Type 2 diabetes affects hundreds of millions of people worldwide and understanding its causes is essential to stem the rapid increase in the number of people affected by this chronic disease. While historic trends in the availability of calorie-rich food and lack of physical exercise are among the main reasons for this rapid increase, type 2 diabetes has a strong heritable component, with genetic factors explaining approximately 50% of its occurrence. Finding genetic variants that predispose to diabetes can provide important information on the causes of the disease, paving the way for new approaches to preventing and treating the disease.

A new article  in the Lancet  authored by Dr Claudia Langenberg and Dr Luca Lotta from the Unit’s Aetiology of Diabetes and Related Metabolic Disorders programme reviews progress over the last decade in finding genetic determinants of type 2 diabetes. The field has been transformed by the advent of ever more affordable DNA analysis technology, allowing researchers to identify DNA sequence differences across the human genome in thousands of people. Another transformative change has been the undertaking in several countries of very large studies, for example the UK Biobank study, which include hundreds of thousands of people and combine genetic and health data (including diabetes status). The most recent genetic studies of diabetes, including close to a million people, were able to identify 250 regions of the human genome where variation affects diabetes predisposition.

These genetic studies have greatly helped the understanding of the mechanisms behind the onset of diabetes, including the failure of the pancreas to produce enough insulin, the resistance of muscles and other organs to the action of this hormone, the dysregulation of appetite control in the brain or the inability to store excess energy from overeating and sedentary lifestyle in the form of peripheral adipose tissue.”

Dr Langenberg said, adding that, however, a limitation of current studies is that they have been mostly conducted in people of European ancestry.

Dr Lotta said:

Studies in non-European ethnicities and those in isolated populations such as Inuits or Samoans have been immensely helpful in finding genetic variants that increase susceptibility to obesity and diabetes, leading to a better understanding of the metabolic mechanisms involved.

While ongoing large-scale studies, such as the DIAMANTE consortium, include a substantial proportion of individuals with non-European ancestries, research in the field remains heavily “Eurocentric”.

The authors also examined the impact of these genetic findings in clinical practice. While there are now hundreds of genetic variants robustly associated with type 2 diabetes risk, genetic analysis is not used in the clinic to predict who is at risk of future development of diabetes. This is largely because information that can be collected non-invasively, such as age, sex, weight, blood pressure, or family history, is reasonably accurate in finding people at risk, in whom glucose levels can then be measured. While initial studies suggest a possible role of genetics in classifying subtypes of type 2 diabetes and predicting the response to diabetes drugs, genetic testing is not yet used in these fields because the clinical impact of genetic information has not been clearly defined.

A promising approach is the use of genetic associations to guide the development of new drugs for the treatment of diabetes and other metabolic disease, in particular by finding protective genetic variants that disrupt or activate certain gene products, and using this information to guide design of therapies to mimic these effects. This is something that is being actively pursued in large academia-industry partnerships aimed at applying large-scale DNA sequencing in hundreds of thousands of people.

The article discusses the important ethical and scientific implications of these ongoing endeavours, and the opportunities and challenges that larger scale and more diverse genetic studies will bring.

• Read the full review in the Lancet: Claudia Langenberg and Luca A Lotta. Genomic insights into the causes of type 2 diabetes. Lancet (2018) 391 (10138): 2463–2474