Insulin and atherosclerosis: villain, accomplice, or innocent bystander?

Initial descriptions of an association between insuli-naemia and both atherosclerotic cardiovascular disease and its risk factors appeared nearly 30 years ago. In 1969, Stout and Vallance-Owen suggested a direct role for insulin in atherogenesis.' Stout recently summarised laboratory studies supporting a direct atherogenic effect of insulin through stimulation of vascular smooth muscle proliferation and arterial wall lipid deposition.2 Insulin has also been implicated as an indirect cause of atheroge-nesis through promoting the development of hyperten-sion and dyslipidaemia.3-5 Several risk factors for atherosclerosis which cluster in individuals at high risk of atherosclerotic cardiovascular disease are associated with hyperinsulinaemia and/or insulin resistance. Reaven in 1988, postulated that insulin resistance and compensatory hyperinsulinaemia underlie this clustering.6 He coined the term "syndrome X" (or the "insulin resistance syndrome") to describe the associations among insulin resistance, hyperinsulinaemia, glucose intolerance, dyslipidaemia, and hypertension, speculating that this syndrome may be an important cause of atherosclerotic cardiovascular disease in affluent societies. Several mechanisms have been proposed for the association of insulin with atherosclerotic cardiovascular disease risk factor abnormalities. Insulin may contribute to the pathogenesis of hypertension by stimulating the sympathetic nervous system, promoting renal sodium retention , modulating cellular cation transport, and/or stimulating vascular smooth muscle hypertrophy.7 Insulin also may induce dyslipidaemia by stimulating hepatic synthesis of very low density lipoprotein (VLDL), leading to raised concentrations of triglyceride and depressed concentrations of high density lipoprotein (HDL) cholesterol .6 Indeed, hyperinsulinaemia is common in some populations with high rates of atherosclerotic cardiovascular disease such as Edinburgh men8 and immigrant Asian Indians.9 Three prospective population studies-the Helsinki Policemen Study,'0 the Paris Prospective Study," and the Busselton Study2-have associated high insulin concentrations with an increased risk of athero-sclerotic cardiovascular disease in men, but not in women (only the Busselton study included women). These studies have some limitations: HDL cholesterol was not measured and the findings were not consistent regarding a relation between atherosclerotic cardiovascular disease and fasting or post-glucose challenge insulin concentrations. In addition, a follow up of the Busselton study found that insulinaemia was an independent risk factor for total mortality in men, but not for cardiovascular mortality in either men or women."3 Insulin was not a risk factor for atherosclerotic cardiovascular disease in Edinburgh or Gothenburg men.'4'5 Pima Indians, who are markedly hyperinsulinaemic, have a low prevalence rate of atherosclerotic cardiovascular disease, and insulin-aemia is not a predictor of ischaemic electrocardiographic abnormalities.'6 Thus insulinaemia is not consistently associated with …