Lecture 6- Diabetes Flashcards
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
Name two monogenic types of diabetes
Maturity onset diabetes of the young (MODY)
Permanent neonatal diabetes (PND)
What is the inheritance of MODY?
Autosomal dominant monogenic
Name two genes that might cause MODY and explain their function
HNF-1alpha (hepatic nuclear factor) = TF
Glucokinase = Enzyme
What is the function of HNF1-alpha?
A transcription factor stimulating insulin production
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
What can be used to manage MODY?
sulphonylurea- which causes the K+ channel to close
May require insulin therapy
What might be the complications of MODY?
microvascular and microvascular complications
What is the function of glucokinase?
- An enzyme converting glucose to G6P which works around 4mmol/l
- involved in Beta cell glucose sensing
What do mutations in glucokinase cause?
Higher set point at which insulin secretion is triggered
What are the clinical features of gluocokinase MODY?
- stable, mild hypoglycaemia
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
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
What is Permanent Neonatal Diabetes?
- Diabetes in the first 6 month of life
Which genes are mutated in PND?
KCNJ11, ABCC8 and INS
What happens when KNCJ11 is mutated?
ATP sensitive channels do not close, membrane remains hyper polarised, insulin filled vesicles not exocytosed
What is the treatment for PND? and how does it wok
- sulphonyureas
- binds to and closes ATP channel = ATP independent closure
What causes monogenic diabetes?
- Single nucleotide changes causing:
- missense, frameshift, nonsense
- autosomal dominant but maybe recessive
What are the two types of DNA sequencing methods?
Sanger and Next Gen sequencing
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
How is mitochondrial diabetes inherited?
Maternally
Which mitochondrial disorders feature diabetes?
MIDD- maternally inherited diabetes and deafness
MELAS- myopathy, encephalopathy, latic acidosis, stroke like episodes
What is heteroplasmy
Variable phenotype caused by variable load of mt
What are the general features of mitochondrial disorders?
- diabetes
- young- onset sensorineural deafness
- high lactate
- muscle aches
- short stature
What is necessary for polygenic diabetes?
- an environmental factor
- lifestyle aspect
What is polygenic diabetes?
A compilation of genetic changes that increases your predisposition to developing T1D and T2D
What is the purpose of GWAS studies?
To see if a disease is statistically associated with Single Nucleotide Polymorphisms
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
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
What is precision medicine and why could it be useful?
- Using genetic information to provide targeted therapy
- Diagnosis
- Treatment
