Indian and US researchers identify new MODY diabetes subtype linked to ABCC8 gene

Researchers from the Madras Diabetes Research Foundation (MDRF), Chennai, and Washington University School of Medicine in St. Louis have identified a new subtype of Maturity-Onset Diabetes of the Young (MODY), based on a novel mechanism involving the ABCC8 gene. The findings, published online in Diabetes, the journal of the American Diabetes Association, offer new insights into the classification, diagnosis and treatment of genetic forms of diabetes.

The study involved detailed genetic and functional analysis of Indian patients clinically diagnosed with MODY. It highlights a form of the disease linked to loss-of-function (LOF) mutations in the ABCC8 gene. The gene plays a key role in pancreatic β cell function, and its altered behaviour has traditionally been associated with gain-of-function (GOF) mutations in neonatal diabetes and MODY 12.

Prof Colin G Nichols, lead researcher from Washington University, said, “Usually ABCC8 mutations work through Gain Of Function (GOF) mutations which lead to enhanced ABCC8 protein activity. This can occur in neonatal period when it is known as Neonatal Diabetes. In adults it occurs as ABCC8 MODY or MODY 12. Through our collaborative work with MDRF, using various experiments in the laboratory, we were able to show some novel mutations in the Indian patients with MODY which occur as Loss Of Function (LOF). LOF mutations abolish or reduce the activity of protein and they normally lead to Congenital Hyperinsulinism (CHI) which presents as persistent low blood glucose levels (hypoglycemia) in childhood. These patients seem to have had CHI earlier but crossed over to the opposite condition, of high blood sugar (diabetes) in later life. This is the first demonstration of this mechanism in a MODY subtype to our knowledge.”

Dr Radha Venkatesan, Executive Scientific Officer and Head of Molecular Genetics at MDRF, and the lead researcher from the Indian side, said, “This discovery of novel genetic subtype of MODY represents a significant advancement in our understanding of MODY and explains the function of potassium ATP (K-ATP) channels in the pancreatic beta cell membrane. Through our work in the lab and follow-up of our patients, we propose that diabetes driven by KATP-Gain of Function and KATP-Loss Of Function mutations should officially be recognised as distinct disease subtypes, with different molecular basis and different clinical and therapeutic implications.”

Dr V. Mohan, Chairman of MDRF, said, “We are excited that we have discovered a new sub type of MODY diabetes. This work underscores the importance of genetic testing and functional understanding for precision diagnosis of diabetes in general and MODY subtypes of diabetes in particular. By identifying these unique subtypes of MODY, we are close to providing more precise diagnosis, treatment and better care for individuals affected by this novel subtype of MODY. Patients with this new (Loss of Function) MODY subtype do not respond to Sulphonylureas unlike other forms of MODY like MODY 3, MODY 1 and MODY 12. Further studies are needed to assess the best antidiabetic medicines to treat this novel type of diabetes. This study also opens up new avenues for discovery of novel drug targets in diabetes treatment.”

MODY is a rare inherited form of diabetes caused by mutations in a single gene. It typically presents in adolescents and young adults. Until now, 13 subtypes of MODY had been recognised. The newly identified variant shifts current understanding of how the disease develops and responds to therapy.

The study highlights the need for greater access to genetic screening, especially in India where such testing is not yet standard in diabetes care. Researchers suggest that improved classification could support more personalised treatment and long-term management for individuals with undetected or misdiagnosed MODY subtypes.