The observation that obesity, insulin resistance, dyslipidemia, and arterial hypertension often occur in the same patient is not new. The clustering of these risk factors in epidemiological studies and in clinical practice is so obvious that the combination received a name. Now, the risk-factor cluster is referred to as metabolic syndrome. Other names have been around over the past decades including insulin resistance syndrome, syndrome X, or deadly quartet. No doubt, the term metabolic syndrome has clinical and scientific merits. For example, physicians recognizing the clustering of cardiovascular and metabolic risk factors may be more likely to target treatments to patients at highest risk. Pattern recognition is a powerful tool in clinical medicine. Meanwhile, screening for metabolic risk and its treatment is part of routine care in hypertensive patients. Furthermore, the epidemiological and clinical association between cardiovascular and metabolic risk factors provided guidance for basic and clinical research. The idea that there could be common mechanisms mediating cardiovascular and metabolic disease led to important scientific discoveries.
Hyperinsulinemia, secondary to insulin resistance, a hallmark of the metabolic syndrome, is associated with increased risk for arterial hypertension. Whereas a statistical association is hypothesis-generating and cannot prove causality, there is ample evidence that insulin can affect the cardiovascular system. Clinical investigations testing how insulin regulates the cardiovascular system require sophisticated physiological methodology because direct insulin actions can be obscured by concomitant changes in glucose levels. Hypoglycemia is a potent stimulator of the sympatho-adrenal system. Direct muscle sympathetic nerve activity recordings using the microneurography during hyperinsulinemic–euglycemic clamping have been particularly useful in this setting. In healthy young humans, experimental hyperinsulinemia acutely increases sympathetic nervous system activity, whereas blood pressure does not increase . Apparently, insulin elicits peripheral vasodilation, thus, compensating for the increase in sympathetic outflow . The response is likely mediated through endothelial nitric oxide release . In contrast to high-dose insulin, modest insulin doses produce sympathetic excitation without peripheral vasodilation . In older healthy individuals, hyperinsulinemia produces sympathetic activation and vasoconstriction . Insulin's sympathomimetic actions could conceivably contribute to the graded increase in sympathetic activity from obesity to metabolic syndrome and then to overt type 2 diabetes mellitus [6,7]. Hyperinsulinemia may contribute to arterial hypertension and cardiovascular organ damage through increased sympathetic drive. Body weight reduction improves insulin sensitivity, sympathetic activity, and blood pressure even in normotensive obese individuals . In obese mice with leptin-receptor deficiency, increasing peripheral insulin sensitivity by protein tyrosine phosphatase 1B deletion normalizes blood pressure in the absence of body weight reduction .
Lytsy et al. analyzed data from two cohorts, namely the Uppsala Longitudinal Study of Adult Men and the Prospective Investigation of the Vasculature in Uppsala Seniors. The first study begun in the early 1970s and enrolled men who were 50 years old at that time. The second study included 70-year-old men and women recruited in the years 2001–2004. The pooled data set included participants with complete data on blood pressure and antihypertensive medications. The investigators tested whether being overweight or obese or insulin-resistant at baseline predisposes to new-onset hypertension in previously normotensive individuals or to the progression in hypertension severity in hypertensive individuals. Normal-weight participants without insulin resistance had the lowest risk of developing arterial hypertension. The risk was modestly increased in normal-weight participants with insulin resistance. Both overweight and obese participants, with or without insulin resistance, featured an increased hypertension risk. The observation suggests that hyperinsulinemia cannot be the sole mechanism driving sympathetic activity and blood pressure. The obvious implication is that we should seek alternative explanations how obesity raises blood pressure. For example, sympathetic activity and blood pressure may be increased through other mechanisms, such as adipose tissue-derived leptin acting on hypothalamic melanocortin receptors [10,11]. Perhaps, more exciting is the idea that in some people, blood pressure may be insulin-sensitive and in others insulin-resistant.
The study by Lytsy et al. in this issue is in line with previous observation on dissociation of cardiovascular and metabolic regulation in obesity. Rare patients with monogenic obesity caused by leptin deficiency exhibit a profoundly increased risk for type 2 diabetes mellitus. Yet, the condition is associated with signs and symptoms of reduced, rather than increased, sympathetic activity . Blood pressure and urinary norepinephrine excretion are reduced in overweight and obese patients with genetic melanocortin 4 receptor deficiency compared with adiposity-matched control individuals . Finally, in Pima Indians, a population with an extreme risk for type 2 diabetes mellitus, sympathetic activity and blood pressure are not related to the degree of adiposity . All these studies identified populations in whom hyperinsulinemia was not associated with sympathetic activation and hypertension through genetic mechanisms. Remarkably, environmental factors, such as physical exercise, also modulate insulin-induced sympathetic activation and vasodilation .
Perhaps, the leptin melanocortin system connects insulin to the sympathetic nervous system, thereby setting blood pressure. Indeed, central nervous melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons . Genetic melanocortin 4 receptor deletion abrogates obesity-induced arterial hypertension in mice, whereas re-expression of these receptors in cholinergic neurons restores the hypertension . Remarkably, sympathetic activation observed with insulin infusion is abolished by local melanocortin receptor blockade in the hypothalamic paraventricular nucleus . The melanocortin pathway may be regulated by sympathoexcitatory insulin receptors located upstream in the arcuate nucleus . Therefore, we could speculate that the neural insulin–melanocortin pathway may contribute to the connection or disconnection between metabolic and cardiovascular regulation in patients.
The study by Lytsy et al. is a reminder that single mechanisms cannot explain the relationship between adiposity, metabolic abnormalities, particularly insulin resistance, and arterial hypertension. Moreover, the study suggests that in patient care and in science, we should pay attention to the outliers refusing to adhere to an overriding hypothesis. Studies in outliers in whom blood pressure and metabolic diseases are disconnected from each other provide important mechanistic insight. ‘Treasure your exceptions’, is a worthwhile strategy here.
Conflicts of interest
J.J. served as scientific advisor for Boehringer-Ingelheim, Novartis, Eternygen, Vivus.
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