Same BMI, Different Diabetes Risk

Two people with the same body mass index or BMI may have entirely different risks of developing type 2 diabetes, depending on the biological mechanisms underlying their overweight. Some types of obesity increase a person’s risk of diabetes, while others do not influence the risk at all, or even appear to be protective against the disease. In a new study, researchers describe the different molecular processes that drive these differences.

Obesity and type 2 diabetes are two of our biggest public health challenges globally. Obesity is strongly linked to an increased risk of developing type 2 diabetes, but far from everyone with obesity develops the disease. The connection is more complex than previously thought. Today, BMI is used as a simple measure to determine if a person is at risk, but this new study, published in Nature Communications, shows that BMI is far too blunt an instrument for predicting this risk.

Previous studies have shown that there are at least two different types of overweight – one associated with a greater risk, and one that is more metabolically beneficial. The new study builds on this and shows that this variation is even greater than that.

“Previous research has shown that obesity is not a uniform condition. We show that there are several different biological mechanisms that lead to different risks of developing diabetes – and we can also now better map the molecular processes that drive these differences,” says Professor Åsa Johansson at Uppsala University, who led the study.

Four biological profiles with different risks

The researchers analysed genetic data from hundreds of thousands of individuals and combined these with big molecular data including proteins, metabolites and clinical biomarkers. The results show that genetic variants linked to BMI can be divided into four clusters. Two of these are linked to a moderately or greatly increased risk of developing type 2 diabetes, while the other two cluster are linked to no risk or a protective effect.

“This means that two people with the same BMI may have a completely different risk of developing diabetes, depending on the biological mechanisms that underlie their weight,” Åsa Johansson says.

Large-scale molecular mapping behind the results

An important strength of the study is that the researchers have been able to link these genetic profiles to extensive molecular-level changes in the body. By analysing over 3,000 molecular traits, the researchers were able to identify more than 100 metabolic and many clinical biomarkers that help explain why these different profiles have such a different impact on the risk of developing diabetes.

The two profiles at an increased risk are characterised by an unfavourable lipid and adverse metabolite profile in which the body’s lipid metabolism is disrupted. This includes a redistribution of lipids between different lipoproteins, leading to triglyceride-rich particles in both harmful cholesterol particles such as LDL and in the protective HDL cholesterol. When the HDL particles become triglyceride-rich, their protective function is impaired. At the same time, the groups with an increased risk exhibited markers for insulin resistance, inflammation and altered amino acid metabolism – factors that together contribute to an increased risk of type 2 diabetes.

The reduced risk group, on the other hand, showed a more favourable lipid metabolism, in which cholesterol and other lipids are efficiently transported from the body’s tissues back to the liver. This was accompanied by a better balanced lipoprotein profile and a more anti-inflammatory environment. All in all, this reflects a well-functioning metabolism with better control of both blood lipids and blood sugar, which contributes to their lower risk of developing type 2 diabetes.

“The unique thing about our study is that we not only see the differences, but can also begin to explain them at the molecular level,” Johansson says.

Could lead to more personalised diabetes prevention

The results may be of importance for both risk assessment and the treatment of type 2 diabetes.

“Today, BMI is used as a simple measure of risk, but our results show that it is inadequate. In the future, we may need to take into account the individual’s biological profile to better assess their risk and implement measures in good time,” says Pascal Mutie, first author and former postdoc at Uppsala University.

At the same time, the researchers stress that individuals do not belong to just one profile, but rather all individuals are a mosaic of different biological risk profiles. In order to prevent disease effectively, it is therefore important to identify those individuals in which the mechanisms that drive the risk dominate.

The study also identifies several molecular mechanisms that could be targets for new drugs or preventive measures, and in the long term this can contribute to more accurate strategies to prevent type 2 diabetes and reduce the burden of disease.