Biochemistry

Question 1

what makes insulin

Answer 1

beta cells found in pancreatic islet

Question 2

what do the cells of the pancreatic islets produce

Answer 2

β cells - secrete insulin
α cells - secrete glucagon
δ cells - secrete somatostatin
PP cells - secrete pancreatic polypeptide

Question 3

where about in the beta cell is insulin synthesised and what is the make up of the cell

Answer 3

in the rough ER
Contains two polypeptide chains linked by disulfide bonds.
Connecting (C) peptide, a byproduct of cleavage

Question 4

how does glucose enter the beta cell and what enzyme is responsible for its phosphorylation

Answer 4

through the GLUT2 glucose transporter

glucokinase

Question 5

what else is glucokinase responsible for

Answer 5

glucose sensor

i.e. change of glucose concentration leads to a dramatic change in glucokinase activity

Question 6

pathway of secretion of insulin

Answer 6

1 - glucose enters beta cell
2 - increase in intracellular ATP concentration
3 - ATP inhibits the ATP-sensitive K+ channel Katp
4 - inhibition of this channel leads to depolarisation of the membrane
5 - results in opening of voltage-gated calcium channels
6 - increase in calcium concentration leads to fusion of secretory vesicles with the cell membrane and release of insulin

Question 7

how much ATP is produced per glucose

Answer 7

36

Question 8

what does inhibition of Katp lead to

Answer 8

depolarisation of cell membrane

Question 9

what does depolarisation of cell membrane result in

Answer 9

opening of voltage-gated Ca2+ channels, an increase in internal calcium concentration, fusion of secretory vesicles with the cell membrane and release of insulin

Question 10

what type of pattern is insulin release

Answer 10

biphasic

Question 11

what are the two phases of insulin release

Answer 11

1st phase - Readily Releasable Pool (RRP)

2nd phase - Reserve pool

Question 12

what are the two proteins of the Katp channels

Answer 12

An inward rectifier subunit (KIR) - pore subunit - Kir6.1

A sulphonylurea receptor - regulatory subunit - SUR1

Question 13

what do sulphonylurea class of drugs do

Answer 13

directly inhibit Katp channel

causing channel to open, increase in calcium and eventually insulin release

Question 14

what drug stimulates Katp to inhibit insulin secretion and what conditions is it used in

Answer 14

Diazoxide

congenital hyperinsulinism due to mutations in Kir6.2 or SUR1

Question 15

what mutation can lead to neonatal diabetes

Answer 15

Kir6.2

overactive Katp channel

Question 16

what condition is a Monogenic diabetes with genetic defect in β cell function

Answer 16

Maturity-onset diabetes of the young (MODY)

Question 17

what genes can be mutated to cause MODY

Answer 17

glucokinase

Question 18

why does a mutation in glucokinase cause MODY

Answer 18

glucokinase activity impaired Glucose sensing defect, blood glucose threshold for insulin secretion is increased

Question 19

why should we differentiate whether a patient has MODY or Type I diabetes

Answer 19

allows treatment with sulphonylurea rather than insulin.

Question 20

Type I diabetes features

Answer 20

Loss of insulin secreting beta cells

Question 21

MODY features

Answer 21

defective glucose sensing in the pancreas and/or loss of insulin secretion

Question 22

Type II diabetes features

Answer 22

Initially hyperglycemia with hyperinsulinemia so primary problem is reduced insulin sensitivity in tissues

Question 23

what is the insulin receptor that insulin binds to

Answer 23

Receptor Tyrosine Kinases

Question 24

what is the Receptor Tyrosine Kinases composed of

Answer 24

dimeric
two extracellular α subunits with insulin binding domains
two transmembrane β subunits
linked by disulfide bonds

Question 25

what binds at each subunit of the RTK

Answer 25

alpha subunit
- hormone binding domains

beta subunit
- ATP-binding and tyrosine kinase domains

Question 26

where does insulin bind and what does it cause

Answer 26

bind at alpha subunit

causes beta subunit to phosphorylate themselves (autophosphorylation)

Question 27

what happens after the beta subunit phosphorylate

Answer 27

Releases Insulin receptor substrates and it works 2 ways:
1 - IRS activates Ras&raquo_space; MAP kinase pathway&raquo_space; gene expression

2 - IRS activate PI3K&raquo_space; PKB&raquo_space; glycogen synthesis

Question 28

what stimulates GLUT 4 translocation and what does this cause

Answer 28

PKB

glucose to be taken up and cell growth to be stimulated

Question 29

what is Leprechaunism – Donohue syndrome

Answer 29

Mutations in the gene for the insulin receptor
Caused by defects in insulin binding or insulin receptor signalling
Severe insulin resistance
Developmental abnormalities

Question 30

what abnormalities are seen in Leprechaunism – Donohue syndrome

Answer 30

elfin facial appearance
growth retardation
absence of subcutaneous fat, decreased muscle mass

Question 31

what is Rabson Mendenhall syndrome

Answer 31

Severe insulin resistance, hyperglycemia and compensatory hyperinsulinemia
Developmental abnormalities
Acanthosis nigricans (hyperpigmentation)

Question 32

where are ketone bodies formed

Answer 32

in liver mitochondria

- derived from acetyl-CoA from β oxidation

Question 33

what are ketone bodies important for

Answer 33

energy metabolism for heart muscle and renal cortex

- converted back to acetyl-CoA, which enters TCA cycle

Question 34

what does Acetyl CoA depend on for the formation of citrate

Answer 34

oxaloacetate

Question 35

when is gluconeogenesis needed and what is used in the Kerb cycle to do this

Answer 35

when glucose is not available and fatty acids need to be broken down for energy

oxaloacetate needed

Question 36

what happens because of gluconeogenesis

Answer 36

Excess acetyl-CoA is converted to ketone bodies, blood levels increase

Question 37

what does accumulation of ketone bodies cause

Answer 37

acidosis

coma, death