Diabetes

Question 1

What is type 1 diabetes caused by?

Answer 1

Diminished or absent endogenous (from yourself) beta cell function

Question 2

What is type 2 diabetes caused by?

Answer 2

Resistance to insulin, increase in production and eventually the pancreas is exhausted, and secretion reduces

Question 3

What is the treatment for type 1 diabetes?

Answer 3

Insulin, blood glucose meter, education, carbohydrate counting

Question 4

What is the treatment for type 2 diabetes

Answer 4

Metformin, tablets, no routine glucose testing, education, diff insulin regimes

Question 5

What are some examples of monogenic diabetes?

Answer 5

MODY - collection of autosomal dominant monogenic disorders affecting genes involved in beta cell glucose sensing and insulin secretion

PND - Permanent neonatal diabetes - occurs in the first 6 months of life and mutations are spontaneous

Question 6

What is HNF1 alpha mutation (MODY)?

Answer 6

Transcription factor normally stimulating insulin production
In absence, insulin production reduced, but only manifests in adulthood when beta- cell function starts to naturally decline. Best managed by sulphonylureas and when diagnosed insulin can be stopped. May eventually need insulin. Future risk of micro/macrovascular problems.

Question 7

What is glucokinase MODY

Answer 7

Beta cell glucose sensor, mutations mean there is a higher set point at which insulin secretion starts. Patients have same relationship as age changes as normal individuals. Mild life long, non- progressive hyperglycaemia. No long- term complications, treatment not needed

Question 8

What is the KCNJ11 mutation (PND)?

Answer 8

Normally glucose enters via the transporter and is converted via glycolysis by hexokinase. The ATP that is made closes the K+ channel (made of two subunits, including sur 1). Then the membrane depolarises and there is calcium influx and the granules containing insulin are released.
KNCJ11 mutation causes the channel to stay open, membrane hyper-polarised and calcium doesn’t enter.

Question 9

What is the treatment for PND (KCNJ11 mutation)?

Answer 9

Sulphonylureas – Binds to the sur1 subunit force closing the membrane and insulin can be secreted

Question 10

What are the three main stages involved in genetic testing?

Answer 10

1) Decide genetic testing appropriate

2) Genetic counseling
Pros and cons of testing
Impact on treatment
Impact on family members

3)Blood test
Next generation sequencing technologies
Confirmation via Sanger sequencing

Question 11

What is mitochondrial diabetes? Key features and examples? What is the severity of the diabetes affected by ?

Answer 11

Maternally transmitted, causes diabetes.

Presentations:
young-onset sensorineural deafness
high lactate
muscle aches
short stature
Seizures (brain problems in general)
\+ diabetes 

Examples
MIDD maternally inherited diabetes and deafness
AND MELAS Myopathy, encephalopathy, lactic acidosis, stroke like episodes - this also has diabetes as a symptom

Heteroplasmy

Question 12

Monogenic vs polygenic diabetes treatment differences

Answer 12

monogenic:

• sulfonylureas
• diet
• exercise
• may not need anything else

polygenic:

• metformin
• diet
• exercise
• insulin

Question 13

What is the relevance of GWAS/SNPs in diabetes?

Answer 13

In type 1 diabetes the HLA SNP has an odds ratio of 6.5
Type 2 diabetes there are about 90 loci involved but the effects are very small
Effects are not significant especially for type 2 diabetes so not useful to clinicians.

Question 14

Give examples of polygenic diabetes

Answer 14

Type 1 and Type 2 diabetes

Question 15

What are some rarer types of MODY?

Answer 15

HNF4 alpha, HNF1 beta

Question 16

What do polygenic diabetes need in addition to genetic factors?

Answer 16

Unlike monogenic diabetes, polygenic diabetes (types 1 and 2) require a second hit:
either:
-environmental (type 1 patients often had a viral infection that triggered the T1 diabetes)
-lifestyle (eg unhealthy lifestyle for type 2)

Question 17

How has GWAS studies helped with understanding types 1 and 2 diabetes

Answer 17

Type 1: We found that some SNPs in HLA gene (human MHC) can give an odds ratio of 6 for developing type 1 diabetes
However, still not much u can do as a clinician but may be interesting for like a geneticist doing research etc

Type 2: about 90 SNPs identified but overall have small effects so pretty trivial.

Question 18

What are copy number variants?

Answer 18

Some sections of genome are repeated and the no of repeats varies within population
Can be affected by deletions, duplications and insertions.

However, not much evidence with regards to their effect on diabetes

Question 19

Summarise monogenic and polygenic diabetes with regards to the effect of the gene variants on the risks of diabetes and also how common these gene variants are

Answer 19

Monogenic: Rare gene variants but have a profound effect on increasing the risks of diabetes

Polygenic: Common gene variants that have small effects

Question 20

explain the implications of genetics for clinical management of diabetes

Answer 20

Precision medicine- using patients genetic info can help with;
Diagnosis- is it type 1 or MODY etc
Treatment- pharmacogenetics (how patient respond to drugs depending on genes)