| X Marks the Spot |
| Friday, 05 May 2006 | |
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Metabolic syndrome affects one fifth of adults in the West, but most people do not know what it is. Neil Singh draws together recent research which suggests that the culprit may be dysfunctional mitochondria, offering new hope for efficient diagnosis and treatment of the 21st century’s silent plague. Summary Box
Some people call it bad luck - but why is it that some individuals remain healthy well into old age whilst others seem to be magnets for disease? It was this question that troubled Gerald Reaven at Stanford University in 1988 (Reaven 1988). In particular, he wondered why many of his patients presented with a distinctive constellation of pathologies, consisting of: diabetes, obesity, dyslipidaemia and hypertension. Were they just unlucky? In 1988, he dubbed this characteristic clustering of cardiovascular risk factors “Syndrome X” – an enigmatic name well suited to a disease with unidentified aetiology. It has also been known as “diabesity” and “dyslipidaemic hypertension”. Once it was elucidated that the underlying casue is insulin resistance the condition became known as metabolic syndrome. Why is metabolic syndrome important?Metabolic syndrome is largely a disorder of countries of high life-expectancy. According to a recent report from the Centers of Disease Control and Prevention, 115 million people suffer from this condition in the West – equating to one fifth of the developed world. The distinguishing symptoms of metabolic syndrome are important because they
are major risk factors for cardiovascular disease (see summary box). Moreover,
having insulin resistance means that the body will have abnormally high concentrations
of  Figure 1. Relationship between the causes (orange) and consequences (blue) of metabolic syndrome. What causes metabolic syndrome?The underlying pathology in metabolic syndrome is thought to be insulin resistance (Modan 1985), but the cause of this is being hotly disputed. What is certain is that metabolic syndrome is caused by a complex interplay between environmental and genetic factors. Some scientists argue that these patients are merely suffering from the manifold consequences of an unhealthy modern lifestyle. They are not totally wrong – environmental factors do play a big role in causing insulin resistance. This has been proven by studies in which patients that undergo rigorous diet and exercise regimens show great improvements in symptoms when compared to controls. But others hold that the clustering of these diseases is more than just chance – that there may be a common genetic determinant that predisposes these individuals to metabolic syndrome. Could there be a single route of pathogenesis to explain the many manifestations of “Syndrome X”? The prospect is irresistible. With metabolic syndrome set to reach pandemic proportions over the next 20 years, pharmaceutical companies would strike gold by discovering a drug to target the faulty genes and cellular pathways. Mitochondrial dysfunction may cause metabolic syndromeOne line of research suggests that the culprit may be dysfunctional mitochondria. Richard Lifton’s team at Yale University showed in 2004 that a mutation in mitochondrial DNA – mtDNA for short – causes carriers to develop the group of symptoms characteristic of metabolic syndrome (Wilson, Hariri et al. 2004). Lifton’s study centered on a woman whose relatives had an unusual preponderance
for hypertension and dyslipidaemia. Moreover, both hypertension and hypercholesterolaemia
segregated with the maternal lineage. This triggered an idea that perhaps the
genetic determinant was not nuclear DNA at all, but rather mtDNA. Unlike the
equal contribution of nuclear DNA from mother and father, mtDNA is solely maternally
inherited. The outcome of their study was clear: metabolic syndrome appeared
to be due to mitochondrial malfunction. 1. Mitochondrial mutations are an established cause of oxidative stress and
aging (Singh 2004), and metabolic syndrome is an age-related disorder. The futureBased on the above evidence, there is clearly an urgent need for a series of biochemical, physiological and genetic studies to confirm this mitochondrial hypothesis and to develop more effective diagnostic and therapeutic tools to lessen the burden of metabolic syndrome on society.Excitingly, one team in California have recently set out to meet these needs. In February this year, Prof. Douglas C. Wallace, a founder of the field of human mitochondrial genetics, has received a $2.25 million award to fund a 5 year study entitled: "A Mitochondrial Basis for Metabolic Syndrome" (University of California, Irvine: Press Release, 2006). However, the significance of mitochondrial dysfunction in metabolic syndrome is far from established, and is absent from current textbooks. There are many equally reasonable alternatives that could explain the underlying insulin resistance of metabolic syndrome. Besides, even if the genetic mutations responsible for metabolic syndrome are found, they probably play only a partial role in causing the disease; their effects are likely to be influenced by other genetic and environmental modifiers. In short, the best thing a doctor can currently do for a patient with "Syndrome X" is to advise them to make improvements to their diet and exercise patterns. Meanwhile, the hunt for the possibly responsible genes continues.
ReferencesUniversity of California, Irvine: Press Release, 2006. http://today.uci.edu/news/release_detail.asp?key=1431Vartanian, V., Lowell, B., Irina G. Minko, and Thomas G. Wood, J. D. C., Shakeeta George, Scott W. Ballinger, Christopher L. Corless§, Amanda K. McCullough, and R. Stephen Lloyd. The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. (2006) Lowell, B. B. and G. I. Shulman. "Mitochondrial Dysfunction and Type 2 Diabetes." Science 307(5708): 384-387. (2005) M Modan, H Halkin., S Almog, A Lusky, A Eshkol, M Shefi, A Shitrit, and Z
Fuchs. "Hyperinsulinemia. A link between hypertension obesity and glucose
intolerance." J. Clin. Invest. (1985) Reaven, G. M."Role Of Insulin Resistance In Human-Disease." Diabetes
37(12): 1595-1607. (1988) Metabolic Syndrome - Ticking Time Bomb |
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