At what point in time the correct type of treatment is started also makes a difference to diabetes management, the study found. Photograph used for representational purposes only
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The fact that South Asians are more susceptible to Type 2 diabetes compared to some other populations has been established now. India is in an especially precarious position when it comes to this non-communicable disease – an estimated 10.13 crore people in the country have diabetes – and faces a huge challenge in screening, management and treatment. But what are the exact genetic pathways that make South Asians more prone to getting diabetes? And can insight into them help with better treatment?
A new study by Sam Hodgson et al, ‘Genetic basis of early onset and progression of Type 2 diabetes in South Asians’ published in Nature Medicine, explores this. One of the reasons this study was undertaken, the paper notes, is that genetic research is largely focused on European ancestry groups, meaning the genetic risks of other populations such as South Asians is poorly understood.
The study used the Genes and Health cohort, a community-based study of British Bangladeshi and British Pakistani individuals, evaluating data of 9,771 persons with Type 2 diabetes and 34,073 diabetes-free controls. The participants’ genetic information was linked to records maintained by the UK’s National Health Service, and a partitioned polygenic score (pPS) was applied to this data to create a genetic signature of sorts for each individual.
What the study found, says Moneeza K. Siddiqui, lecturer in genetic epidemiology at Queen Mary University of London, who co-led the paper, was that two unique features in South Asians contribute to their genetic burden: a dysfunction in the beta cells of their pancreas which hinders the ability to produce enough insulin, and the unfavourable distribution of fat (lipodystrophy) in the central abdominal region, rather than say in their thighs or arms, in their bodies. An extremely high genetic risk for both factors leads to an onset of diabetes at least eight years earlier and at 3 kilograms per metre square lower body mass index (BMI) in South Asians, the study found.
Resistance vs. deficiency
“We know that in people of European ancestry diabetes is primarily caused by obesity-related insulin resistance – that is, when your body’s cells do not respond properly to the insulin that is secreted by the pancreas. But in India, even those at lower weights develop diabetes. Indians have the thin-fat phenotype, which means they may have normal or low weight, but have a higher body fat percentage, which puts them at risk. The findings from this study show that the genes for the risk of insulin deficiency (the pancreas are not secreting enough) are prominent in South Asians. In addition, the genes associated with lipodystrophy also came out significantly,” says V. Mohan, chairman, Dr. Mohan’s Diabetes Specialities Centre, Chennai.
Why do Indians have a higher risk of producing less insulin? The answer, says Chittaranjan S. Yajnik, well known for his work on the thin-fat Indian, may lie in epigenetics. Dr. Yajnik’s Pune Maternal Nutrition Study, which is now in its 24th year, explored maternal and foetal undernutrition as a driver of diabetes in India. “India leads the world in low birth weight babies, and these babies have a higher risk of developing diabetes at a younger age and at lower BMIs. In many cases in India, diabetes is less a lifestyle issue and more a factor of poor foetal growth due to nutritional deficiencies in the mother. There is a strong, environmental driver in terms of intrauterine undernutrition, which leads to poor growth in the womb, leading to smaller abdominal organs (including the pancreas), which predisposes you to lower insulin secretion,” he says. And so, he underscores, that since genes learn how to behave while in the womb, epigenetics is as crucial as genetics in understanding our risk for diabetes.
Tailoring treatment
What does this mean for the way diabetes is treated and how people with these ‘genetic signatures’ respond to medication? “We found that the standard treatment protocol that exists in the U.K., where metformin is given as the first-line treatment drug and the patient subsequently progresses through a pathway of care, may not work for many South Asians who have one or more of these genetic features. Metformin (which works for insulin resistance) is often given as monotherapy – just the one drug is used – but in South Asians where insulin deficiency and not insulin resistance is a problem, a more tailored approach with metformin alongside other drugs – for instance those that promote insulin secretion, and even insulin itself – may be initially needed to help them manage their diabetes,” says Dr. Siddiqui.
At what point in time the correct type of treatment is started also makes a difference: the study found that those with a genetic risk of producing insufficient insulin did not do well with the sodium-glucose co-transporter 2 (SGLT2) inhibitors – a class of medications used in diabetes treatment to help manage blood sugar levels. “This is perhaps because these patients were put on these drugs quite late in their treatment and their sugar levels were already quite bad by the time they were started,” theorises Dr. Moneeza, underscoring the need for tailored therapy.
However, more research is needed to understand how treatment based on the pathophysiology of diabetes could work, points out Dr. Mohan, whose centre, the Madras Diabetes Research Foundation, is currently working on a randomised controlled trial on this.
‘Do away with stigma’
One crucial aspect to come out of this study, says Dr. Moneeza, is that the stigma around diabetes being associated with lifestyle perhaps needs to be eradicated. This, however, does not mean maintaining a healthy lifestyle with a good diet and exercise is not important – in fact, it becomes more important. “With our genetic risks, we have to work harder at our lifestyles to keep ourselves healthy in order to avoid diabetes,” she says.
Published – December 06, 2024 03:52 pm IST
