Scientists discover new form of diabetes caused by gene mutation

A new type of monogenic diabetes, caused by a gene mutation and fueled by a lack of the insulin-stimulating hormone GIP, has been discovered by a team of researchers across Europe and Asia.

The doctors, who span in location from the U.K. to Finland to Japan, documented their recent findings in Nature Communications after identifying the previously unknown form of diabetes, which stems from a mutation in a gene known as RFX6. Patients who carry the RFX6 mutation are likely to develop diabetes—80 percent of subjects with the mutation were living with disease by the time they turned 50, Michael N. Weedon, MD, and colleagues wrote in their study. The disease can take root, though, before a patient turns 20.

Maturity-onset diabetes of the young (MODY) is a type of monogenic diabetes that develops as a result of beta-cell dysfunction and generally presents itself in affected patients before they’re 25 years old. Individuals with MODY also tend to be non-obese, non-insulin-dependent and have an autosomal dominant inheritance of diabetes.

“There has been limited recent success in finding new MODY genes,” Weedon and co-authors wrote. “The reason for this limited success is the difficulty of distinguishing monogenic diabetes patients from those with type 1 diabetes, or from the increasing number of patients with early-onset type 2 diabetes due to rising rates of obesity.”

The team could identify the RFX6 mutation with the help of rare-variant association testing, which is more accessible now than in the past due to new resources like the ExAC database of protein coding variants. Weedon and colleagues examined the sequencing of MODY cases that had unknown etiologies, ultimately comparing the frequency of protein-truncating variants (PTVs) to large control cohorts to find new MODY genes. Heterozygous RFX6 PTVs, they found, were directly linked to MODY.

After examining both Finnish and non-Finnish European patients—Finns tended to have a 10-fold higher frequency of RFX6 PTVs than non-Finnish Europeans—the doctors discovered individuals carrying the RFX6 mutation had reduced insulin secretion by the pancreas. Lack of insulin is an established characteristic of diabetes, but Weedon and colleagues also noted a reduced production of the hormone GIP, which stimulates and regulates insulin secretion. This is the first study of its kind that links diabetes to low production of GIP, which is produced in the intestine after a person eats.

Because of this discovery, Weedon and co-authors wrote, there’s hope in treating this new type of diabetes with GIP analogs that mimic the hormone’s structure.

Of 27 patients who expressed RFX6-MODY, 81 percent were female. Most patients were around 32 years old at the time of diagnosis.

This study underlines the need for further research into specific forms of diabetes, the authors wrote, so doctors will ultimately be able to provide more individualized, effective care for diabetes patients.