[HTML][HTML] Insulin resistance and cardiovascular disease

HN Ginsberg - The Journal of clinical investigation, 2000 - Am Soc Clin Investig
The Journal of clinical investigation, 2000Am Soc Clin Investig
454 The Journal of Clinical Investigation| August 2000| Volume 106| Number 4 uptake and
storage by adipocytes, such as those for hormone-sensitive lipase (HSL)(9), lipoprotein
lipase (LPL)(10), and complement component C3a (whose proteolytic product is the
acylation-stimulating protein [ASP][ref. 11]), as well as for various fatty acid transporters and
binding proteins. Although some investigators have suggested links between HSL, LPL, and
ASP, and either the insulin resistance/obesity syndrome or combined hyperlipidemia (which …
454 The Journal of Clinical Investigation| August 2000| Volume 106| Number 4 uptake and storage by adipocytes, such as those for hormone-sensitive lipase (HSL)(9), lipoprotein lipase (LPL)(10), and complement component C3a (whose proteolytic product is the acylation-stimulating protein [ASP][ref. 11]), as well as for various fatty acid transporters and binding proteins. Although some investigators have suggested links between HSL, LPL, and ASP, and either the insulin resistance/obesity syndrome or combined hyperlipidemia (which some believe is also the result of insulin resistance), no firm evidence yet exists linking these important proteins to the insulin resistance syndrome. Indeed, separate studies of a mouse in which the gene for ASP was deleted have resulted in contradictory results regarding its role in lipid metabolism (11, 12). On the other hand, recent data from mice carrying null mutations in the gene for the fatty acid transporter CD36 are quite revealing as to the consequences of the inability of fat cells to store fatty acids as TG. These animals had increased levels of plasma FFAs and hypertriglyceridemia, indicative of the response of the liver to an increased flux of energy from the periphery (13). Of interest, CD36 knock-out mice, which lack the fatty acid transporter in both adipose and muscle tissue, are not insulin-resistant. Indeed, they seem to be more insulin-sensitive, possibly as a result of diminished uptake of fatty acids by muscle. The dissociation of insulin resistance and TG metabolism in this model suggests a direct and critical role of increased plasma fatty acid flux to the liver in the genesis of hypertriglyceridemia. This conclusion is supported by work with transgenic mice overexpressing CD36 in muscle (14): these animals have low plasma levels of both fatty acids and TG but are insulin-resistant. These findings in gene-modified mouse models were paralleled by the observation that a strain of the spontaneously hypertensive rat (SHR) had mutations in CD36 that appeared to be associated with insulin resistance (15, 16). However, a very recent report indicated that the original SHR line, which is insulin-resistant, has no defects in its CD36 gene (17). Further developments in this area of investigation are eagerly awaited.
In summary, the inability of insulin-resistant fat cells to store TG is very likely the initial step in the development of the dyslipidemia characteristic of insulin resistance. Importantly, this link between the fat cell and hepatic production of VLDL does not seem to be necessarily linked, in mouse models, to insulin resistance at the level of muscle. No candidate genes have been linked unequivocally to either the dyslipidemia or the insulin resistance in humans. Indeed, although the CD36 gene appears to be an important candidate, the data from the CD36 knock-out mice indicate to me that any CD36 defect would have to be specific to adipose tissue to cause both hypertriglyceridemia and insulin resistance.
The Journal of Clinical Investigation