

MealsB L D

Insulin

Glucose

*Note: sustained high Blood glucose will elicit a Biphasic Insulin release

*Note: quantity of Insulin secretion is proportionalto the amound of blood glucose

Hormone

Insulin

Glucagon

Epinephrine

Cortisol

Function

-Promotes fuel storage after a meal-Promotes growth

-Metabolizes fuel-Maintains [Glc]blood during fasting

-Mobilizes fuel during acute stress

-Stress Response

Major Pathways Aected

-Glycogenesis in Muscle + Liver-FA synthesis and storage after CHO meal-AA uptake + Protein Synthesis

-Activates Gluconeogenesis during fasting-Activates Glycogenolysis during fasting-Activates FA release from adipocytes

-Stimulates Glycogenolysis from Muscle + Liver-Stimulates FA release from Adipocytes

-Stimulates FA mobilization from Muscle Protein-Stimulates Gluconeogenesis-Stimulates FA release from Adipocytes

Glucose G6P (+) Insulin(+) Insulin

Glycogen

Fat

CO2 (OXPHOS)

AA (cytoplasm)AA (plasma) Protein

(+) Insulin(+) GH(+) IGF-1

(+) Insulin(+) GH(+) IGF-1

(+) Glucocorticoids

(-) Insulin

Insulin, GH, IGF-1 -Increased entry of AA into the cell -Increase protein synthesis

1) Insulin increase Glucose uptake into cells & phosphorylation to G6P

*Glucocorticoids enhance proteolysis

3) Insulin Inhibits utilization of AA for fuel

2) Insulin Increase -Glycogenolysis -Lipogenesis -utilization of carbohydrates a fuel

Intro to Insulin