Paul Zimmet Discusses the Evolution of Metabolic Syndrome
Special Topic of Metabolic Syndrome Interview, September 2011
How has the field as a whole changed over the past 10 years? Would you say we are in a better position today in terms of our knowledge of metabolic syndrome than we were in the 1990s? Why or why not?
Despite the attempts of the ADA to show that the metabolic syndrome did not exist, the position of the metabolic syndrome, if anything, is now much stronger. In the past, people dealing with diabetes have been far too gluco-centric and the greater recognition now of the metabolic syndrome means that other cardiovascular disease risk factors are addressed much earlier in people with diabetes or those who are at risk of diabetes. We joke to the primary health care practitioners that, if a person's stomach comes through the door of the consulting room before they see the person's face, the first thing they must do is to check blood pressure, blood lipids, and blood sugar!
Is there a significant difference between the concept of pre-diabetes, a term that used to be used widely, and what we now call metabolic syndrome?
That's the key question. And the answer is that in many instances, it's really the same state. A larger percentage of people with pre-diabetes will have not only a glucose abnormality, but a lipid abnormality, hypertension, and or obesity. So there's not much difference between them. And now the term pre-diabetes doesn't have much status anymore, other than as a term that gives lay people an idea of their future risk of diabetes.
Along those lines, is it reasonable to also think of metabolic syndrome as a kind of pre-heart disease, or existing on a continuum that goes from health on one end, through metabolic syndrome, to either or both diabetes and heart disease?
Put that way, I'd have to answer yes.
Where do you hope to see metabolic syndrome research go in the next decade?
A high priority is to better understand the basic pathogenetic mechanisms that cause the metabolic syndrome. Are all of the components of the metabolic syndrome linked through a common mechanism or is it, like type 2 diabetes, a heterogeneous condition? These are important issues in relation to developing better strategies for both its treatment and its prevention. Another research priority is whether therapies can be developed that address the complex cardiovascular risk factors, either through a "polypill" or, if there was a single common etiology, a therapeutic agent that targets that one mechanism.
You refer to type 2 diabetes as a "heterogeneous condition." What exactly do you mean by that?
Field work in Mauritius; on-site at National Survey for
Diabetes, Metabolic Syndrome and Cardiovascular disease.
Simplistically, a lot of people think of type 2 diabetes as just one metabolic state. It's quite clear that it's not, that there may be as many as five or ten different metabolic or enzymatic defects, for example, which result in hyperglycemia. That's why when we're treating type 2 diabetes, in many instances one drug won't solve even the hyperglycemia, we may need two or even three.
This is why Ralph DeFronzo, for instance, in his 2008 Banting Lecture at the annual meeting of the ADA, suggested that when patients come into your office with newly diagnosed type 2 diabetes, you may want to put them on three or four drugs from the start. It may deter what many people consider inevitable, which is deterioration of pancreatic beta cell function over time and eventually having to use insulin therapy to control the disease.
You consider your 1989 Diabetes medicine paper—"Non-insulin-dependent (Type 2) Diabetes Mellitus: Does It Really Exist?" to be one of your more prescient articles. In it you say, "While the association between obesity and NIDDM has been appreciated since the earliest times, is the relationship one of innocent bystander (guilt by association), partner-in-crime (potentiator) or culprit (causal)?" Today, 22 years later, how would you answer that?
I guess the innocent bystander hypothesis is now out of contention. But the other two remain possibilities.
Another question raised in your 1989 paper is which comes first in metabolic syndrome—hyperinsulinemia, which are chronically elevated insulin levels, or insulin resistance? How would you answer that today?
The key question, I think, is a slightly different one: is hyperinsulinemia the result of insulin resistance, which itself may be determined genetically, or is there a genetic abnormality that drives hyperinsulinemia and that in turn drives insulin resistance? At the time I wrote that, and I still believe it, I thought hyperinsulinemia is the driver. There are very good studies in animals from Bernard Jeanrenaud in Geneva supporting that. So I still believe that it's hyperinsulinemia causing insulin resistance, whereas most people would probably say it's the other way around—that insulin resistance is the key metabolic abnormality.
If we lived an ideal world and you had unlimited funding for your research, what experiment would you do that you couldn't do now?
Just to preface this, two years ago the Australian Government established a preventive health task force to provide the government with directions to deal with problems of alcohol and tobacco use and obesity. I was one of seven people on that task force. One of the things I kept jumping up and down about was the importance of maternal and child health. We have a lot of animal and rodent data suggesting that maternal nutrition is very vital in driving adult chronic disease and indeed some mental disorders, too, such as schizophrenia.
The study I would ideally like to do, although it would take 30 or 40 years to get answers, would be a definitive human study that shows how important or unimportant this whole question of maternal nutrition, or even maternal smoking or alcohol use is during pregnancy. This is one of the recommendations of our preventive health task force—that a key step in the prevention of chronic disease is to focus on the mother and the fetus. That's a study I would like to do, even if you wouldn't see the results and so the benefits for 30 to 40 years.
Professor Paul Zimmet, AO
Baker IDI Heart & Diabetes Institute
Melbourne, Victoria, Australia
PAUL ZIMMET'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Zimmet P, Alberti KGMM, Shaw J, "Global and societal implications of the diabetes epidemic," Nature 414(6865): 782-7, 13 December 2001 with 1,621 cites. Source: Essential Science Indicators from Clarivate .
KEYWORDS: METABOLIC SYNDROME, DIABETES, GROWTH HORMONE, EPIDEMIOLOGY, PUBLIC HEALTH, PACIFIC ISLANDS, GAD ANTIBODIES, TYPE 2 DIABETES, CENTRAL OBESITY, DYSLIPIDEMIA, HYPERTENSION, ETIOLOGY, RISK FACTORS, INSULIN RESISTANCE, HYPERINSULINEMIA, CONSENSUS STATEMENTS, PATHOGENESIS, AUSDIAB, AUSTRALIA, CARDIOVASCULAR RISK FACTORS, PREVENTION PROGRAMS, RISK CALCULATOR, SLEEP DISTURBANCES, AMERICAN DIABETES ASSOCIATION, MATERNAL HEALTH.