Clinicians have long known that there’s a link between obesity and diabetes. People with obesity are seven times more likely to develop diabetes compared to those of a healthy weight. But it is still not clearly known how obesity can lead to type 2 diabetes (T2D). For example, not all people with obesity develop T2D, and not all people when diagnosed with diabetes have BMIs [body mass index] that reach the obesity threshold.
Recent research funded by the Innovative Medicines Initiative (IMI) project SOPHIA shows that some genetic differences in people with obesity could help protect them from developing diabetes. The research was published in Nature Metabolism.
The paper’s authors wanted to better understand the relationship between obesity and diabetes, a heavily-debated subject in metabolic research. Obesity-caused T2D is likely caused by extra fatty tissue creating a resistance to insulin. But although around 80% of people with T2D are obese, between 10-30% of people with obesity are ‘metabolically healthy’ (i.e. are diabetes-free). Likewise around 30% of people with a regular weight will develop T2D.
“We [used to] think of the relationship between obesity and type two diabetes as always increasing simultaneously,” said Daniel Coral of the Lund University Diabetes Centre in Sweden. “But what has been shown in previous research is that a lot of individuals don't have the metabolic risk for their given BMI, including risk for type 2 diabetes.”
This paradoxical observation led researchers to compare the genetic background of both those who are obese and have T2D, and those who are obese and yet are T2D-free. They first checked databases that list the physical characteristics associated with changes in the genetic code. These changes are called ‘single nucleotide polymorphisms’ (SNPs) and can change how genes are expressed in the body. They found 67 SNPs – 48 associated with having both obesity and T2D, and 19 associated with having obesity but instead being protected from T2D.
“We compared these two extremes of risk in obesity to see what really separates these two obesity processes,” said Dr Coral. Previous research had directly compared these genetic profiles to what could be measured at the clinic, such as a person’s waist-to-hip ratio or blood pressure.
Dr Coral and the paper’s co-authors wanted to better understand the mechanisms that led from SNPs to diabetes. That led them to explore how these SNPs affect the body’s mechanisms at a molecular level. For example, how SNPs could eventually lead to different proteins and lipids in the blood of a person with obesity, which then causes them to develop T2D.
The researchers first determined which clinically-measurable traits were most likely involved in a person with obesity developing T2D, and then checked how these traits correlated to the gene-expression data. This involved three analytic methods. A transcriptomic analysis analysed cellular gene expression, a metabolomic analysis analysed the varieties of lipid molecules in the body, and a metagenomic analysis analysed genetic material in blood samples from biobanks.
These analyses meant the researchers were able to get a clearer idea of the mechanisms behind T2D caused by obesity. For example, a person’s higher capacity to expand fat tissue around the thigh area plays an important role in genetically-determined obesity without T2D. Other such ‘biomarkers’ include blood pressure, the cholesterol content of high-density lipoproteins, and levels of the protein HS6ST2.
Finding and understanding these biomarkers marks an important step to precisely identify whether a person with obesity is susceptible or resistant to developing T2D, says Dr Coral. Also knowing the genetic background to these biomarkers can help when designing future medications. More research, says Dr Coral, could find ways to target these cells acting in obesity to shift someone to a lower risk. “I think that will be very important for both prevention and also treatment in obesity,” he said.
SOPHIA is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.