LOS ANGELES – In the opinion of Paul Zimmet, MD, PhD, the
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Dr. Paul Zimmet
This scenario created the “perfect storm” for rising rates of metabolic syndrome, which is related to low HDL cholesterol levels, central obesity, hypertension, hyperglycemia, and high triglyceride levels, Dr. Zimmet said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. These cardiometabolic risk factors “all seem to cluster together in relation to the changes in our society,” he said. “It’s on that basis and research findings that I think we should understand that most of them, if not all, have been demonstrated to relate to circadian rhythm disturbance.”
In fact, the associated comorbidities sleep apnea, depression, and fatty liver disease should be included in the metabolic syndrome cluster and should be renamed the “circadian syndrome,” according to Dr. Zimmet, professor of diabetes at Monash University, Melbourne.
The term metabolic syndrome is anathema, he said. “There have been numerous different definitions, which finally led to an effort to come up with a harmonized definition” by the International Diabetes Federation Task Force on Epidemiology and Prevention, with involvement from the American Heart Association (Circulation 2009;120[16]:1640-5).
In the early 1970s, Dr. Zimmet and his colleagues at Guys Hospital in London reported on diurnal variation in glucose tolerance. “If you did a glucose tolerance test in the afternoon it could be diabetic, whereas in the morning it was normal,” he noted. “Other researchers reported similar findings. That created in my own mind interest in this area of circadian rhythm. However, I had neglected this until recently, when I was doing background research while trying to find an answer to the elusive question of a central uniting explanation for the cardiometabolic cluster constituting the metabolic syndrome.” So decades later, Dr. Zimmet extended his research to include epigenetics in the quest. Described as the study of heritable changes in gene function that occur without a change in the sequence of the DNA, epigenetic changes “are closely linked to the circadian rhythm, otherwise known as ‘the body clock,’ ” said Dr. Zimmet, who also is codirector with Naftali Stern, MD, of the Sagol Center for Epigenetics of Metabolism and Aging at Tel Aviv Medical Center. “Many aspects of human behavior and metabolism are closely linked to the circadian clock and affected by its rhythm disturbance. We decided that we wanted to further investigate this area: To what extent is circadian rhythm the central feature to explain the clustering of all of these cardiovascular and metabolic risk factors of the metabolic syndrome.”
In recent years, he has been collaborating with Noga Kronfeld-Schor, PhD, of the department of zoology at Tel Aviv (Israel) University. The research focuses on a gerbil from the Negev: Psammomys obesus (otherwise known as the Israeli fat sand rat), which develops elevated blood sugar, obesity, depression, sleep disturbance, fatty liver, and circadian dysrhythmia when removed from the desert environment to the laboratory. “These are all key features of type 2 diabetes in humans,” he said. “This is probably the best animal model of type 2 diabetes, and we felt that it was worth looking more closely to see if there was a similar relationship in humans as to whether circadian dysrhythmia would be causing all or most of these features in humans including obesity.” An epigenetic study of the gerbil in the laboratory of Prof. Sam El-Osta at Monash has shown that parental diet during early life regulated expression of genes associated with DNA methylation in the key FTO gene associated with obesity (Int J Obesity 2016;40:1079-88). It suggests that diet-induced metabolic changes can be transmitted from parent to offspring by mechanisms under epigenetic control.
Published studies from other research groups support the link between other of the cardiometabolic metabolic syndrome characteristics, epigenetic modifications, and circadian dysrhythmia including cardiovascular regulation and disease (Eur Heart J 2018;39[14]:2326-9), sleep loss and alterations in DNA methylation (Science Advances 2018;4[8]:eaar8590), and circadian dysrhythmia and fatty liver (Cell Metab 2012;15[6]:848-60). “In 2009, the FDA approved bromocriptine mesylate, a drug which has effects on circadian rhythm, for treatment of type 2 diabetes, suggesting its use in diabetes may have some role through the alteration of circadian rhythm,” continued Dr. Zimmet, who also is honorary president of the International Diabetes Federation. “Depression is also clearly linked to circadian rhythm and there is evidence from research and human studies that light therapy may be an effective treatment for type 2 diabetes and depression.”
Dr. Zimmet ended his presentation with a strong call for adding sleep apnea, fatty liver, and depression to the existing features of the metabolic syndrome “to encourage clinicians and researchers look at the picture of cardiometabolic risk much more broadly than as just a group of metabolic abnormalities,” he said. “We propose that these comorbidities be embraced within the definition of the cardiometabolic cluster and be renamed the ‘circadian syndrome.’ This cluster is now the main driver of the global chronic disease epidemic and its health burden. This is a disease of civilization – the result of the way we live.”
Dr. Zimmet reported having no disclosures.