Does healthy obesity exist? We tend to believe so. If metabolic function is normal and cardiovascular risk factors are absent, people with obesity are not at increased risk for heart disease, and may live as long as any. However, this belief has been challenged by a recently published paper in the American Journal of Clinical Nutrition. Researchers at the University of Turin in Italy report the risk of metabolic and cardiovascular disease among three important groups of individuals: 1) normal weight individuals with signs of metabolic dysfunction (sometimes termed “normal weight obesity“) 2) obese individuals without signs of metabolic dysfunction (sometimes termed “healthy obese“) and 3) obese individuals with signs of metabolic dysfunction. The results of the study are quite interesting, not least because they contradict our belief that obesity in itself does not increase the risk for disease, as long as metabolic function is normal. Thus, after all, “healthy obesity” may not exist.
The metabolic syndrome
The first description of the metabolic syndrome can be traced back to Eskil Kylin (1889-1975), a Swedish physician and scientist. In 1923, Kylin wrote a scientific paper termed “Studien über das Hypertoni-Hyperglykemi-Hyperurikemi syndrom” that was published in a German Medical Journal, Zentralblatt für Innere Medizin. Kylin was the first to describe a constellation of symptoms or conditions, including high blood pressure (hypertension), high blood sugar (hyperglycemia), obesity, and high levels of uric acid (hyperuricemia) which can lead to gout. This was later to be named syndrome X or more commonly the metabolic syndrome. In 1947, the Marseilles physician Dr. Jean Vague, observed that upper body obesity appeared to predispose to diabetes, atherosclerosis and gout.
In 1977, the German scientist, Hermann Haller used the term “metabolic syndrome” when describing a combination of risk factors for atherosclerosis. These risk factors were obesity, diabetes mellitus, high levels of lipoproteins in blood (hyperlipoproteinemia), hyperuricemia and fatty liver (steatosis hepatis). In his Banting lecture, at the American Diabetic Asoociation´s annual meeting in 1988, Gerald M. Reaven proposed insulin resistance as the underlying factor, and named the constellation of abnormalities Syndrome X. Since then it has been acknowledged that insulin resistance plays a key role in the metabolic syndrome and the term “insulin resistance syndrome” has been used by some specialists.
Today, the clustering of visceral (abdominal) obesity, lipid disorders, elevated blood glucose and hypertension, is generally defined as the metabolic syndrome. The syndrome is a major public health challenge worldwide and is associated with a substantially elevated risk of type 2 diabetes and cardiovascular disease (CVD). The metabolic syndrome is considered a key factor for the modern day epidemic of diabetes and CVD. The recent decline in morbidity and mortality due to heart disease, seen in many countries, may possibly be reversed by the increased occurrence of the metabolic syndrome.
When people are insulin resistant, their muscle, fat, and liver cells do not respond properly to insulin. As a result, their bodies need more insulin to help glucose enter the cells of the body. Therefore, there is an exaggerated glucose and insulin response to a given amount of carbohydrate ingested. The pancreas tries to keep up with this increased demand for insulin by producing more. Eventually, the pancreas fails to keep up with the body’s need for insulin. Excess glucose builds up in the bloodstream, setting the stage for diabetes. Many people with insulin resistance have high levels of both glucose and insulin circulating in their blood at the same time.
Who is at risk for developing insulin resistance? Overweight or obesity increases the likelihood of developing insulin resistance. Other risk factors include increased waist circumference, age above 40 years, history of gestational diabetes, history of polycystic ovarian disease, high blood triglycerides, low levels of HDL-cholesterol, close family members with type 2 diabetes, hypertension or CVD.
Although insulin resistance and the metabolic syndrome are associated with obesity (assessed by BMI), it has been suggested that a substantial number of obese individuals have normal metabolic function. Studies have shown that these individuals have lower risk for CVD than obese individuals with signs of metabolic dysfunction. Furthermore, many normal weight individuals have signs of metabolic dysfunction and are at increase risk for CVD. So, it has been suggested that obesity in itself is not bad, as long as metabolic function is normal.
The Turin Study
The Turin investigators led by Simona Bo studied 1.658 individuals, aged 45-64 years. Metabolic screening was performed at the beginning of the study, thereafter the individuals were followed for a mean of nine years. The HOMA-IR was used to assess the presence of insulin resistance. The metabolic syndrome was defined on the basis of waist circumference, triglyceride concentration, HDL-cholesterol, blood pressure, antihypertensive drug therapy, fasting glucose concentration or hypoglycemic therapy. The Framingham risk score was used to assess cardiovascular risk. The presence of non-alcoholic fatty liver disease (NAFLD) was assessed by the NAFLD liver fat score. A total of 188 individuals died during follow-up.
The individuals were divided into three groups at baseline according to BMI, <25 (normal weight), 25-30 (overweight) and >30 (obesity). Insulin resistant (IR) individuals within all three groups had higher insulin levels, higher waist circumference, higher systolic blood pressure and a worse metabolic pattern: increased uric acid, elevated liver enzymes and higher NAFLD and cardiovascular risk scores. The frequency of insulin resistance was 20 percent in the normal weight group, 56 percent in the overweight group and 78 percent in the obese group. The metabolic syndrome was only present among IR-individuals; 73.7 percent of IR-normal weight, 88.1 percent of IR-overweight and 87.2 percent of IR-obese individuals had signs of the metabolic syndrome.
The onset of new diabetes during the study period was 5.8 percent in IR- normal weight individuals, but only 0.4 percent in normal weight, insulin sensitive (IS) individuals. For comparison 10.5 percent of obese IR-individuals developed diabetes and 5.6 percent of obese IS-individuals. Cardiovascular events occurred in 4 percent of normal weight individuals, 5.7 percent of overweight individuals and 8.5 percent of obese individuals. Cardiovascular events were more frequent among normal weight individuals if they were IR (6.6 percent) than if they were IS (3.3 percent). The same trend was seen among overweight individuals. However, among those who were obese, similar number of individuals who were IS and IR developed new cardiovascular events (8.3 vs. 8.5 percent). The all-cause mortality and cardiovascular mortality rates increased with increasing BMI. The risk of new cardiovascular events was more than 2-fold higher in IS-obese individuals compared to IR-normal weight individuals.
Normal weight obesity and healthy obesity – What have we learned?
There are several take home messages from this interesting Italian study. Firstly, approximately 20% of normal weight individuals are insulin resistant (normal weight obesity) and approximately 20% of obese individuals are insulin sensitive (healthy obesity). Secondly, normal weight individuals are a heterogenous group in terms of cardiometabolic risk. Metabolic dysfunction is present in a substantial number of normal weight individuals. Insulin resistance among these individuals increases the risk of diabetes, non-alcoholic fatty liver disease and heart disease. Thirdly, insulin sensitive obese individuals do have a more favorable metabolic profile than those who are obese and insulin resistant. However, obese, insulin sensitive individuals have higher risk of developing diabetes and heart disease compared to insulin sensitive normal weight individuals. Thus, the study challenges the hypothesis that obesity without metabolic abnormalities is a benign condition.
Main reference: Simona Bo, Giovanni Musso, Roberto Gambino, Paola Villois, Luigi Gentile,Marilena Durazzo, Paolo Cavallo-Perin, and Maurizio Cassader. Prognostic implications for insulin-sensitive and insulin-resistant normal-weight and obese individuals from a population-based cohort. Am J Clin Nutr 2012 96: 962-969;First published online October 3, 2012.doi:10.3945/ajcn.112.040006