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Ele Ferrannini, Metabolic Syndrome: A Solution in Search of a Problem, The Journal of Clinical Endocrinology & Metabolism, Volume 92, Issue 2, 1 February 2007, Pages 396–398, https://doi.org/10.1210/jc.2006-0944
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Extract
The other day I saw Mrs. R. G., admitted for shortness of breath and fatigue. “A lady of 59,” recited the young intern, “has had type 2 diabetes for 15 yr, treated with metformin plus glibenclamide, and hypertension, well-controlled on an angiotensin-converting enzyme inhibitor-thiazide combination. Her body mass index is 30.5 kg/m2, serum triglycerides are 2.2 mmol/liter and high-density lipoprotein cholesterol is 0.99 mmol/liter.” Then, with a triumphant glance at me, “metabolic syndrome,” she stated. A clear message, I thought: the metabolic syndrome is here to stay. A captivating concept, a catchy name, the right blend of mystery (“syndrome”) and novelty, a reputation of global applicability, in consonance with other global epidemics (obesity and diabetes): all ingredients of success. How did it happen?
The Beginning
In 1988 Reaven (1) formalized the concept that insulin resistance clusters with glucose intolerance, dyslipidemia, and hypertension to enhance cardiovascular disease (CVD) risk. These abnormalities did not just segregate with insulin resistance but were related to it by cause-effect relationships, some clearer than others and many still undergoing active investigation. In other words, much less a probabilistic phenomenon than a mechanistic theory: the insulin resistance syndrome (IRS). In IRS, the primacy of insulin resistance (Fig. 1) is posited on the grounds that insulin resistance is an effective transducer of environmental influences, with obesity (especially visceral) (2), cardiorespiratory fitness (3), and stress (4) being the most important ones. On the effector side, insulin exerts potent actions not only in pathways in glucose homeostasis but also on lipid turnover, blood pressure control, and vascular reactivity (nonglucose actions in Fig. 1). Moreover, chronic hyperinsulinemia—the in vivo adaptive response to insulin resistance—has been shown to have pathogenic potential in its own right [for example, by down-regulating insulin action (5), strengthening antinatriuresis (6), or stimulating the adrenergic nervous system (7)], thereby creating reinforcement circuits in the network (8). These facts are supported by a wealth of experimental and clinical investigation (extensively reviewed in Ref. 9). However, it is crucial to emphasize that just as insulin resistance alone is insufficient to alter glucose tolerance—for which some degree of β-cell dysfunction is required—insulin resistance/hyperinsulinemia is neither strictly necessary nor sufficient to alter lipid metabolism, blood pressure, or vascular function. Each of these homeostatic systems is under multifactorial control, and defects in one or more steps of its effector pathway (other factors in Fig. 1) are necessary to drive the system out of control. Also, each of these systems is redundant, with plenty of interactions. For example, a genetic deficiency in glucokinase (or lipoprotein lipase) expression can be enough to impair glucose tolerance (or triglyceride metabolism), and at the same time induce insulin resistance (secondary to glucotoxicity or substrate competition, respectively): the resulting pathophysiological picture would be indistinguishable from one of primary insulin resistance.
