Should the term ‘metabolic syndrome’ be changed to ‘circadian syndrome’?
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Yes. Nearly all, if not all, of the cardiometabolic risk factors that make up metabolic syndrome also have a circadian rhythm and a circadian function.
Every cell in the body — every organ in the body — has a clock linked to a central body clock in the brain. Disruptions of the body clock may play an important role, so far unrecognized by many, in human health. This is a young field, and the complexity of the regulation of peripheral clocks is only beginning to be understood, including its relation to chronic illnesses and the epidemics of type 2 diabetes and cardiovascular disease.
The underlying etiology of the metabolic syndrome, a cardiometabolic risk factor cluster — central obesity, low HDL cholesterol, impaired glucose tolerance, elevated triglycerides and hypertension — remains the subject of debate. Gerald Reaven, MD, the Stanford University researcher who coined the syndrome’s original name of “syndrome X,” suggested insulin resistance was the cause, but this is only partly correct. Insulin resistance is just one of the outcomes of circadian dysfunction, along with the above risk factors.
However, the newly proposed “circadian syndrome” covers the cardiometabolic risk factors but, importantly, also includes often ignored, serious circadian-related comorbidities, including sleep disturbances, mood changes and cognitive dysfunction. These are frequently seen clinically in type 2 diabetes and CVD.
The key message is that when a primary care physician who sees someone with metabolic syndrome, that should trigger the search for the serious comorbidities apart from just treating the cardiometabolic risk factors. This will identify those at highest risk for CVD and type 2 diabetes. The circadian syndrome is a major driver of the global chronic disease epidemic with high morbidity, health and global socioeconomic cost. I view this from both the public health and clinical perspectives. Insulin resistance is a likely component of what metabolic syndrome is, but it fails to explain the full picture. When focusing solely on glucose, cholesterol or blood pressure, clinicians may be ignoring the very high risk from sleep apnea and other comorbidities.
Paul Zimmet, AO, MD, PhD, is professor of diabetes at Monash University in Australia and co-director of the Sagol Center for Epigenetics of Aging and Metabolism at Tel Aviv Medical Center in Israel. Disclosure: Zimmet reports no relevant financial disclosures.
No. Metabolic associations with clock gene abnormalities are simply that — associations. It is not cause and effect.
Metabolic syndrome has had many definitions over the years, and, no question, this has been confusing. Nevertheless, while confusion around the diagnosis may continue, that does not mean the name “metabolic syndrome” should be put on the shelf, so to speak.
When my colleagues and I authored a consensus statement endorsing harmonized metabolic syndrome criteria, in 2009 (Alberti KG, et al. Circulation. 2009;doi:10.1161/CIRCULATIONAHA.109.192644), we stated that, independent of weight and BMI, visceral adiposity measured by waist circumference trumps every other simple measurement of body composition to assess CVD risk. We knew from the very beginning when all of these definitions were ensuing that fasting glucose, which is part of the five-component syndrome definition, is the best predictor of diabetes. Moreover, we never claimed that metabolic syndrome was going to be a better predictor for CVD than the sum of the parts. The metabolic syndrome is not there to replace other risk factors for CVD. Remember, the metabolic syndrome components do not include LDL cholesterol, which is, arguably, one of the best metabolic predictors of CVD risk.
A syndrome is loosely defined as a group of signs or measurements that consistently occur together and are linked by a common mechanism. A syndrome is not a disease. With metabolic syndrome, the pathophysiology seems to be largely attributable to insulin resistance, with excessive flux of fatty acids from adipose tissue that impairs insulin sensitivity in liver and skeletal muscle. The metabolic syndrome is much more than these three of five components we have defined. Clearly, the current definition of at least three out of five is overly simplistic.
The name “circadian syndrome” represents an exciting new area of science but says nothing about its actual etiology. Insulin resistance explains most if not all of the components of the metabolic syndrome. Studies do show an impact of the clock gene on behavior, but where does it all begin? Does sleep affect behavior, or does behavior affect sleep? Does sleep affect the clock? Are we referring to the central clock? Are we referring to peripheral clocks, which can operate independently from the central clock? How do these relate? Is this a pathophysiology in itself, or could alterations in clock genes mediate their effect via insulin resistance?
It is an interesting concept, and I don’t doubt that circadian rhythms are important, but I am not convinced that we need to change the name of the syndrome that has more than 75,000 papers and is well known in the biomedical community.
Robert H. Eckel, MD, is president of Medicine and Science for the American Diabetes Association and professor emeritus of medicine in the divisions of endocrinology, metabolism, diabetes and cardiology at the University of Colorado Denver Anschutz Medical Center. Disclosure: Eckel reports no relevant financial disclosures.