3 - T2DM Flashcards
What are the 4 main risk factors for T2DM?
1) Diet
2) Obesity
3) Sedentary lifestyle
4) Genetic predisposition
What are the 2 components that eventually result in T2DM?
1) Insulin resistance
2) Beta-cell dysfunction
What two properties characterise insulin resistance?
Increasing peripheral insulin resistance
Increasing hepatic glucose output
What two properties characterise Beta-cell dysfunction?
Inability to compensate for increasing insulin resistance
Impaired insulin secretion
In the context of genetic risk factors, what 2 properties in the aetiology of T2DM are most commonly affected?
Beta-cell function
Beta-cell mass
What is the term for when the environment has an effect on genetics?
Epigenetics
What two genes have been shown to be very important in acting as a predisposition to T2DM?
TCF7L2
KCNJ11
What is the effect of a mutated TCF7L2 gene?
Mutation in transcription factor involved in incretin signalling, therefore:
= Decreased incretin signalling
What is the effect of a mutated KCNJ11?
Codes for the K-ATP channel which is involved in insulin secretion.
What are the 5 areas in which mutations can occur and predispose T2DM?
1) Ion channels / transporters
2) Glucose metabolism
3) Insulin gene transcription
4) Packaging insulin in vesicles
5) Incretins
When are epigenetic factors most likely to have an effect on an individual?
In utero
Soon after birth
Name 1 example of epigenetic effects on T2DM
Dutch famine - 1944-1945
Low birth weight (from famine) associated with insulin resistance and diabetes.
In the case of the Dutch famine, what was also noticed and concluded from Diabetic mothers having children?
Children ALSO at high risk of diabetes development.
Epigenetic factors can be inherited!
What are the two main contributing processes to epigenetic coding?
1) DNA Methylation (represses gene activity)
2) Histone modification (alter DNA around)
What gene has been linked to intra-uterine growth retardation in development of T2DM?
What is that gene’s function?
Pdx1 = transcription factor essential for proper beta-cell development + reduced beta-cell mass.
What is the MOST important factor in the development of diabetes?
Diet
subsequently, adiposity –> obesity
30 minutes of physical activity has what effect on T2DM risk?
Halves
In the context of fat distribution, what factor is most important?
Visceral adiposity is much more dangerous.
What is the mechanism of insulin resistance?
1) Build up of toxins from glucose / lipid metabolism.
Then has effects on either:
- No. of insulin receptors
- Insulin receptor function (e.g. autophosphorylation / tyrosine kinase activity)
- Downstream signalling changes
- Translocation of GLUT4 channel (important for uptake)
= insulin resistance.
What is the proposed hypothesis to T2DM pathophysiology?
As weight increases from increased dietary intake, Beta-cell mass can increase by compensation (NGT)
This continues until beta-cell dysfunction occurs = (IGT)
Occurring until beta-cell failure = (T2DM)
NGT - normal glucose tolerance
IGT - impaired glucose tolerance
What are the 4 groups of medications for T2DM?
Insulin secretagogues
Incretin therapies
Insulin sensitisers
Reduce glucose supply
Give 2 classes of drugs that are insulin secretagogues
Sulphonylureas
Meglitinides
Give 2 classes of drugs that are incretin therapies
GLP-1 receptor agonists
DPP-IV inhibitors
Give 2 classes of drugs that are insulin sensitisers
Thiazolidinediones
Biguanides
Give 3 classes of drugs that reduce glucose supply
Alpha-glucosidases
Amylin analogues
SGLT2 inhibitors
Give an example of a DPP4 inhibitor
Sitagliptin
Name the example of a biguanide
Metformin
Name the example of thiazolidodinediones
Pioglitazone
Name an example of an alpha-glucosidase
Acarbose
Name an example of an amylin analogue
Pramlintide
Name an example of an SGLT2 inhibitor
Canagliflozin
Why don’t SGLT2 inhibitors cause hypoglycaemia?
Because of SGLT1 which is found in segments S2 and S3 of kidney have HIGH affinity so still reabsorb glucose.
