6 - Complex genetic disease (diabetes)

Question 1

What are the pattern of events in untreated type 2 diabetes?

Answer 1

Resistance to insulin action, liver doesn’t respond —–> increase in insulin production —–> pancreatic exhaustion + reduced secretion

Question 2

How does the management of type 1 and type 2 diabetes differ?

Answer 2

type 1 - require insulin immediately

type 2 - diet/exercise initially and oral hypoglycaemic agents. Insulin eventually

Question 3

What are the causes of monogenic diabetes?

Answer 3

Single gene defect caused by either:

1. Maturity onset diabetes of the young (MODY)
2. Permanent neonatal diabetes (PND)

Question 4

What kind go genetic condition is MODY?

Answer 4

autosomal dominant

Question 5

What is the most common cause of MODY?

Answer 5

HNF1-α

It is a transcription factor (without it, insulin production reduces)

Question 6

At what age does HNF1-α MODY present?

Answer 6

teens/20s

Question 7

What happens in normal β-cells?

Answer 7

In β cells after glycolysis, the ATP formed needs to go through an ‘ATP-sensitive K+ channel’ in the membrane.

• the channel closes when there’s lots of ATP
• potassium can’t leave cell
• the membrane of β-cell depolarises
• calcium influx into the β cell causes secretion of insulin to the outside of the cell.

Question 8

What happens in HNF1-α MODY?

Answer 8

• mutation reduces rate of glycolysis
• less ATP
• the channel doesn’t close
• insulin not produced

Question 9

What is the other type of MODY?

Answer 9

glucokinase MODY

Question 10

What is permanent neonatal diabetes (PND)?

Answer 10

Diabetes in first 6 months of life.

Type 1 diabetes will usually kick in after 6 months

Question 11

What causes PND?

Answer 11

mutation in genes that code for ATP sensitive protein channel
Eg. KCNJ11/ABCC8 or even the insulin gene (INS)

The channel has 2 subunits. When there is a mutation, the channel will not close when ATP increases. Calcium doesn’t enter the cell, no depolarisation, so no insulin secretion.

Question 12

Define polygenic diabetes

Answer 12

A compilation of genetic changes that increase predisposition to developing T1+2.

NOTE: Unlike in monogenic, there must be a second hit to develop diabetes that comes from environment (exposure to virus)/lifestyle

Question 13

LO:
Diabetes: explain how genome-wide SNP association studies are designed and their contribution to our understanding of diabetes risk;

Answer 13

Take large samples of people with a condition vs people without (control). Sequence their genome, and plot.

It can be observed whether the disease is associated with certain single nucleotide polymorphisms (SNP) i.e. changes in one nucleotide.
So you can see if certain mutations are more prevalent in those who have the disease.
You can see where the genes are located and how susceptible you are to developing type 1 diabetes.