Satish Kumar (centre) with his team

In what could be a potential drug target for type 2 diabetes, scientists have genetically deleted a gene in diabetic mouse models to show that it could be a way of treating this largely lifestyle-driven disease which is slowly turning into an epidemic in India.

A team of researchers led by Satish Kumar from the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad has shown that knocking off the Wdr13 gene in diabetic mouse models massively increased their islet mass1. This caused ‘hyperinsulinaemia’ and better glucose clearance in diabetic mice.

In essence, the absence of the gene has been directly correlated to a correction in the pathology of the disease. Beta cells get destroyed in severely diabetic mouse models – this is something that could be corrected if the Wdr13 gene is removed, the scientists contend.

The increase in beta cell mass in the double mutant mice is due to an increase in beta cell proliferation, says Vijay Pratap Singh, lead co-author of the paper. Along with the increased beta cell mass, the mouse models showed significant reduction in the expression of genes involved in inflammation of pancreas, liver and adipose tissues.

“This in turn leads to increased expression of several lipogenic genes, involved in fat metabolism,” says Chandrashekaran Gurunathan, another lead co-author. The circulating triglycerides and liver triglyceride content was also significantly lower in these mice suggesting an overall improvement in the metabolic imbalances created by obesity, he says.

“Recent researches on obesity and diabetes have shed light on the accompanying chronic low-grade inflammation that triggers the accumulation of macrophages (cells that mediate inflammation). In fact, drugs such as aspirin were considered as a potential therapeutic option for diabetes based on its anti-inflammatory properties,” he adds.

When Wdr13 gene was removed, the researchers saw increased islet mass in pancreas (top), reduced triglycerides in liver (centre) and increase in size of adipocytes and decrease in inflammation (bottom).Credit: Singh, V. P. et al.
According to Satish Kumar, the work specifically presents a new target molecule for the pharmacologist to selectively reduce the expression of the WDR13 protein. “We strongly believe that this work will have implications in combating this disease,” Kumar says.

Diabetes is classified as Type 1 and Type 2. Type 1 happens when insulin producing beta cells lose their autoimmune function. Type 2 diabetes results from insulin resistance coupled with beta cell death as a result of stress.

Animal models have been extensively used in diabetic research. One mouse model – the leptin receptor mutant or db/db mouse – is used for type 2 diabetes research. This mutant mice shows severe obesity, hyperglycaemia, hyperinsulinaemia, insulin resistance and chronic low-grade inflammation. Their beta cells get destroyed resulting in severe hyperglycemia due to lack of insulin production.

In an earlier study2, Kumar and his group had genetically engineered a strain of mice which lacked the gene Wdr13. The team knocked out the gene through gene targeting in mouse embryonic stem cells. This gene encodes a protein which is a member of the WD-repeat protein family.

The scientists found that in the absence of Wdr13, the mice had higher pancreatic islet mass and blood serum insulin levels. As a result of the increased islet mass, the mice had better glucose clearance as compared to mice with the gene. Increase in islet mass in the knockout mice was a result of higher beta cell proliferation, which led to more pancreatic islet mass suggesting the role of Wdr13 gene in cell proliferation.