New subtype of diabetes found in India could change how rare forms of disease are treated
These patients with diabetes, now identified as those with Maturity-Onset Diabetes of the Young (MODY) 15, were subjected to extensive genetic testing due to their atypical biomarkers—measurable indicators that reflect a certain disease.
The discovery by scientists associated with the Madras Diabetes Research Foundation (MDRF), an Indian Council of Medical Research (ICMR) Centre of Excellence, in collaboration with Washington University in Missouri, US, is based on the identification of a new diabetes subtype in 20 patients in India.
New Delhi: Scientists from India, along with their counterparts in the US, have discovered a new subtype of the disease in Indian patients, marking a landmark achievement in diabetes research and potentially transforming how certain rare forms of the disease are diagnosed and treated worldwide.
MODY is a rare and genetic form of diabetes, distinct from commoner forms of the disease such as type 1 and type 2 diabetes. It is caused by mutations in a single gene, typically present in adolescents and young adults. MODY is estimated to affect nearly 2-3 percent of all people with diabetes.
While 14 MODY subtypes have been recognised so far, this newly identified variant—named MODY 15—upends long-standing assumptions about how the disease develops. The discovery has been published in the journal Diabetes two weeks ago.
'We are excited that we have discovered a new subtype 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,' Dr V. Mohan, MDRF chairman and a researcher associated with the discovery, said in a press briefing Thursday.
By identifying these unique subtypes of MODY, clinicians can get closer to providing more precise diagnosis, treatment and better care for individuals.
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How new subtype is distinct
Diabetes, also known as diabetes mellitus, is actually a group of common endocrine disorders, mainly characterised by sustained high blood sugar levels due to absent or low insulin levels. The main symptoms of disease—seen in almost all forms—include excessive thirst, hunger and urination, weight loss, fatigue and blurred vision, and, if left untreated, complications such as disorders of kidney, cardiovascular system, nerves and eyes.
While type 1 diabetes is characterised by complete loss of the insulin-producing beta cells due to autoimmune or idiopathic (unknown) reasons, type 2 diabetes is mainly triggered by insulin resistance or the body's inability to respond to insulin, often combined with relatively reduced insulin secretion.
MODY, on the other hand, is triggered due to one of several single-gene mutations causing defects in insulin production.
Colin G. Nichols, the lead researcher of this work from Washington University's School of Medicine, explained that MODY 15 is caused by an affected ABCC8 gene that controls the functioning of insulin-producing β cells in the pancreas.
Usually, ABCC8 mutations work through Gain Of Function (GOF) mutations, which lead to enhanced ABCC8 protein activity, and this can occur in the neonatal period when it is known as neonatal diabetes, he explained in a statement.
In adults, it occurs as ABCC8 MODY or MODY 12, Nicholas said, adding that through his lab's collaborative work with MDRF, using various experiments in the laboratory, researchers 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,' he said, adding, 'This is the first demonstration of this mechanism in a MODY subtype to our knowledge.'
Radha Venkatesan, executive scientific officer, head of molecular genetics, and the lead researcher from MDRF, said that the discovery of the novel genetic subtype of MODY represents a significant advancement in understanding this type of diabetes and explains the function of potassium ATP (K-ATP) channels in the pancreatic beta cell membrane.
K-ATP channels are a kind of molecular switch which determines whether or not insulin is released.
'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 be officially recognised as distinct disease subtypes, with different molecular basis and different clinical and therapeutic implications,' Venkatesan said.
Implications on treatment for rare forms of diabetes
Type 1 diabetes is mainly treated with insulin replacement therapy. On the other hand, type 2 diabetes, in nearly 90 percent of cases, is managed by anti-diabetic medicines and lifestyle modification, even though nearly 10 percent of patients with this condition tend to need insulin.
Some forms of MODY can be treated with anti-diabetic medicine, while others need insulin, and a few do not need any long-term treatment at all.
Talking to ThePrint, Mohan explained that genetic testing to identify the subtype of diabetes is carried out in atypical cases, when doctors are not sure whether somebody has type 1 or type 2 diabetes.
'We have got certain criteria to do genetic testing for. For example, all children below 6 months of age have to undergo genetic testing,' he said. 'Secondly, if we feel that somebody has type 1 diabetes clinically, but all the markers for type 1 diabetes, like GAD (glutamic acid decarboxylase, associated with type 1 antibodies), antibodies are negative, and there is a family history of diabetes this suggests that it may not be type 1 diabetes.'
Similarly, said the clinician-scientist, if one is treating a patient as type 2 diabetes but if the patient is lean, does not have obesity, and other markers of insulin resistance—such as the thickening of the skin of the neck or 'acanthosis nigricans'—which are all classical features of type 2 diabetes, then doctors need to probe whether this could this be some other form of diabetes and, in such individuals, genetic testing can be planned.
Regarding the treatment, if it is a Gain of Function (GOF) ABCC8 mutation, like neonatal diabetes, MODY 12, MODY 1 or MODY 3, then sulphonylurea—a common medication for type 2 diabetes—is the treatment of choice, Mohan explained.
'In the case of MODY 15 patients, sulphonylurea treatment did not work in any of these patients and they were managed with different drugs,' he said.
But since they were a series of patients who came from different centres and were referred to MDRF mainly for the genetic testing, the researchers are still not clear which drug would be best.
'We will have to collect the largest series of patients and do a randomised clinical trial to see which drug would suit these patients best,' Mohan added.
The discovery not only expands the scientific understanding of MODY, researchers have maintained, but also underscores the urgent need for wider access to genetic screening, particularly in countries like India, where such testing is not yet part of routine diabetes care.
This breakthrough could mark a turning point in advancing personalised diagnosis, treatment, and long-term management for thousands of individuals living with undetected or misclassified forms of diabetes, they said.
(Edited by Sanya Mathur)
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