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Intro to Insulin

ATP
NIMGU

Glucose

CO2 + H2O
Central Nervous System

NEFA = Non-Esterified Fatty Acids


Function
-Promotes fuel storage after a meal
-Promotes growth
-Metabolizes fuel
-Maintains [Glc]blood during fasting
-Mobilizes fuel during acute stress
-Stress Response

Glucose

8
7
Insulin

25

Glucose

5
4

08

12

16

20

24

04

(+) Insulin

G6P

GLUT-4

(+)
Insulin

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

(+) Insulin

08

Clock Time (h)

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

Insulin (+)

NIMGU

Insulin (+)

(+)Catecholamines

GLUT-4

Glycolysis

Insulin (+)
Pyruvate

CO2 + ATP
Lactate

Actions of Insulin on Protein Metabolims


-Increased Protein Synthesis
-Decrease Protein Degredation
-Increased AA transport into cells

The Cori Cycle


(anerobic metabolism)
ATP
Glucose

Gluconeogenesis

Protein

Lactate

Other Actions of Insulin


-Increase influx of Potassium into Cells
-Increase Na retention by Kidneys

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

Liver

*Glucocorticoids enhance
proteolysis

GLUT-2

Regulated Pathway
> 95% Insulin > Proinsulin

(+) ATP : ADP ratio (-)

exocytosis
++[K+]

+ ATP
Glycolysis

Constitutive Pathway
< 5%, Proinsulin > Insulin
Insulin

Ca++
TGN

*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

Beta Cell

n
ati

Kir6.2
(Inward-rectifing potassium channel)
*Inhibit: ATP + ADP
*Activate: PIP2, Fatty Acid Metabolites

Glucose Glucokinase

ProInsulin

Pre-Pro-Insulin

rER

Insulin Secretion
1) Eat >>> blood [Glc]
2) Glc enters B-Cell via GLUT-2
3) Glc metabolism increase ATP:ADP ratio
4) (+) ATP:ADP ratio inhibits Kir6.2/SUR1 potassium channel
5) Increase in intracellular K+ depolarizes cell
6) depolarization opens V-gates Ca++ channels
7) increase intacellular [Ca] activates PLC
8) PLC > IP3 + DAG
9) IP3 > ER > further increase in [Ca]
10) increase in [Ca] >>> vesicle fusion + Insulin exocytosis

Sympathetic

t
tos
ma
So

Depolarization

Parasympathetic

Insulin +
C-Peptide

G6P
SUR-1
*Inhibited by Sulfonyl-ureas
*Activated by: Diazoxide, Mg-ATP, Mg-ADP

Randal Cycle
-Low blood Glucose
= low insulin

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

G6P Skeletal Muscle

Glucose

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

Triglycerides
+ NEFA

Glycogen

CO2 (OXPHOS)

(-) Insulin

(+)
Insulin

Triglyceride

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

3) Insulin Inhibits
utilization of AA for fuel

AA (plasma)

Glycerol

Adipose Tissue

Fat

Plasma [glucose] (mmol/L)

Plasma [insulin] (mU/L)

50

Meals

Insulin (+)

-Stimulates Glycogenolysis from Muscle + Liver


-Stimulates FA release from Adipocytes

1) Insulin increase Glucose uptake


into cells & phosphorylation to G6P

*Note: quantity of Insulin secretion is proportional


to the amound of blood glucose
L

-Activates Gluconeogenesis during fasting


-Activates Glycogenolysis during fasting
-Activates FA release from adipocytes

-Stimulates FA mobilization from Muscle Protein


-Stimulates Gluconeogenesis
-Stimulates FA release from Adipocytes

*Note: sustained high Blood glucose


will elicit a Biphasic Insulin release

Glucose

on

Cortisol

NIMGU

Glu
cag

Epinephrine

-Glycogenesis in Muscle + Liver


-FA synthesis and storage after CHO meal
-AA uptake + Protein Synthesis

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

NEFA

uli
n

Glucagon

Insulin (+)

Ins

Insulin

Major Pathways Affected

Blo
od
Flo
w

Hormone

Glucagon
Somatostatin

Insulin Processing
1) 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

To Portal Vein