Kerry Loomes 7 Flashcards
What is the difference between type 2 diabetes and type 1 diabetes?
Type 2 has a more gradual onset
And in stead of a lack of insulin there is insulin resistance
What occurs to cells in insulin resistance?
Cells (particularly muscle) become unresponsive to the actions of insulin which results in it taking longer to remove glucose from the blood
What occurs to the liver in the development of insulin resistance?
There is a failure to inhibit glucose production as the genes involved in gluconeogenesis are no longer inhibited by insulin
There is a failure to effectively convert glucose to glycogen to triacylglycerol as genes involved in glycolysis and lipolysis will be stimulated in the absence of insulin
What occurs to the pancreas in type 2 diabetes?
The pancreas will attempt to pump out more insulin to overcome the resistance, this will initially work but eventually causes the death of of the insulin producing beta-islet cells resulting in the development of both insulin deficiency and resistance
What is the cause of insulin resistance?
Increased calorie intake and reduced energy expenditure, leading to a prolonged time in the energy positive state
This results in adipocytes becoming less efficient at storing triglyceride and increased lipolysis
This leads to fatty acid spillover from adipose tissue to non adipose tissue
Leading to impaired glucose uptake by muscle
The liver will have impaired hepatic glucose metabolism and increased VLDL production
How does increased intracellular lipid content cause insulin resistance?
Free fatty acids and their derived forms may directly impair glucose transport across the cell membrane
Inhibition of pyruvate dehydrogenase
Impairment of the insulin signalling pathway
How does inhibition of pyruvate dehydrogenase cause diabetes?
Skeletal muscles prefers fats to glucose as a fuel source the increase of beta oxidation leads to an increase in the ratio:
Acetyl coA/coA, NADH/NAD+, ATP/ADP
These high ratios inactivate pyruvate dehydrogenase through pyruvate dehydrogenase kinase
This results in pyruvate not being oxidised and instead it is used in the synthesis of alanine and lactate which can be transported to the liver to make more glucose which is released to the circulation
How can impairment of the insulin signalling pathway occur in insulin resistance?
The elevated levels of long chain coA convert a down stream signal mediator -insulin receptor substrate 1 - to an inactive form so the glut-4 transporter remains internalized in the cell so glucose is not taken up
How can Metformin help to reduce the effects of type 2 diabetes?
Activation of AMP-activated kinase results in decreased glucose output from the liver by reducing the conversion of pyruvate to glucose
What is a strategy involving adipocytes that could be used against type-2 diabetes?
Increase the storage in the adipocyte to decrease spill-over of fatty acids to make them more sensitive to insulin this can be done through glitazone
How does glitazone increase fatty acid storage in adipocytes?
The adipocyte does not usually express glycerol kinase, however the drug can induce expression of this enzyme in the adipocyte so it is no longer reliant on glucose uptake of the cell in order to store fat
It also makes storage more efficient as when lipolysis occurs the free fatty acid generated can be recycled as the enzyme can produce glycerol 3P from glycerol, this reduces the free fatty acid leakiness seen in type 2 diabetes
