Lecture 6- Diabetes Flashcards Preview

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Flashcards in Lecture 6- Diabetes Deck (30):
1

How is insulin secreted by the pancreatic Beta cell?

- Glucose enters Beta cell
- Glucose is used to generate ATP
- rise in ATP closes ATP dependent K+ channels
- membrane depolarises
- VGCC open and Ca2+ influx
- vesicles containing insulin fuse with membrane + exocytosis

2

Name two monogenic types of diabetes

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

3

What is the inheritance of MODY?

Autosomal dominant monogenic

4

Name two genes that might cause MODY and explain their function

HNF-1alpha (hepatic nuclear factor) = TF
Glucokinase = Enzyme

5

What is the function of HNF1-alpha?

A transcription factor stimulating insulin production

6

What happens when HNF1-a is mutated?

- Insulin production is reduced because ATP sensitive K+ channel doesn't close
- Manifests in adulthood when B-cell function declines naturally

7

What can be used to manage MODY?

sulphonylurea- which causes the K+ channel to close
May require insulin therapy

8

What might be the complications of MODY?

microvascular and microvascular complications

9

What is the function of glucokinase?

- An enzyme converting glucose to G6P which works around 4mmol/l
- involved in Beta cell glucose sensing

10

What do mutations in glucokinase cause?

Higher set point at which insulin secretion is triggered

11

What are the clinical features of gluocokinase MODY?

- stable, mild hypoglycaemia

12

What is the treatment for GCK MODY?

- Do not need treatment, don't really have long term complications
- Diagnosis of GCK MODY instead of T1D means treatment can be stopped

13

Name two rarer types of mutations causing MODY and their clinical manifestations

1) HNF4-a: older age of onset, low renal glucose threshold, macrosomia and transient neonatal hypoglycaemia
2) HNF-1B: Renal cysts and diabetes, genital tract mutation

14

What is Permanent Neonatal Diabetes?

- Diabetes in the first 6 month of life

15

Which genes are mutated in PND?

KCNJ11, ABCC8 and INS

16

What happens when KNCJ11 is mutated?

ATP sensitive channels do not close, membrane remains hyper polarised, insulin filled vesicles not exocytosed

17

What is the treatment for PND? and how does it wok

- sulphonyureas
- binds to and closes ATP channel = ATP independent closure

18

What causes monogenic diabetes?

- Single nucleotide changes causing:
- missense, frameshift, nonsense
- autosomal dominant but maybe recessive

19

What are the two types of DNA sequencing methods?

Sanger and Next Gen sequencing

20

What is the key difference between Sanger sequencing and NGS?

NGS sequences multiple genes simultaneously but Sanger sequences one gene at a time so it has high precision

21

How is mitochondrial diabetes inherited?

Maternally

22

Which mitochondrial disorders feature diabetes?

MIDD- maternally inherited diabetes and deafness
MELAS- myopathy, encephalopathy, latic acidosis, stroke like episodes

23

What is heteroplasmy

Variable phenotype caused by variable load of mt

24

What are the general features of mitochondrial disorders?

- diabetes
- young- onset sensorineural deafness
- high lactate
- muscle aches
- short stature

25

What is necessary for polygenic diabetes?

- an environmental factor
- lifestyle aspect

26

What is polygenic diabetes?

A compilation of genetic changes that increases your predisposition to developing T1D and T2D

27

What is the purpose of GWAS studies?

To see if a disease is statistically associated with Single Nucleotide Polymorphisms

28

What did GWAS studies in T2D show?

- around 90 loci are associated with increased risk
- SNPs account for 6% of T2D risk
- most affect B cel function

29

What is the relationship between diabetes and obesity?

Have copy number variants in obesity and there might be an increased risk of diabetes with CNVs but not sure. More like to be related to single nucleotide changes

30

What is precision medicine and why could it be useful?

- Using genetic information to provide targeted therapy
- Diagnosis
- Treatment