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The pancreas’ failure to secrete adequate insulin appears to have been the trigger for type 2 diabetes in over half of the Indian patients (especially those diagnosed before the age of 45) in an Indo-Swedish study. This is in contrast to Western countries, where type 2 diabetes is mostly caused by insulin resistance, said the study, which was published in The Lancet Regional Health-Southeast Asia.
Insulin resistance occurs when the body is unable to use insulin the proper way. On the other hand, as type 2 diabetes worsens, the capacity of the pancreas to produce insulin keeps dropping, resulting in deficiency.
“In Indians, we have to use drugs which will help the pancreas create more insulin,” said lead author Dr C S Yajnik, who is also the Diabetes Unit Director and Consultant at Pune’s King Edward Memorial Hospital and Research Centre.
Explaining this, Dr Yajnik said: “A normal person secretes enough insulin to achieve the desired effect on the tissues. But when the tissues cannot respond to the usual amounts of insulin, the pancreas has to secrete more. When this happens over a longer period of time, the pancreas gets fatigued and diabetes develops.”
“The other situation is where the tissues are responding reasonably well but the pancreas is not able to secrete insulin either because of genetic defects or its poor development in the womb or factors in the environment which may affect and damage the pancreatic beta cells. This is primarily an affection of the pancreas.”
The study highlights the predominance of insulin deficiency in Indian type 2 diabetes patients, while in the Swedish cohort it was associated with obesity and insulin resistance.
According to Dr Piyush Lodha, Diabetologist and General Physician at Pune’s Ruby Hall Clinic, every patient with type 2 diabetes can behave differently. “This genetic classification is a new step in identifying the underlying pathophysiology in a particular patient. Classifying every patient and starting appropriate treatment will help decrease diabetes-related complications in the Indian population,” he said.
According to Dr Yajnik, these findings will help improve the treatment of type 2 diabetes in India, where it is estimated that 74.2 million people had the disease in 2021. Researchers said this was the first study to investigate associations of European-derived genetic risk scores with type 2 diabetes, insulin-glucose indices, body composition and lipid-related traits in subgroups in India. These were then compared with Swedish patients.
“We found that genetic scores developed in Europeans for type 2 diabetes and its traits (obesity/insulin secretion/insulin resistance/lipid abnormalities) are usable in Indians. However, there are differences in the associations of these scores with some of these traits in the two populations. For example, for a given level of gene score for body mass index (BMI, a measure used to define obesity) Indians have a much lower BMI compared to the Swedish. It suggests that for a given genetic potential, Indians reach a lower BMI, probably because of undernutrition, which has existed for several generations” Dr Yajnik said.
Type 2 diabetes is usually linked to obesity. Dr Yajnik and his team have for the past 35 years extensively investigated why diabetes is so common in Indians despite a relative lack of obesity. Dr Yajnik found that though Indians have a lower BMI compared to Europeans, they have higher body fat percent and that this develops when they are growing in the mother’s womb. Hence, not only the adults but the newborn Indian babies are also compared to European babies, even though Indian babies are many hundred grams lighter.
Multigenerational undernutrition of young Indian mothers seems to have contributed to this, according to the expert. The findings were described in the Pune Maternal Nutrition Study which has followed more than 700 families spanning three generations over the last 30 years. Pune studies have tracked the development of diabetes and shown that poor growth of babies (lower birth weight or length) predisposes them to develop diabetes in later life. The risk is the highest in those who were born small but grew big in later life. If the system has low capacity, it cannot tolerate a load of excess calories in later life.
The new study is part of the collaborative research between KEM Hospital and Research Centre in Pune and the Diabetes Centre at Lund University in Sweden. It studied genetic similarities and differences between subgroups of type 2 diabetes in India and Europe. This was supported by the Department of Science and Technology, Government of India and the Swedish Research Council.
The study was led jointly by Dr Rashmi Prasad, Associate Professor in Genomics, Diabetes and Endocrinology at Lund University Diabetes Centre and Prof Dr Yajnik, the results of the study are based on clinical data from 2217 patients from Pune with type 2 diabetes.
Researchers at Lund University, Malmo, Sweden had in 2018 shown that diabetes can be divided into five subgroups, including SAID (severe auto-immune diabetes), SIDD (severe insulin-deficient diabetes), SIRD (severe insulin-resistant diabetes), MOD (mild obesity-related diabetes) and MARD (mild age-related diabetes). SAID is also known as type 1 diabetes, the remaining four subgroups belong to type 2 diabetes. Dr Rashmi Prasad was one of the authors of this acclaimed study.
In 2021, the Swedish group at LUDC published a new study in Nature Genetics that demonstrated genetic differences between the four subgroups of type 2 diabetes in Sweden. “The paper generated a lot of interest and was replicated in many other populations which confirmed that diabetes can be divided into the above subgroups based on clinical and biochemical characteristics and that this classification is useful to guide treatment and may help predict complications”, Dr Prasad had said. The collaboration, therefore, decided to study the genetics of type 2 diabetes subgroups of Indian and Swedish patients, not restricting to those diagnosed below the age of 45 years. The largest subgroup was still the SIDD.
Two other interesting differences between Indian and Swedish cohorts refer to genes associated with the deposition of fat in the liver and with vitamin B12 status. A number of studies in India and abroad have shown that increased liver fat is a characteristic feature of Indian type 2 diabetes patients.“ In our study, we found associations of a genetic risk score for liver fat in 3 out of 4 subgroups in the Indian cohort but none in Swedish. In addition, vitamin B12 deficiency-related genes were associated with the MOD subgroup only in Indians, not in the Swedish,” Dr Yajnik said, adding that this suggests that the causes of type 2 diabetes differ between the two populations.
According to Dr Piyush Lodha, Diabetologist and General Physician at Ruby Hall Clinic , the findings of the study were important as the Indian population with type 2 diabetes has a different phenotype as compared to Caucasians likely due to genetic differences. “`It is well known that every patient with type 2 diabetes can behave differently. This genetic classification is a new step in identifying the underlying Pathophysiology in a particular patient and thus individualisation of treatment. Various subgroups of patients might have distinctive responses to various diabetes medications and hence this classification has implications as far as treatment and selecting an appropriate glucose-lowering agent is concerned. Classifying every patient and starting appropriate treatment will help better glycemic control and decrease the diabetes-related complications in the Indian population,” Dr Lodha said.
