Q & A session with Dr. C. S. Yajnik: the one who coined the term “thin-fat”
“Paulo Coelho had once said, ‘When you want to do something, Lord and all the universe conspires to help you achieve it’; I am a living example”
This is how Dr. Yajnik opened his conservation with us, and we were certain that the next few minutes would bring along ample of scholarly insights and profound learning. Work speaks louder than words; Dr. Yajnik needs no introduction; however, it’s our honour to formally introduce him; Dr. Chittaranjan S. Yajnik is the Director & Consultant at the Diabetes Unit at KEM Hospital, Pune and a leading medical scientist in India who has been relentlessly working on “why Indians have so much diabetes”. His work is exemplary and has aided the medical fraternity to comprehend beyond the usual theoretical concepts of diabetes.
It’s an absolute honour to have this sneak peek session with you, Dr. Yajnik; you are one of the few researchers who have made India proud, and your contribution in the domain of diabetes is commendable. Please let us know how did it get started?
It all started with my aspiration of becoming a molecular biologist but circumstances persuaded me to become a doctor and thereon my inclination in diabetes research grew profound.
My introduction to molecular biology was through a learning of ribosome cycle. The ribosome is assembled at the initiator codon (AUG) which codes for the amino acid Methionine. Forty years later I learnt that elevated homocysteine levels in the mother are a driver of foetal growth restriction which in turn increases risk of diabetes in the child (foetal programming). Methionine is nothing but methylated homocysteine and this convergence is held by Vitamin B12 and folate. Such interest in molecular biology and my interest in foetal programming in diabetes completed the full circle.
Sir, what made you coin the term “thin-fat” and how were you convinced that your observation can describe several individuals in India?
Historically, diabetes is mostly associated with over-nutrition. When I was in the medical school we had a heavy outpatient department (OPD) at the Sassoon General Hospital, Pune; patients were predominantly from the lower-socioeconomic classes visiting the hospital for treatment as the OPD provided free medical kits. Dr. Gururaj Mutalik, a renowned Physician-geneticist was my professor in those days; who had returned to India after training at the Johns Hopkins University. He introduced the patient record form where nutritional history, body mass index (BMI), and obesity index of patients with diabetes were captured. My encounter with first few patients revealed that they were distinctly different from what was described in western textbooks. Books described type 2 diabetes occured in older and obese individuals while most of our patients were young, thin and undernourished. Many of them came from slums. When I reported this contrast to my teacher, and expressed my interest to delve deeper into the phenomenon, he advised me to first complete my formal education for MD without questioning the dogma. I took his “fatherly” advice then, but skepticism did not stop me thinking. This was the beginning of my interest in finding out why undernourished Indians had so much diabetes.
And how did the universe conspire and help you to pursue your research at the University of Oxford?
After completing my masters in medicine, I applied to five Universities in the United Kingdom, where diabetes research was a top priority. I had secured a fellowship from the Birla Sharak Kosh, Bombay Hospital; however, that wasn’t enough. At a point where I was just about to give up, Dr. Derek Hockaday (my mentor) offered me a registrar’s position at the University of Oxford. Later I learned that I was one of the beneficiaries of the grant that the University had received from Sheikh Rashid of Dubai. And this is how I landed at the Oxford; out there I learnt several things, but most importantly I learnt the art of asking an answerable question; as a researcher, one has to frame a proper research question to be able to find the correct answer.
In one of your talks you had referred to Oxford as the ‘mecca of diabetes’. So, it’s intuitive to believe that you would have continued in Oxford. What made you change your mind and come back to India?
I call Oxford as the “Mecca of diabetes” because of the galaxy of the experts there who made a huge contribution to the understanding and treatment of diabetes. I learnt about patient care, importance of clinical record keeping, and many techniques in research. Importantly, I also learnt about the newly described association between ‘central’ obesity, insulin resistance and diabetes while in Oxford. Edwin Gale introduced me to the world of dose-response between insulin and glucose, fatty acids and ketones. While the learning was profound, my inquisitiveness to compare Indian diabetic patients with those in the United Kingdom impelled me to spend a month back in India. During this visit, I collected clinical data from patients in Pune and carried their blood samples to Oxford for measurements. A simple comparison of data in Indian patients with that in the English patients revealed very interesting findings. Indian patients were diagnosed younger and were shorter and thinner, however, they had thicker skinfolds compared to the English patients. Indian patients also had higher insulin concentrations for a given weight. These findings looked counter-intuitive, but events that followed provided an explanation! First, I was a ‘volunteer’ for an ongoing study which measured glucose and insulin levels in blood after a glucose drink. My insulin concentrations were much higher than those in an Englishman who was 15 cm taller and 25 kg heavier. I weighed only 55 kg and had a BMI of 20 kg/m2 but I became the ‘insulin-resistant diabetes doctor’ at the Radcliffe Infirmary. Second, when the results of the Southhall survey were reported at a British Diabetic Association meeting, data revealed that Indian residents had a much higher risk of diabetes compared to the English. This was thought to be the result of ‘stress’ of migration but I knew that similar things were happening in India itself. I decided that if we want to know more about diabetes in Indians, the best place to study can only be India. So I declined the offer to pursue PhD at the University of Oxford. My karma and dharma brought me back to India.
That is very interesting, Sir. Am sure it wasn’t easy to set up a research facility in those days in India? How was your journey?
You’re right. Resources and infrastructure were scarce. And there were no Good Clinical Practices (GCP) guidelines. Ethics Committees also came later. A verbal agreement by the patient was sufficient. Anyways, coming back to your question, my journey to establish a research department was eventful and memorable. My first stint was at the BJ Medical College and Sassoon General Hospital as a Pool Officer of the Council for Scientific and Industrial Research (CSIR). I started collecting data on malnourished patients with diabetes in collaboration with Oxford mentors. Though it provided an excellent opportunity, it did not take me long to realize that I needed to move to a place where it was possible to set up long-term cohorts and studies. KEM Hospital in Pune had a good reputation. My requests to CSIR to transfer me to KEM Hospital failed completely. I was quite desperate. And a miracle happened. One day I switched on the TV to wach 9pm DD News. Prime Minister Shri Rajiv Gandhi was addressing Indian scientists in the USA. He promised them that they will be placed in the institute of their choice if they decided to migrate back to India ! I wrote to him and was surprised to receive a letter from his office in three weeks, transferring me to the KEM Hospital ! I knew God was with me.
The real push to my research came from a Wellcome Trust (London, UK) grant. Dr Hockaday had persuaded me to visit Dr Bridget Ogilvie, the Director of the Wellcome Trust before returning to India. She was surprised that I was requesting support to settle in India than to travel abroad. She requested Dr Hockaday to visit Pune to confirm that I had the necessary infrastructure on which to build. The result was a grant in 1987 which helped us start the Wellcome Diabetes Study to ‘characterize diabetes in Indians’. The findings from the study established the importance of central obesity (waist–hip ratio) over generalized obesity (BMI) as a risk factor for diabetes in Indians. We also described the associations of insulin resistance with cardiometabolic risk factors in Indians. In addition, we described the spectrum of exocrine–endocrine pancreatic involvement in different types of diabetes in Indians. These were pioneering ideas at the time.
Your Y-Y paradox published in 2004 in The Lancet could instantly connect with the audiences; can you share some tidbits around the same?
Well, let me start by saying that it is unfortunate that we did not patent this image (laughs). It took me six years to publish the “thin-fat” baby paper, but this image of my friend John Yudkin and I proved an instant success. The paper depended on simple anthropometric measurements; the picture depends on a machine (DXA) measurement. Somehow, world respects ‘black box’ pictures than simple measurements. The Lancet Editor carefully screened all the original data before accepting it for publication. I also joke that this picture cost 39,000 Sterling pounds, the cost of our DXA machine. This image represents a simple fact – despite an identical BMI, I had more than twice the body fat percentage than that of John Yudkin, thus highlighting the thin-fat phenotype of Indians. This picture must be one of the most frequently shown in the obesity and diabetes conferences.
When we talk about Dr. Yajnik, we cannot miss the Pune Maternal Nutrition Study (PMNS); can you share the story behind this one?
Very soon it will be the 30th birthday of the PMNS; it is one of the longest prospective studies in India with a follow-up rate of over 90 percent. It has provided rich and pioneering ideas in the field of foetal programming. It was set up in collaboration with Prof David Barker and Caroline Fall, after we described the association of low birth weight with insulin resistance in children in the Pune Children’s Study. The PMNS is pre-conceptional and community based in 6 villages near Pune. We reported the ‘thin-fat’ Indian babies and showed that maternal micronutrient deficiencies and deranged 1-C metabolism influence foetal growth and programming of diabetes. Again, many researchers had ‘programmed’ me to investigate pregnancy nutrition to find root causes of diabetes. First it was Prof Joe Hoet, then IDF President, who discussed his protein-deficient rat model with me during his visit to India in 1988. It had convinced him that under-nutrition in utero increases the risk of diabetes and he was quite impressed by our papers on malnutrition-related-diabetes. He trained my first PhD student Anand in his lab who subsequently set up a multi-generationally undernourished rat model (‘Thrifty Jerry’). The second thread was provided by Prof Norbert Frienkel who suggested that I study pregnancy metabolism and fuel-mediated teratogenesis of diabetes in Indians. The final push came from David Barker. He described the low birthweight – diabetes association in a UK study. This appealed to me instantly because I could I relate it my own story: I was born less than 5 pounds and was the ‘insulin-resistant doctor’ in Oxford. I have to say that I had suggested the ‘thrifty phenotype’ title for Barker hypothesis in our first meeting. This completely changed my career path. I jokingly say that David Barker ‘reprogrammed’ my ideas about diabetes aetiology from genetics to epigenetics.
We’ve heard that you have a rather unique biobank of samples including those of placenta. How did you manage this in a country like India and in the times when you started your study?
(Smiles) Yes, we have thousands of blood, urine and stool samples and of placenta and cord blood that could be a unique legacy for future studies. These will allow measurements of DNA, RNA, metabolites, hormones, and so on. A story about placenta: in the PMNS. majority of the deliveries took place at home in those days. It was customary for the villagers to bury the placenta in an earthen pot, soon after the delivery. We provided plastic bags to the family to wrap placenta before burying it, to reduce drying. When we arrived on the scene to meet the family and make our measurements in a day or two, we ceremoniously exhumed, weighed and reburied the placenta. In those days there were no mobile phones; news of a delivery reached us through somebody on foot or cycling, via a public phone call (PCO), or a telegram, We constructed a mobile van with a basic laboratory and an ultrasound machine, which allowed us to carry out door-to-door investigations. We executed over 500 oral glucose tolerance tests in the early hours of morning at home and were able to measure more than 90% of babies within 72 hours of birth in home deliveries. We have many more stories and reminiscences.
Your journey is not just interesting but also very inspiring; where do you get all the energy from?
My journey had its own high-n-lows, ups-n-downs! What we see today has been possible because of academic parenting, guidance from teachers, tireless contribution from colleagues and my ability for somewhat lateral thinking. Pallavi and boys stood firmly behind me, and she took responsibility for all the logistics. Our studies have been simple but were carefully designed and executed by a diligent in-clinic and field force. We developed robust laboratory measurements and deployed a simple but effective data management system. I am grateful to all in my world, who conspired to make it possible! Finally, as Atticus says, ‘we are made up of those who built us and broke us’, I subscribe wholeheartedly!
