Mstn Ii - Lecture 23

Front 1

Insulin

Back 1

5.8 kDa Protein homrone secreted by the beta cells of the pancreas

protein is made of two polypeptide chains, the A chain (21 residues) and B chain (30 residues), held together by 2 disulfide bonds.

Front 2

Preproinsulin

Back 2

Insulin is initially translated by beta cells as a single polypeptide, preproinsulin.

Front 3

Proinsulin

Back 3

The 19 residue signal sequence is then removed in the ER lumen, and preproinsulin is now proinsulin

Front 4

Mature insulin

Back 4

final processing in the Golgi cleaves of the 33 residue C peptide chain to give mature insulin, consisting of an A and B chain.

Front 5

C peptide

Back 5

33 residues

used to align the A and B chain for proper S-S bonding.

only result from endogenous insulin production. Administered insulin is pure and lacks the C peptide.

Front 6

Effects of insulin

(4)

Back 6

- stimulate glycogen synthesis in the muscle and liver (decrease [blood glucose])
- stimulate uptake of glucose by muscle cells, adipocytes, and other cells by increasing the number of GLUT4 transporters on the plasma membrane.
- Promotes update of branched amino acids, favoring the build up of muscle proteins.
- Stimulate protein synthesis, inhibits intracellular protein degradation.

Front 7

Glucagon

Back 7

3.5 kDa polypeptide hormone secreted by alpha cells of the pancreas

29 AA polypeptide

secreted in response to low blood glucose levels. increases the release of glucose into the bloodstream by the liver.

Front 8

Glucagon targets

Back 8

liver is the principal target, adipocytes are also targeted. For all practical purposes, it has no effect on skeletal muscle cells.

Front 9

Effects of Glycagon

(5)

Back 9

- stimulates glycogen breakdown in liver
- inhibits glycogen synthesis by triggering phosphorylation of phosphorylase and glycogen synthase
- inhibits fatty acid synthesis by diminishing the production of pyruvate and lowering the activity of acetyl-CoA carboxylase
- stimulate gluconeogenesis by lowering F2,6BP, thus inhibiting glycolysis
- activates lipase in the adipocytes to promote the mobilization of fatty acids

Front 10

Catecholamines

Back 10

epinephrine

norepinephrine

Front 11

Norepinephrine (noradrenalin) and epinephrine (adrenalin) synthesized from:
secreted by:
stored in:

Back 11

synthesized from tyrosine

secreted by the adenal medulla and sympathetic nerve endings

stored in granules to be released under the control of the sympathetic nervous system

Front 12

catecholamines target:

released when:

Back 12

target skeletal muscle cells, but the hepatocytes and adipocytes are also targeted

released under stress, physical exertion

Front 13

effects of Catecholamines

(4)

Back 13

1) mobilizes glycogen in muscle and liver and triacylglycerols in the adipocytes
2) stimulates secretion of glucagon and inhibits secretion of insulin
3) inhibits the uptake of glucose by muscle. As glycogen stores are depleted, fatty acids released by adipocytes are used predominantly as fuel.
4) increase the amount of glucose released into the blood by the liver. Decreases utilization of glucose by muscle.

Front 14

GLUT2 specific for:

Back 14

glucose

Front 15

hexokinase IV
(glucokinase)

Back 15

Phosphorylate glucose as it is taken up by the pancreatic beta cell.

specific for glucose, doesn't phosphorylate other carbs

glucose -> G6P

Front 16

Glucose in the pancreatic beta cell:

Back 16

- turn into G6P by hexokinase IV (glucokinase)
- glycolysis
- citric acid cycle
- oxidative phosphorylation
- becomes ATP

Front 17

Differential permeability of pancreatic beta cell membrane:

Back 17

K+ diffuse out more than Na+ diffuse in. + outside of cell, and - inside of cell.

Front 18

Increase [ATP] in pancreatic beta cells:

Back 18

- cause ATP-gated K+ channel on the plasma membrane to close.
- Membrane depolarizes and cause voltage-dependent Ca2+ channels to open.
- Ca2+ flows into the cell and causes insulin granules to fuse with the membrane, releasing insulin.

Front 19

Insulin receptor

structure:

Back 19

2 components

2 alpha units that's in the extracellular space
2 transmembrane beta subunits with kinase activity

Front 20

How does the insulin receptor work?

Back 20

alpha subunit binds the insulin, then the beta units undergo a conformational change. They auto-phosphorylate, and activate Tyr kinase.

Front 21

Tyrosine Kinase

Back 21

intracellular side of the insulin receptor

once insulin binds to the receptor, Tyr kinase is activated. It P itself first, thus activating it, then target a variety of target proteins, and P these proteins.

Front 22

Diabetes II

Back 22

insulin receptor is present in deficient amount, or require much more insulin to get the same physiological effect compared to a normal patient.

Front 23

IRS-1

Back 23

Insulin Receptor Substrate I

P by the insulin receptor, when binds, it will P protein kinase b (PKB).

Front 24

Protein Kinase B (PKB)

2 effects

1st one:

Back 24

- stimulate glycogen synthesis by activating glycogen synthase. Glycogen will be synthesized in large amounts in this muscle cell
- Glycogen synthase is active as a kinase when it's nonP

- PKB P GSK3 from its active form to inactive form.

Front 25

Glycogen Synthase Kinase 3

(GSK3)

Back 25

- active as a kinase when it's nonP

when it's inactive, there is no longer a kinase converting the glycogen synthase to its inactive form.

Front 26

GLUT4 transporters

Back 26

transporters of glucose on the plasma membranes of muscle cells and adipocytes

normally, there are not so many of these GLUT4. A lot of it is sequestered in intracellular vesicles.

Front 27

Protein Kinase B (PKB)

2 effects

2nd one:

Back 27

- When activated, it cause the GLUT4 vesicles to fuse with the plasma membrane, and increase the number of GLUT4 transporters.
- stimulate glucose uptake by muscle and fat cells, thus reduces blood glucose

Front 28

Catecholamines inhibit secretion of insulin... what happens to PKB?

Back 28

PKB is inhibited

Front 29

Exercise and diabetes

Back 29

when exercising, another kinase become activated, which promotes this process without insulin. Exercise can stimulate the increase in GLUT4 transporters without insulin.

Front 30

adenylate cyclase

Back 30

- activated by glucagon and catecholamines

- take ATP and stimulate its conversion to cAMP.

Front 31

cAMP

Back 31

- cyclic form of adenosine monophosphate
- very important second messenger
- P linked at the 5' and 3' position

This is the signal that's going to activate protein kinase A

Front 32

adenylate cyclase activated by:

Back 32

- catecholamines bind to beta-adrenergic receptors
- glucagon bind to G protein receptor

Front 33

alpha-adrenergic receptor

Back 33

- another receptor for catecholamines
- second messenger that's different from cAMP, and it's target protein is PIP2 (phosphatidylinositol-4,5-bisphosphate)

Front 34

PIP2 (phosphatidylinositol-4,5-bisphosphate)

Back 34

lipid moiety that's embedded in the membrane.

Front 35

when alpha-adrenergic receptor binds:

Back 35

- phospholipase c is activated

Front 36

Phospholipase C

Back 36

catalyzes PIP3 -> DG (1,2-Diacylglycerol) + IP3 Inositol-1,4,5-triphosphate)

- it severs the polar head group from the membrane component and leaves behind the DG, and release IP3 into the cytosol in soluble form.

Front 37

1,2-Diacylglycerol (DG)

Back 37

serves as a second messenger

Front 38

Protein Kinase A (PKA)

Back 38

- will P glycogen synthase

- inactive in the absence of cAMP
- cAMP bind to regulatory subunits that inhibit the catalytic subunits of PKA.

Cate binds and activates adelyl cyclase, makes cAMP, binds to the inactive PKA, release catalytic subunits = active PKA

Front 39

what happens after PKA is active?

Back 39

it can stimulate the P of glycogen, and P phosphorylase b kinase into its active form, phosphorylate a kinase. This active kinase can then convert the less active glycogen phosphorylase b to its active glycogen phosphorylase a form.
This will then: glycogen -> G1P and release blood glucose.

Front 40

PKA inhibit:

Back 40

the action of an enzyme that dephosphorylates Glycogen Phosphorylase, which would inactivate it.

This enzyme, Protein Phosphatase-1 (PP1), has an inhibitor that is actiavted by phosphorylation from PKA.

- also phosphorylate GS to inactivate it.

Front 41

Effect of alpha-adrenergic receptor?

Back 41

activate phospholipase C activity when bound by the catecholmaines. This enzyme targets the plasma ipid PIP2 and convertrs it into two potent second messengers, DG and IP3.

Front 42

How is protein kinase C activated?

Back 42

PKC needs Ca2+ and needs to be bound to DG for its activation. IPS needs to bind to a Ca2+ channel in ER. That opens up the channel, elevates Ca2+ level in the cytosol. Provides the cation needed.

DG and IP3 are generated by alpha-adrenergic receptors activating phospholipase C

Front 43

hormone sensitive lipase

Back 43

mobilize fatty acids in adipocytes

cAMP produced in adipocytes in response to catecholamines or glucagon phosphorylate and activate this enzyme.

Front 44

Hormones that regulate the activity of acetyl-CoA carboxylase in the liever:

Back 44

Glucagon, catecholamines, and insulin

determine when there will be fatty acid synthesis.