Week 4 Flashcards
purpose of beta cells
produce store and release insulin in response to rising blood glucose
how does glucsoe enter beta cell
Glut 2
What occurs to glucose in beta cell
metabolised so ATP inceased binds to K channel so K no longer exits
what occurs after ATP bnding to K channels in B cell
K channel shuts so K cant exit and cell depolarizes and calcium ions can now enter the cell leading to insulin release
K channel structure
4SURI subunits and 2 Kir6.2 subunits
Importance of mutations in K channels in B cells
prevent closing so break link between glucose levels and insulin release- neonatal as mutations in K channels in 40% of patients
Characteristics of MODY
early diagnosis and seems to be type 1 but autosomally dominantly inherited not tyoe 1 characteristics and can take breaks from insulin
What is MODY
maturity onset diabetes of the young
non insulin dependent- gene defect causes defect in beta cell function
different types and frequencies
66% by trans factors 22% by glucokinase
What does glucokinase MODY do
is pancreatic glucose sensor so setpoint higher- born with higher blood glucose
best treatment for glucokinase MODY
do not treat as if give insulin body stops producing tis own and has no effect
HNF1a and HNF4A mutation frequency and effect
61% and 4% of mody respectively
autosomal dominant
beta cell reduced function
treatment of HNF1a MODY
respond 4 fold better to SU compared to T2D so low dose of SU better treatment than insulin
Sulphonylurea effect
binds to K channel causing elss K to leave cell so more depol an more ca entering so more insulin release
HNF1B MODY effect
recued number of beta cells as problems with pancreatic development- it is smaller
HNF1B MODY treatment
Need insulin to treat, don’t respond to SU
neonatal diabetes diagnosis
below 6 months caused by genetics
HLA analysis suggests type 1 diabetes very uncommon before 6 months
Kir6.2 neonatal effect
ATP binding sites on K channel mutated so dont close
Kir6.2 neonatal treatment
high dose SU- casues k clsoing
lowers glucose values and less fluctuation
Kir6.2 mutation V59M
causes neurological problems
Developmental delays in 21% of Kir6.2
Developmental delays in neonatal
5% DEND- developmental delay (severe), epilepsy, neonatal diabetes
16% intermediate DEND mild developmental delay no epilepsy nd neonatal diabetes
Treatment of type 1 diabetes
Insulin
treatment of type 2 diabetes
Metformin
Importance of evaluation of tests
Measurement of what value of something new is relative to current precise- reveal new values
ACCE wheel
Analytic validity
Clinical validity
Clinical utility
Ethical legal and social implications
Disorder and setting
essential background
What is disorder
what are clinical findigns,
Analytical vailidity
Defines ability to accurately and reliably measure genotype of interest
Sensitivity and specificity
Clinical validity
Ability of a test to detect or predict the associate disorder
Sensitivity, specificity, PPR and NPV
Clinical utility
Defines the elements that need to be considered when evaluating risk and benefits with intro to routine practice
Focuses on health outcomes positive and negative
Ethical, legal and social implications
What is known about stigma, primary. Are there consent issues
sensitivity calculation
true positive rate= TP/P
specificity and calc
true negative rate= TN/N
PPv
TP/TP+FP
NPV
TN/Tn+FN
predictive risk
Relative risk would be 1 if test was not beneficial
If positive then above 1
The test’s ability to predict the occurrence of the adverse event of interest
Clinical Validity
The probability of an adverse event when the genetic variant is present
PPV
The probability of no adverse event when the genetic variant is absent
NPV
Indicates potential benefit of a pharmacogenetic test (expected reduction in adverse events or number of patients requiring a different treatment)
Population impact
measurement of population impact
Population attributable fraction
The number of individuals who would need to be genotyped to prevent one patient having an adverse event
Number needed to gentype
Required for the implementation of a pharmacogenetics test as a well as clinical validity and population impact evaluation
economic evaluation
The ability of a test to discriminate between adverse events, measured by sensitivity and specificity
discriminative accuracy
