The Association Between Type 2 Diabetes Treatment Response and Genetic Variants

People who are at a high risk of developing type 2 diabetes can be prescribed a variety of medications to decrease blood sugar levels, but it is not always apparent which people would benefit from which treatments the most.

Researchers at Mass General Brigham (MGB), a founding member of Massachusetts General Hospital (MGH), revealed genetic variants linked to responsiveness to two of these medications, metformin, and glipizide, in a study published in Diabetologia. The results could aid in individualized care for type 2 diabetes prevention and treatment.

It is difficult to design customized therapies since the type 2 diabetes drugs that are currently on the market do not take an individual’s underlying genetics or disease pathophysiology into account.

The team of researchers looked at whether a genome-wide approach could reveal new pharmacogenetic associations and develop insight to understand the significance of recognized genetic risk factors for type 2 diabetes.

The team was co-led by Josephine Li, MD, an endocrinologist in the Diabetes Unit at MGH and an Instructor in Medicine at Harvard Medical School.

Researchers gathered genetic information on 1,000 people at risk of developing type 2 diabetes who took a brief course of metformin and glipizide as part of the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) study, which sought to understand the genetics of the acute response to metformin and glipizide in humans.

The researchers also recorded the patients’ insulin and blood sugar levels before and after these drugs were taken.

We performed a genome-wide association study to comprehensively identify genetic variants associated with drug response. We also tested the influence of previously reported genetic variants for type 2 diabetes and glycemic traits on SUGAR-MGH outcomes. Our study was unique in that over a third of SUGAR-MGH participants were of non-European descent, in contrast to existing pharmacogenetic genome-wide association studies.”

Josephine Lee, MD, Endocrinologist, Diabetes Unit, Massachusetts General Hospital

Acute sensitivity to metformin or glipizide was substantially correlated with five genetic variants. Those of African origin tended to score three more frequently.

One of these variants (named rs111770298), peculiar to African ancestry, was verified in the Diabetes Prevention Program, where people with this variant responded to metformin therapy less favorably than those without it.

Li added, “Understanding the impact of ancestry-specific variants can help guide and tailor treatment selection for population subgroups in the future.”

In a different analysis, a different mutation (known as rs703972), which has previously been associated with a reduced risk of type 2 diabetes, was linked to greater levels of active glucagon-like peptide 1, which increases insulin production and decreases hunger.

“Next steps include functional experiments to confirm the implications of the novel genetic variants we have identified that are associated with the body’s response to these glucose-lowering therapies,” Lee further stated.

Jose C. Florez, MD, PhD, study co-senior author and chief of the Endocrine Division and the Diabetes Unit at Massachusetts General Hospital and a professor of Medicine at Harvard Medical School, added, “SUGAR-MGH is designed to allow investigators to use two commonly-used drugs with different mechanisms of action to probe the role of specific genes on glucose regulation.”

The researchers published their findings as a resource for the general public so that other academics could build on their work.