6 Complex Genetic Diseases: Diabetes Flashcards
Q: What causes diabetes? What can it result in? What determines treatment?
A: -beta cell dysfunction and/or insulin resistance
- chronic hyperglycaemia
- classification
Q: What is type 1 diabetes? When can it present? Treatment?
A: -autoimmune system destroys pancreatic beta cells (diminished/ absent endogenous pancreatic beta cell function)
- any age
- insulin replacement
Q: What is type 2 diabetes? When can it present? Treatment?
A: primary problem= tissues are resistant to insulin action -> causes increased insulin production -> ultimately ‘pancreatic exhaustion’ and reduced secretion
- usually middle age/older (but increasing in youth) and incidence changes in different ethnic groups
- initially by diet and exercise and oral hypoglycaemic agents=produce more insulin and increase sensitivity (relies on endogenous insulin production) but insulin eventually
Q: What’s included in a type 1 diabetes management package? (6)
A: -insulin injections/pump/islet cell transplant
- self monitoring blood glucose
- type 1 diabetes education
- ketoacidosis prevention
- carbohydrate counting
- driving guidance and employment
Q: What’s included in a type 2 diabetes management package? (5)
A: -metformin/sulphonylurea GLP1 antagonist
- SGLT-2 inhibitors
- DPP4 inhibitors
- no routine glucose testing
- type 2 specific education
*Q: What is monogenic diabetes? Difference? 2 types?
A: due to a single gene defect
very different to type 1 and 2 ; are born with it as there’s a mutation and you can’t stop its development - not to do with diet, virus or obesity
- MODY: maturity onset diabetes of the young
- PND: permanent neonatal diabetes
Q: What is MODY? Most common cause? (2)
A: -maturity onset diabetes of the young
- collection of autosomal dominant monogenic disorders affecting genes involved in beta-cell glucose sensing and insulin secretion
- HNF-1alpha gene defect which affects a transcription factor involved in promoting transcription of lots of genes involved in ^
- glucokinase gene defect
Q: What is the role of glucokinase? How does a defect in glucokinase cause MODY? Misdiagnosed as?
A: rate limiting step: glucose-> glucose 6 phosphate
-regarded as beta cell glucose sensor as when blood glucose reaches certain point (above 4mmol/L) it kicks in and starts reaction ^
- mutation makes it work less effectively: increases set-point at which insulin secretion is triggered
- allows glycolysis and without -> no ATP which means ATP sensitive K+ channels don’t close and don’t cause depolarisation which means insulin can’t be secreted
- post prandial (period during or after meal) sugars are classically not raised
-T2DM, IFG (impaired fasting glycemia), GDM (Gestational diabetes)
Q: How does a beta cell secrete insulin?
A: 1. glucose enters cell via transporter
- gluocose-> G6P via hexokinase
- glycolysis/krebs cycle -> ATP
- high ATP closes ATP sensitive K+ channel
- membrane is depolarised
- voltage gated Ca2+ channel opens and Ca2+ floods in
- insulin is secreted (granules filled with insulin migrate and fuse with cell membrane)
Q: What are HNF-1 alpha? What do mutations in this cause? Absence of HNF-1 alpha? Presentation? Best treatment? why?
A: -hepatic nuclear factor 1 alpha = transcription factor normally stimulating insulin production
- accounts for most cases of MODY in UK
- insulin production is reduced, but only manifests in adulthood when beta cell function starts to naturally decline (potassium channels don’t close effectively or at all as not enough ATP produced)
-present from birth but doesn’t really appear until teenage years
- sulphorylureas drug forces K+ channel (used in T2)
- works well as problem is insulin production and not resistance
- may eventually require insulin therapy much later (rather than sulph. forever)
Q: What is a mutation in HNF-1 alpha often misdiagnosed as? What happens? People with HNF-1 alpha mutation are at risk of?
A: T1DM
-often stop insulin in misdiagnosed patients
-future microvascular and macrovascular complications (as with all diabetes)
Q: How is MODY identified from potential cases of T1 and T2 diabetes mellitus?
A: clinical features and biomarkers
can get genetic test but expensive
Q: What do patients with glucokinase mutations often have?
A: mild hyperglycaemia (high blood sugar)
Q: What is GCK MODY? Association? Treatment?
A: -non progressive mild life long hyperglycaemia
- not associated with long term complications
- rarely needs treatment as body’s physiology is working just at a higher glucose set point
- diagnosis means incorrect treatment can be stopped
Q: What are 2 rare causes of MODY? (5, 2) How do they differ to the 2 common types?
A: HNF 4 alpha
- clinically similar to HNF-1 alpha
- older age of onset
- low renal glucose threshold
- macrosomia (newborn who’s significantly larger than average)
- transient neonatal hypoglycaemia
HNF-1 beta (RCAD)
- renal cysts and diabetes
- genital tract mutations
both are MODY that can also present with multisystemic features
-unlike the most common 2 causes which present like diabetes
