In summary, there are various mechanisms proposed to explain the biochemical pathways involved in the progressive development of dietary fat-induced insulin resistance (Fig. 2.2). Fatty acids seem able to modulate the intracellular metabolism of glucose either directly (e.g. glucose fatty acid cycle), or indirectly via their effects on the insulin signalling cascade and on insulin secretion. This cross-talk between glucose (and insulin) and fatty acids plays a vital role in the coordination of whole body and cellular energy metabolism. Fatty acid stimulation of insulin secretion ensures a heightened insulin response under conditions where the adverse effects of the glucose-fatty acid cycle would otherwise result in impaired glucose uptake and hyperglycaemia. However, under conditions of chronic over-provision (either via the diet or through excessive release into the circulation from adipose tissues stores as in obesity), excess fatty acids may lead to intracellular accumulation of LC acyl CoA, with adverse effects on insulin signalling leading to cellular insulin resistance. In the beta cell, LC acyl CoA-mediated insulin secretion may break down, with consequent inability to mount an adequate insulin response to carbohydrate ingestion. Eventually overexposure of the beta cell to excess fatty acids may lead to the abolishment of insulin secretion in the beta cell through apoptosis.
FFA and/or metabolites may:
• have direct effects on insulin stimulated glucose uptake via GLUT4
• have indirect effects on insulin signalling cascade, influencing phosphorylation of IRS-1
• affect membrane fluidity and thereby insulin receptor accessibility
• have direct or indirect effects on GSIS via modulation of ion channels
• affect GSIS differently dependent on chain length and degree of saturation
• regulate insulin secretion through protein acylation
• lead to hyperinsulinaemia through LCacyl CoA accumulation
• affect gene expression
FFA: free fatty acids, IRS-1: insulin receptor substrate-1 protein, GSIS: glucose stimulate insulin secretion, LC: long chain.
Fig. 2.2 Summary of proposed mechanisms that may be involved in fatty acid induced insulin resistance.
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