LIPOTOXICITY
The main
function of adipose tissue is to store energy in the form of TAG in postprandial
state and release them as glycerol and FFA in fasting or starved state.
Accumulation of lipids and their harmful effect is called lipotoxicity which
can cause hepatic steatosis, lipid induced cardiomyopathy, insulin resistance
and type 2 diabetes mellitus. Increase in NEFA cause underutilization of
glucose and insulin resistance by 3 mechanisms.
(1) Via
randle cycle glucose cannot enter glycolytic pathway due to accumulation of
citrate that inhibit PFK.
(2) DAG
which is formed during fatty acid metabolism activates PKC which phosphorylates
insulin receptor and insulin receptor substrate (IRS)-1 inactivating them
(3) it also
activates NFkB which damages vessels. In liver NEFA inhibit the suppression of
glycogenolysis by insulin. Many patients with obesity and increased plasma NEFA
do not develop diabetes because NEFAs are potent stimulators of insulin
secretion in normal individuals an effect that might mitigate the tendency for
NEFAs to induce insulin resistance.
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