Intro to Insulin
1
Glucose CO2 + H2O ATP NIMGU Central Nervous System NEFA = Non-Esterified Fatty Acids Liver G6P GLUT-4 NIMGU Glucose Glycogen Glycolysis Pyruvate Lactate CO2 + ATP Skeletal Muscle Insulin (+) (+)Catecholamines Insulin (+) Insulin (+) Glycerol GLUT-4 NIMGU Adipose Tissue Glucose Triglyceride NEFA Insulin (+) (+) 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 Gluconeogenesis Glucose 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 influx of Potassium into Cells -Increase Na retention by Kidneys D B A Insulin Somatostatin Glucagon To Portal Vein Blood Flow Insulin Glucagon Somatostatin Parasympathetic Sympathetic SUR-1 *Inhibited by Sulfonyl-ureas *Activated by: Diazoxide, Mg-ATP, Mg-ADP Kir6.2 (Inward-rectifing 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 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 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 Pre-Pro-Insulin Pro- Insulin GLUT-2 G6P Glucose + ATP Glycolysis (+) ATP : ADP ratio ++[K+] (-) X exocytosis Depolarization Ca++ Glucokinase Insulin + C-Peptide Regulated Pathway > 95% Insulin > Proinsulin Constitutive Pathway < 5%, Proinsulin > Insulin Beta Cell rER TGN 50 25 0 08 12 16 20 24 04 08 8 7 6 5 4 Plasma [insulin] (mU/L) Plasma [glucose] (mmol/L) Clock Time (h) Meals B L D Insulin Glucose *Note: sustained high Blood glucose will elicit a “Biphasic” Insulin release *Note: quantity of Insulin secretion is proportional to 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 Affected -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
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Transcript of Intro to Insulin
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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
