Insulin Resistance and T2DM Flashcards
(22 cards)
What are the fundamental causes of T2DM?
Reduced glucose uptake and metabolism
Relative deficiency in insulin secretion.
Increased endogenous glucose production
What are some of the effects of insulin on the body?
Increased glucose uptake and metabolism Liver glycogen synthesis Uptake of aa and minerals/ions cell growth and differentiation lipid sparing effect (reduced lipolysis and increased fat storage)
What might be seen on a blood test in a diabetic patient?
Increased BG and lipids
What are the actions of Thiazolidinediones?
Reduced hepatic gluconeogenesis
Increased uptake and metabolism of glucose in the liver
Reduced release of FFAs
What does Metformin do?
Increase uptake of glucose to skeletal muscle
Suppression of hepatic gluconeogenesis.
How else can T2DM be treated pharmacologically?
a-glucosidase inhibitors
sulfonylureas
meglitinides
What was the original theory of the development of T2DM?
Skeletal muscle resistance to insulin would eventually lead to beta cell exhaustion.
What is the new understanding of the disease and how has this come about?
Intrinsic problem with beta cell funtion.
At risk individuals shown to have beta cell dysfunction, mainly related to inappropriate processing of insulin. Many single gene disorders seem to result in chronic hyperglycaemia.
What evidence is there that T2DM is a result of environmental factors?
Risk factors such as: physical inactivity, obesity (truncal obesity) and diet identified. Obesity is a very strong independant risk factor.
How is this countered by genetic evidence?
High incidence in ethnic groups e.g. pima indians and in cultures that are rapidly adopting a western lifestyle.
What are T2 SNPs associated with?
They map very close to genes involved with islet cell gene expression and are associated with dysfunctional insulin processing.
How do monogenetic disorders of adipose tissues affect IR?
Disorders of development and function can lead to “fat failure” which may divert nutrients to liver and muscle which impair insulin action at these sites.
Why is this interesting?
Fat is not a major site of glucose disposal or production.
What is interesting about manipulating the brain to control glucose?
It acts independently of energy homeostasis.
What do neurological gene variants seem to have most effect on glucose tolerance through?
Variations in adipisoty.
Why is it hard to identify DM risk genes that affect liver and muscle?
Environmental effects are major on these tissues so it is hard to “pin down” genes.
The ability of the normal pancreas to compensate for insulin resistance in these tissues is great, so one might not see the consequences of mutations to these tissues without other defects in place.
What is the relationship of entero-endocrine cells to DM?
TCF7L2 is a significant SNP in DM and is expressed in these tissues. However, there is no conclusive role for their function in contributing towards insulin resitance.
Why are glucose clamp studies needed?
Insulin and glucose can be very varied and do not neccessarily correlate to each others levels so single blood measurements dont really tell us much about underlying processes.
What are the two type of clamp design?
Hyperglycaemic
Euglycaemic
What is the difference between them?
Hyperglycaemic raises the blood glucose and keeps it at a constant level. The infusion rate can then be used to calculate the amount of glucose metabolised. Insulin response levels can also be measured.
Euglycaemic clamp is in control of insulin (above basal) as well as a variable rate of glucose. This allows measurement of the bodies sensitivity to insulin.
What needs to be corrected for when using the hyperglycaemic clamp?
Urinary glucose loss (and space correction)
Why is the euglycaemic clamp better?
All of the insulin infused is known to be biologically active so it gives a better measure of sensitivity to insulin.
