The Reaven syndrome: An historical perspective

When reliable plasma insulin assays and accurate triglyceride methods became available in the 1960s, the scene was set for Gerald Reaven and colleagues to discover the association between the insulin response to carbohydrate feeding and serum triglyceride levels. ¹ Higher insulin responses were associated with higher triglyceride levels. Initially, Reaven hypothesised that the increased insulin levels were the cause of the hypertriglyceridaemia, because insulin was believed at that time to stimulate hepatic very low density lipoprotein (VLDL) secretion. ¹ However, in the 1980s, it became possible to culture adult hepatocytes without the necessity for insulin to maintain their viability and it was then evident that the primary effect of insulin on hepatic VLDL secretion was inhibitory. ² This proved to be due to an increase in the proteolytic degradation of newly synthesised apolipoprotein B100 [the major protein moiety of VLDL and low-density lipoprotein (LDL)] before it could be assembled into VLDL. ³ Thus, hypertriglyceridaemia must be due not to hyperinsulinaemia, but to resistance to insulin. Reaven then argued that, like muscle, the liver must be resistant to the action of insulin, at least in regard to its diminished capacity to take up glucose. Increased insulin levels were thus a response to overcome this resistance in order to maintain euglycaemia [or the failed attempt to maintain normal glucose levels in the case of type 2 diabetes mellitus (T2DM)]. Hepatic insulin resistance releases the brake imposed by insulin on VLDL production and thus explains the hypertriglyceridaemia of metabolic syndrome and T2DM. This theory was later confirmed by human studies of VLDL kinetics. ³ Subsequently, a clinical syndrome emerged associated with an exaggerated insulin response to carbohydrate feeding. In addition to hypertriglyceridaemia, this syndrome comprised increased risk of atherosclerotic cardiovascular disease (CVD), T2DM or a predisposition to develop it, low high-density lipoprotein (HDL) cholesterol, non-alcoholic steatohepatitis, hypertension, hyperuricaemia, raised indices of inflammation and of coagulation (plasminogen activator inhibitor-1, fibrinogen), hirsutes and male pattern obesity in women [polycystic ovary syndrome, low sex hormone binding globulin (SHBG)] and in extreme cases acanthosis nigricans.^3,4 This, Reaven termed ‘Syndrome X’, ² although it is now more widely known as the metabolic syndrome, particularly when associated with central obesity. That insulin resistance and the hyperinsulinaemia arising as a consequence are the causes of this syndrome is the current iteration of the Reaven hypothesis. Visceral adipose tissue is believed to release inflammatory cytokines, which, arriving at the liver in high concentration via the portal vein, oppose the anabolic actions of insulin.

Diabetologists will be familiar with the large doses of insulin required to make even modest improvements in hyperglycaemia in obese patients with T2DM, often far greater than are required in type 1 diabetes. However, while Reaven was developing his hypothesis, rarer syndromes involving insulin resistance came to light in which a hundred or more units of exogenous insulin may be required each day. Among these are insulin receptor mutations, which lead to hyperglycaemia, but not hypertriglyceridaemia, and abnormalities of body fat distribution, such as Dunnigan–Kobberling syndrome (due most commonly to mutation of LMNA which codes for lamins of the inner nuclear membrane) in which the insulin resistance is associated with both hyperglycaemia and hypertriglyceridaemia. ⁵ It thus became obvious that resistance to insulin-stimulated glucose uptake (and consequent increased insulin secretion) could arise at the pre-receptor level [e.g. by non-esterified fatty acid inhibition of glucose uptake (Randle effect)], at the level of the insulin receptor (due say to a gene variant) or occur as post-receptor phenomena within the cell where insulin signals to many processes by a variety of mechanisms. Indeed, when the insulin receptor is intact, some of these processes may be underactive due to insulin resistance to their particular signalling mechanism while others may be overstimulated because their regulatory pathway can still respond to the raised insulin levels. Furthermore, these effects might vary in different tissues. Ideas such as these might provide some resolution of the conflict which exists between which components of the Reaven syndrome are due to resistance to insulin (too little insulin action) and which are due to the consequent hyperinsulinaemia (too much insulin action). For example, SHBG is decreased in insulin resistance, leading to increased free androgen levels in both men and women. This at least partly explains the androgenisation of insulin-resistant women and thus their male pattern (visceral; central) obesity and hirsutes. Despite the association of insulin resistance with decreased SHBG, however, tissue culture experiments with human hepatocytes reveal insulin to have an inhibitory action on SHBG production. Thus, unlike the VLDL production pathway where insulin resistance decreases the inhibitory effect of insulin, the pathway for the production of SHBG must escape resistance to the action of insulin and be inhibited by the hyperinsulinaemia which occurs to overcome resistance to glucose uptake. Also acanthosis nigricans (a cutaneous disorder manifested by symmetric, hypertrophic, papillomatous, velvety, hyperpigmented plaques commonly found in the axillae and on flexural and intertriginous areas) appears secondary to excessive insulin concentrations.

Reaven’s hypothesis has generated a substantial body of research and has stood the test of time better than many scientific concepts and continues to provide insights into atherogenic mechanisms and to stimulate many new lines of enquiry. An outstanding, fundamental issue relating to metabolic syndrome is which came first – the insulin resistance or the predisposition to deposit fat centrally rather than peripherally which then leads to insulin resistance? If androgenisation is secondary to insulin resistance, then it cannot explain a predisposition to deposit fat preferentially in the abdomen before insulin resistance has occurred. Recently, genetic antecedents of visceral as opposed to peripheral obesity have been revealed, which are likely to provide a more satisfactory explanation in individuals susceptible to metabolic syndrome. ⁶

Traditionally treatment has been directed at individual components of the metabolic syndrome, such as hyperglycaemia, dyslipidaemia or hypertension. The syndrome is not only frequently occurring in people with T2DM and CVD but is present before either are clinically evident. It thus presents an opportunity for disease prevention, certainly of central obesity, its most common cause. Treating this with diet, medication or surgery is thus the most obvious therapeutic approach. New targets for pharmacological intervention are likely, however, to be identified from patients with a substantial genetic component to their insulin resistance. These may lead to the development of novel therapies which could prove more generally applicable to the syndrome first fully recognised by Gerald Reaven.