Insulin: production, release and action

Question 1

Where is preproinsulin synthesised?

Answer 1

Pancreas

Question 2

Where is preproinsulin cleaved?

Answer 2

Liver

Question 3

Why is lispro insulin fast acting?

Answer 3

Swapping positions of lysine (B28) and proline (B29) destablises insulin and so makes it more reactive

Question 4

What makes glargine a long-acting form of insulin

Answer 4

aspargine -> glycine (A21) adding 2 argenines to the end of C terminus Makes protein react over longer acting period

Question 5

What cells produce the following: 1. Glucagon 2. Polypeptide protein 3. Somatostatin 4. Insulin

Answer 5

a-cell PP-cell d-cell B-cell

Question 6

What is happening at each stage of insulin release from the B cell

Answer 6

1. Phosphorylation: glucose enters cells by GLUT-2 and is phosphorylated (makes it more reactive) by glucokinase
2. Metabolism: of glucose yielding 46 ATP per molecule
3. Inhibition: ATP produced inhibits the K+-ATP pump. The lack of K+ efflux triggers depolarisation
4. Influx: depolarisation of membrane causes Ca2+ channels to open and Ca2+ flows in
5. Release: Ca2+ activates vesicles which then merge with membrane and release insulin

Question 7

At what concentration of glucose does secretion of insulin occur

Answer 7

5mM

Question 8

What 2 are the two problems with insulin that lead to diabetes

Answer 8

No production: loss of B cells means no insulin produced

Insulin insufficiency: Km of glucokinase is outside physiological limits. This means that a steep increase in glucose will not result in a proportional increase in GKase activity (unable to ‘sense’ glucose as accurately)

Question 9

Why is insulin said to have ‘biphasic’ release?

Answer 9

It is released in two stages:

1. Oral: minutes after eating, incretins are released which stimulate the release of a ‘reserve’ pool of insulin
2. Reserve: After oral phase, more insulin is prepared and released more gradually

Question 10

What are the two key sunbunits of K+-ATP pump in insulin release?

Answer 10

Kir 6.2 and SUR-1

Question 11

How do sulphonylureas and diazoxides act on SUR-1?

Answer 11

Sulphonyureas: inhibits K pump so increases release of insulin

Diazoxides: Stimulates SUR-1 to reduce insulin release

Question 12

How to mutations contribute to neonatal diabetes?

Answer 12

Mutations spawn too many/overreactive Katp channels

Question 13

How to mutations contribute to MODY?

Answer 13

Codes for faulty GKase/transcription factors

Impaired function of B cells results

Question 14

Why must MODY be differentiated from T1DM?

Answer 14

Can treat MODY with SUs instead of insulin therapy

Question 16

Insulin is a catabolic hormone: T/F?

Answer 16

False

Insulin is anabolic as it builds up glycogen

Question 17

What is donohue syndrome?

Answer 17

Autosomal recessive condition that results in ‘leprechaun’ appearance (small stature, elven face and thin due to lack of muscle/fat)

Question 18

What is Rabson-Mendenhall syndrome?

Answer 18

Autosomal recessive

Insulin resistance along with:

Hyperpigmentation

Developmental delays

Hypoglycaemia

DKA

Question 19

Why does a lack of insulin lead to a DKA?

Answer 19

Lack of insulin means:

Impaired glucose uptake: so the body resorts to use of fatty acids in TCA. Fatty acids tend to undergo B oxidation to ketone bodies more easily

Increased lipolysis: .’. More fatty acid -> more aCoA -> more ketones via B oxidation

No oxaloacetate: Nothing to ‘carry’ aCoA .’. more aCoA builds up .’. more diverted to producing ketones.

This increase in ketones results in acidosis (DKA)