Triglycerides, fatty acids and insulin resistance - hyperinsulinemia

There is now much interest in the mechanisms by which altered lipid metabol ism might contribute to insulin resistance as is found in Syndrome X or in Type II diabetes. This review considers recent evidence obtained in animal models and its relevance to humans, and also likely mechanisms and strategi es for the onset and amelioration of insulin resistance. - A kev tissue for development of insulin resistance is skeletal muscle. Animal models of Syn drome X leg high fat fed rat) exhibit excess accumulation of muscle triglyc eride coincident with development of insulin resistance. This seems to also occur in humans and several studies demonstrate increased muscle triglycer ide content in insulin resistant states. Recently magnetic resonance spectr oscopy has been used to demonstrate that at least some of the lipid accumul ation is inside the muscle cell (myocyte). Factors leading to this accumula tion are not clear. but it could derive from elevated circulating free fatt y acids. basal or postprandial triglycerides. or reduced muscle fatty acid oxidation. Supporting a link with adipose tissue metabolism, there appears to be a close association of muscle and whole body insulin resistance with the degree of abdominal obesity. While causal relationships are still to be clearly established. there are now quite plausible mechanistic links betwe en muscle lipid accumulation and insulin resistance. which go beyond the cl assic Randle glucose-fatty acid cycle. In animal models. dietary changes or prior exercise which reduce muscle lipid accumulation also improve insulin sensitivity. It is likely that cytosolic accumulation of the: active form of lipid in muscle, the long chain fatty acyl CoAs. is involved. leading to altered insulin signalling or enzyme activities leg glycogen synthase) eit her directly or via chronic activation of mediators such as protein kinase C. Unless there is significant weight loss, short or medium term dietary ma nipulation does not alter insulin sensitivity as much in humans as in roden t models, and there is considerable interest in pharmacological interventio n. Studies using PPARgamma receptor agonists. the thiazolidinediones, have supported the principle that reduced muscle lipid accumulation is associate d with increased insulin sensitivity. Other potent systemic lipid-lowering agents such as PPARalpha receptor agonists leg fibrates) or antilipolytic a gents leg nicotinic acid analogues) might improve insulin sensitivity hut f urther work is needed, particularly to clarify implications for muscle meta bolism. In conclusion, evidence is growing that excess muscle and liver lip id accumulation causes or exacerbates insulin resistance in Syndrome X and in Type II diabetes: development of strategies to prevent this seem very wo rthwhile.