Discovery of Rare Gene Variants Provides Window Into Tailored Type 2 Diabetes Treatment

A new study published in Communications Medicine, a Nature publication, details the discovery of rare gene variants that increase the prevalence of Type 2 diabetes in multiple generations of Asian Indian people. The unusual finding is a step toward more targeted treatment for all people with Type 2 diabetes, a disease with complex genetic influences.

“We wanted to study several generations of Asian Indians because understanding genetics in families can give us better information, and Asian Indians have up to six times higher risk of developing Type 2 diabetes than Europeans. In addition, Asian Indians tend to live clustered together and marry within the same caste system,” which helped us to identify these rare variants, said lead author Dharambir Sanghera, Ph.D., a professor of pediatric genetics at the University of Oklahoma College of Medicine.

“Our study found that the participants have their own rare gene changes, which aren’t found in other unrelated populations around the world,” Sanghera added. “This is important because it helps us understand the different causes of diabetes. It also gives us ideas for creating new medications that target specific proteins or pathways. Treating diabetes in a tailored way is important because not everyone responds well to metformin or other medications that lower blood sugar. Moreover, we need to prevent or delay diabetes in children from families who carry many of these gene changes.”

When people develop Type 2 diabetes, their genes contribute about 50% to the onset of the disease, and the other 50% is due to lifestyle factors such as poor diet and lack of physical activity. There are three main ways genes can affect diabetes: monogenic, where one gene causes the disease; oligogenic, where a few genes have a big impact, regardless of diet or exercise; and polygenic, where some portion of many genes (over 400) each contribute a small effect, combined with lifestyle factors. Scientists have found these genes by studying millions of people, mostly of European descent. The rare gene variations that Sanghera’s team found are an example of oligogenic diabetes, she said.

Sanghera and her team also made an unexpected finding: The gene variants were non-coding. While coding genes are like a “recipe” for building a protein, non-coding gene variants are like “instructions” for when to use the recipe, therefore controlling when and where a protein is made.

“Because these families have multiple generations of diabetes, we thought we would discover coding genes because they directly affect a person’s susceptibility to diabetes,” Sanghera said. “But by finding rare non-coding variants in a handful of genes correlating strongly with diabetes, we realized this is an example of oligogenic diabetes.”

In an incidental finding, the researchers discovered that three of the genes with many rare variations are MODY genes (maturity-onset diabetes in youth). A single MODY gene can cause diabetes (monogenic) no matter how healthy a person’s lifestyle is, Sanghera said. There are about 14 MODY genes that cause this kind of diabetes in young adults, but their link to Type 2 diabetes isn’t well understood.

“These findings suggest we need to study the role of MODY genes in Type 2 diabetes more closely by looking at the genes of families affected by it,” Sanghera said. “The most interesting part of this study was that families with many cases of late-onset Type 2 diabetes and a number of rare non-coding gene changes had fewer common genetic risk factors, known as the ‘polygenic risk score.’ Usually, people with higher polygenic scores have more rare genetic changes.

“The genetic component of diabetes is very complex because the condition is so heterogeneous (has several root causes), just like there are several types of breast cancer and different treatments based on the subtypes of breast cancer,” Sanghera added. “The more we understand about the genetics of diabetes, the closer we move to precision medicine – treating people according to the specific type of diabetes that they have.”

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About the Project

The study, “Excess of rare noncoding variants in several type 2 diabetes candidate genes among Asian Indian families,” can be found at https://doi.org/10.1038/s43856-025-00750-9. Additional principal investigators on the study include Dileep Kumar K, Rajeev Gupta, Solomon Franklin D. Paul and Ravindranath Duggirala.

This study was supported by grants from the Indian Council of Medical Research Project: No. 55/6/2/Indo-US/ 2014-NCD-II and the National Institute of Diabetes and Digestive and Kidney Diseases grants R21DK105913, R01DK082766 and R01DK118427. Additional support came from the Dr. Geoffrey Altshuler Children Hospital Foundation Endowment Fund and the Presbyterian Health Foundation, both in Oklahoma City.