012 Molecular Defecits in Diabetes Mellitus

Question 1

Which HLA genotype is most highly associated with T1DM?

Answer 1

HLA DR3/4 DQ8

Question 2

Which alleles present more in T1DM individuals?

Answer 2

DQA301/DRB401

Question 3

Other genes associated with T1DM

Answer 3

IGF
FGF
Insulin gene

Question 4

Mechanism of action - acarbose

Answer 4

Prevents breakdown and absorption of carbohydrate enzymes

Question 5

Which part of the body does insulin resistance first arise?

Answer 5

Skeletal muscle and adipose tissue due to reduced uptake of glucose via GLUT4 transporters

Question 6

Describe how Krebs cycle might initiate insulin response

Answer 6

The increase in ATP formed will alter ATP:ADP ratio so that it rises. This will close ATP dependant K+ channels and cause depolarization in plasma membrane. It will open Ca2+ channels, causing insulin granule exocytosis.

Question 7

Which glucose transporter is associated with beta cells?

Answer 7

GLUT 2

Question 8

What is Fanconi-Bickel syndrome?

Answer 8

A mutation in GLUT2 often present with postprandial hyperglycemia and reduced insulin levels.

Question 9

Which IRS is more responsible for insulin response in muscle and adipose tissue?

Answer 9

IRS1

Question 10

Which IRS is more responsible for insulin response in pancreas?

Answer 10

IRS2

Question 11

Describe relationship between growth hormone, IGF -1 and ISR1 and 2

Answer 11

IGF1 is stimulated by growth hormone, released by liver.
IGF can activate ISR1 and ISR2.
Hence ISR1 and 2 activation is linked to increased growth function.
IRS tyrosine phosphorylation leads to further activation, signalling of metabolism and growth.

Question 12

How do NEFA’s and DAG work in terms of insulin resistance?

Answer 12

NEFA’S and DAG will increase serine phosphorylation of IRS 1 and 2, inhibiting their ability to stimulate metabolism and growth the normal way.

Question 13

Which is the most common gene responsible for MODY

Answer 13

HNFa1

Question 14

Describe mutations in MODY 1 and what impact does this have

Answer 14

MODY 1 is caused by mutation in HNFa4. Insulin production is normal birth but decreases dramatically with age.

Question 15

Describe mutations of MODY 2 and what impact does this have

Answer 15

MODY 2 is caused by a mutation in glucokinase. Insulin production is impaired at birth but remains quite stable.

Question 16

Describe mutations of MODY 3 and what impact does this have

Answer 16

MODY 3 is caused by a mutation in HNFa1. Insulin production is normal at birth but decreases dramatically with age.

Question 17

Describe mutations for MODY 4 and what impact does this have

Answer 17

PDX1 transcription factor in beta cells is impaired.

Question 18

Describe the mutation involved in MODY5

Answer 18

Mutation in HNF1B transcription