L15

Question 1

what is glucose stored as

Answer 1

glycogen

Question 2

what is the normal concentration of glucose in the blood

Answer 2

5mM

Question 3

Insulin and Glucagon are released by the pancreas, in the Islets of Langerhans

Answer 3

True

Question 4

what are the cell types in the pancreas

Answer 4

α cells (15 – 20%) – produce glucagon

β cells (65 – 80%) – produce insulin and amylin

γ cells (3 – 10%) – produce somatostatin

Question 5

how many amino acids does insulin have when first secreted

Answer 5

84

Question 6

where is pro insulin produced from

Answer 6

Golgi

Question 7

pro insulin is biologically active

Answer 7

no

Question 8

how is pro insulin activated

Answer 8

by prohormone convertase 1 and 2 remove 33 amino acids (C chain)

Question 9

what are the chains in the final insulin

Answer 9

A Chain – 21 amino acids
B Chain – 30 amino acids

Question 10

where is insulin stored

Answer 10

Stored within secretory granules of the
β cells

Question 11

what else is stored with insulin

Answer 11

some pro-insulin and the C peptide

Question 12

C peptide is inactive

Answer 12

false

Question 13

how does Glucose induce insulin secretion

Answer 13

Infusion of glucose to maintain elevated glucose immediately promotes insulin
secretion from β cells

First phase – release of insulin stored within secretory granules

Second phase – synthesis / secretion of new insulin

Very little binding of insulin to plasma proteins – circulates in free form

Insulin degraded by insulinase (mainly liver but also muscle / kidneys)

Plasma half life ~6 min so effects on tissues
rapidly reversible

C chain is more stable – assayed in order to provide an indicator of insulin secretion

Question 14

when is insulin at maximum concentration

Answer 14

when glucose is at ~9mM

Question 15

how does glucose level in the blood cause insulin secretion

Answer 15

β cells express a type 2 glucose transport system (GLUT2)

This system is hormone-insensitive and
therefore always active

In the β cells Glucose is phosphorylated to glucose 6-P by glucokinase and metabolised by glycolysis and mitochondrial oxidation to generate ATP / ADP

β cells express a ATP-sensitive K+ channels
These channels are open at normal levels of ATP

High levels of ATP close channel

Since these channels set the membrane potential (Vm) – channel closure causes depolarization

when Vm goes up to -25mV from -65 mV, voltage-gated Ca2+ channels open

Ca 2+ influx leads to insulin secretion

Question 16

where is pancreatic blood drained into

Answer 16

hepatic portal vein

Liver therefore first organ to be exposed to insulin

Portal circulation transports glucose from gut to liver

Question 17

what are the features of insulin receptors

Answer 17

Dimeric receptor

Each receptor consists of 2 subunits α and β

Insulin binding promotes receptor
dimerization and activation (see previous lecture)

Once the receptors dimerise, then the 2 subunits phosphorylate each other at multiple tyrosine residues

Question 18

what happens after insulin binds the receptor

Answer 18

active receptors phosphorylate IRS-1

IRS-1 activates PI3K resulting to cellular response to insulin

IRS-1 also activates MAPK cascade, resulting in stimulating cell growth and survival

Question 19

how does insulin promote glucose uptake by the liver

Answer 19

through glucose transport system (GLUT4)

In unstimulated cells GLUT4 is mainly found in intracellular membrane vesicles and not in plasma membrane

Plasma membrane therefore has low glucose permeability

Insulin activates PI3K…

…which then activates protein kinase B (PKB)

Which evokes the translocation of
GLUT4 by phosphorylation to the plasma membrane….

…and thus allows glucose uptake into the hepatocyte

Question 20

what does glycogen synthesis look like normally

Answer 20

active (dephosphorylated) GSK-3 phosphorylates (inactivates) glycogen synthase

no glycogen synthesis

Question 21

how does insulin promote glycogen synthesis

Answer 21

PKB activated by insulin phosphorylates (inactivates) GSK

leads to dephosphorylation of glycogen synthase

active glycogen synthase promotes glycogen synthesis

Question 22

in the absence of insulin, Fatty acids are metabolised. and when insulin is present glucose is metabolized

Answer 22

True

Question 23

which cells can take up glucose independantly of insulin

Answer 23

CNS cells

Question 24

the brain metabolises fatty acids

Answer 24

False

Question 25

how is fat released from adipocytes

Answer 25

hormone sensitive lipase separates fatty acids from glycerol

fatty acids are then released to fuel metabolic processes

Question 26

how does Insulin promote the deposit of fat in adipocytes

Answer 26

glucose enters cell

glucose is metabolised to glycerol

insulin inactivates lipase

fat synthesis

Question 27

how does Insulin promote the synthesis of new proteins

Answer 27

Insulin receptors activate PI3K

PI3K phosphorylates TORC1 (Central regulator of protein synthesis)

When amino acids are abundant, insulin stimulates their incorporation into protein

Question 28

summarize the effects of insulin

Answer 28

Promotes uptake and storage of glucose (mainly liver
/ skeletal muscle)

Promotes metabolic utilisation of glucose and so “spares” fatty acid

Promotes storage of fat

Promotes synthesis of new protein

Question 29

what conditions allow all the insulin effects to take place

Answer 29

hyperglicemia

raised level of amino acids

Question 30

which transport protein is a target of PKB activity

Answer 30

GLUT4

Question 31

what are the features of glucagon

Answer 31

single polypeptide chain (29 amino acids)

Synthesized within α cells of pancreatic islets and stored in secretory granuled (like insulin in β cells)

Major factor for glucagon release is
hypoglycaemia

very potent hyperglycaemic

Glucagon is also released during exercise

Glucagon receptor is not present on skeletal muscle cells

Exercise also promotes translocation of GLUT4 to surface of skeletal muscle

Glucagon therefore allows (indirectly) skeletal muscle to metabolise glucose

Question 32

how is glucagon secreted by Alpha cells

Answer 32

During hypoglycemia, glucose enter Alpha-cells via GLUT1 transporter

Glucose undergoes glycolysis lowering ATP levels (no oxidative phosphorylation)

Low intracellular ATP levels cause closure of K+ sensitive channels

The efflux of K+ is reduced

This induces depolarization and Calcium influx

Glucagon is released

Question 33

how can Glucagon promote glycogenolysis (glucose release from liver)

Answer 33

Glucagon receptor is a G protein-coupled receptor (7 transmembrane
domains)

Couple to Gs and activates the cAMP / PKA-dependent signalling pathway

Adrenaline can also activate this pathway via β adrenoceptors (provides
alternative way of promoting glucose release from liver and extra-fuel for the nervous system and skeletal muscles)

Question 34

how do High levels of glucagon release fatty acids from adipose tissue

Answer 34

reduce permeability of glucose

glucagon also activates lipase which breaks fats into glycerol and fatty acids

fatty acids are then released

Question 35

what happens when you eat a lot of protein

Answer 35

Amino acids raise both insulin and glucagon levels

Following a meal rich in proteins but low in carbohydrates, plasma amino acid level rise, but glucose levels do not change

The rise in amino acids stimulates insulin secretion to promote increase in amino acids update by cells, but also promote a reduction of plasma glucose (inappropriately)

The rise in amino acids also stimulates glucagon secretion which will promote an increase in plasma glucose, compensating the “inappropriate” response to insulin

N.B. Glucagon does no affect amino acid uptake

Question 36

how is glucagon important during starvation

Answer 36

Once glycogen stores are depleted, glucagon stimulates the formation of glucose from lipids and amino acids

This takes place via complex metabolic processes in liver and kidney-gluconeogenesis

Glucagon will promote lipid and protein degradation to fuel gluconeogenesis in order to maintain glucose for brain metabolism

Question 37

summarize the effects of glucagon

Answer 37

Promotes glucose release from glycogen stores (mainly liver)

Promotes gluconeogenesis to convert lipids and amino acids in glucose

Question 38

what conditions allow the effects of glucagon to take place

Answer 38

Hypoglycemia

Vigorous exercise

Raised level of amino acids