Insulin secretion and action

Question 1

What are glucose levels after fasting, and after a meal?

Answer 1

Fasting: 3.5-5.5 mmol/L

After meal: >8 mmol/L

Question 2

How does the metabolism adapt to fasting?

Answer 2

• increased secretion of glucagon
• increased gluconeogenesis; glycogen release via glycogenolysis = gluconeogenesis
• triglycerides broken down by hormone-sensitive lipase –> glycerol and free fatty acids
• the glycerol is used for gluconeogenesis
• the free fatty acids are used for the Kreb cycle
• there is accumulation of acetyl-CoA therefore ketone bodies form
• glucogenic amino acids are used for gluconeogenesis

Question 3

What are the main fuel sources in prolonged starvation?

Answer 3

triglycerides
ketone bodies
amino acids

Question 4

What is the role of the pancreas?

Answer 4

regulates insulin - promoted glucose storage

- regulates glucose output in starvation

Question 5

Where is insulin synthesised?

Answer 5

by beta cells within islets of langerhans in the pancreas

Question 6

Apart from beta cells, what other cells are within the islets of langerhans and what do they produce?

Answer 6

delta cells = somatostatin
alpha cells = glucagon
pp cells/f cells = pancreatic polypeptide
epsilon cells = ghrelin

Question 7

What is the difference between the storage form and active form of insulin?

Answer 7

• monomers of insulin tend to form dimers when concentration is high
• dimers will form hexamers in the presence of Zn2+ and specific pH
• hexamers = STORAGE form of insulin
• once hexamers are secreted, insulin dissociated into monomers (ACTIVE form)

Question 8

How is insulin formed?

Answer 8

pre-proinsulin – endoplasmic reticulum –> proinsulin – endopeptidase (golgi apparatus) –> insulin

Question 9

What is the role of endopeptidase?

Answer 9

To cleave off C-peptide from insulin –> break bonds

Question 10

Describe the process of insulin secretion.

Answer 10

• glucose enters beta cells via GLUT4
• glucokinase = glucose sensor for insulin secretion: converts glucose to G6P to pyruvate
• this enters krebs cycle which progresses to the ETC
• glucose concentration is substimulatory –> K ATP channels open
• resting membrane at hyperpolarised level (~70mV)
• increase in ATP:ADP ratio causing kATP channels to close
• membrane becomes depolarised and voltage-gated Ca2+ channels open
• causes an increase in intracellular Ca2+ resulting in insulin secretion

Question 11

How can amino acids such as leucine and arginine stimulate insulin release?

Answer 11

Leucine:

• acts through allosteric activation of glutamate dehydrogenase
• can also be transaminated to alpha-ketoisocaproate which is converted to acetyl-CoA (Kreb cycle)
• leads onto ETC which produces energy required to trigger influx of Ca2+ into cell allowing insulin release

Arginine:

• directly depolarise plasma membrane
• stimulate Ca2+ influx, allowing insulin release

Question 12

What other signals can potentiate insulin release?

Answer 12

1. gastrointestinally-derived incretins - act on GLP-1
2. glucose dependent insulinotropic peptide - gastric inhibitory peptide, stimulates insulin secretion
3. fatty acids
4. parasympathetic release of ACh (via phospholipase C)
5. Cholecystokinin (CCK, via phospholipase C) –> most can only potentiate glucose-induced insulin secretion

Question 13

What can activate insulin receptors?

Answer 13

• insulin
• IGF-1
• IGF-2

Question 14

What class of receptor is the insulin receptor?

Answer 14

tyrosine kinase receptor

Question 15

Describe how insulin activates the insulin receptor.

Answer 15

• insulin binds to the extracellular portion of the alpha subunit
• causes a change —> activates tyrosine kinase domain (intracellular portion of the beta subunit)
• activated tyrosine domain autophosphorylates tyrosine residues (C terminus of receptor and within the adaptor protein insulin receptor substrate - IRS)

Question 16

What changes occur in metabolism when insulin is not present?

Answer 16

1. IRS, PI3K (lipid kinase) and Akt (protein kinase) = inactive
2. No glucose uptake
3. No glucose –> glycogen
4. GLUT4 contained within intracellular vesicles

Question 17

What changes occur in the liver, muscle and adipocytes in the presence of insulin?

Answer 17

Liver:

• increased glycogenolysis
• increased lipogenesis
• reduced glycogenesis

Muscle:

• increased glucose uptake
• increased glycogenesis
• reduced protein catabolism

Adipocytes:

• increased glucose uptake
• increased lipogenesis
• reduced lipolysis

Question 18

How does insulin increase glucose uptake?

Answer 18

• insulin induces Akt activation
• this stimulates GLUT4 translocation from the intracellular vesicles to the plasma membrane
• results in increased glucose uptake (increased glucokinase activity)

Question 19

How does insulin increase glycogen synthesis?

Answer 19

• insulin activates Akt
• activated Akt dephosphorylates and inactivates glycogen synthase kinase
• glycogen synthase is no longer inhibited
• therefore glycogen is synthesised

Question 20

How does insulin increase lipogenesis?

Answer 20

• inhibits lipolysis and reduces hormone sensitive lipase
• reduced fatty acids in the blood
• increases malonyl CoA which inhibits the transport fo free fatty acids into the mitochondria via CPT-I in turn inhibiting beta-oxidation therefore free fatty acids used for lipogenesis

Question 21

What effects does insulin have on the liver (in terms of protein)?

Answer 21

• promotes protein synthesis + storage
• stimulates transport of amino acids into cells
• increases translation of mRNAs
• inhibits catabolism of proteins
• promoted K+ intracellular uptake

Question 22

How is insulin signalling ‘switched off’?

Answer 22

• endocytosis and degradation of receptor bound to insulin
• dephosphorylation of tyrosine residues by tyrosine phosphatases
• reduced number of (membrane-bound) receptors = reduced insulin signalling
• serine/threonine kinase = reduced activity of insulin receptor

Question 23

What is the result of insulin resistance?

Answer 23

hyperglycaemia and dyslipidaemia