IISER study provides shift away from traditional understanding of diabetes

For decades, glucose and insulin have taken the centre stage in diabetes research and clinical practices. But, in recent years, the picture has become more complex, with studies revealing that many molecular, neuronal and behavioural signals are also altered by Type 2 Diabetes Mellitus (T2DM). Yet, understanding remains fragmented, despite such efforts.

Now, in a seminal step, a team from the Pune-based Indian Institute of Science Education and Research Pune (IISER) has, in a first, put together all known metabolic, hormonal, neuronal, immunological and behavioural signals under T2DM in a computer model, in an effort published by the global PLOS (Public Library of Science) journal. Conducted by professor Milind Watve of IISER’s biological department and two PhD students, it has used a ‘network model’ — a giant cobweb in which perturbing one thread disturbs the whole network. So, many new possibilities are raised, as any change ends in one of two possible configurations — insulin sensitive or insulin resistant.

“It successfully mimics many known patterns and processes of T2DM. It also made many surprise predictions — one of them being that T2DM can be completely reversed,” said Watve.

Large-scale clinical trials in recent years have implied that normalisation of glucose is not sufficient to arrest all diabetic complications. In some trials, death rates actually increased after aggressive glucose normalisation. Watve elaborated, “The model suggests that even when sugar is controlled without hypoglycaemia, the progress of diabetes pathology is not arrested. In a complex network, increased blood glucose is not central to pathophysiological changes of T2DM — so, controlling sugar is not effective in reversal. Increased blood glucose is just a symptom — not a root cause. Treating symptoms is not sufficient to reverse any condition.”

At present, T2DM is considered irreversible, yet not a single step in its known pathophysiology is irremediable. Once an individual gets into an insulin resistant or diabetic trap, it is difficult to come out of it — but, coming out of it is certainly not possible by just regulating insulin and glucose, says the network model. “There are many other ways of coming out, suggesting that diabetes can be curable. Other targets – signals in the brain, behaviour, etc. – make reversal possible. If this can be done in a computer model, it could be in real life, too,” informed Watve.

PhD student Shubhankar Kulkarni, a part of the study, said, “Reversals are not happening today as perhaps we are not hitting the right targets. Glucose and insulin are both not central to the T2DM pathophysiology. This perception is a burden of history. Over 70 molecules are involved in inter-organ signalling — glucose and insulin are just two. Our model raises the hope that T2DM will be fully curable one day. But, there must be a paradigm shift. We need to give up on insulin-centred thinking, and be open. Many alternatives need more empirical research. In biomedicine, experiments have the final word, but theoretical, mathematical and computational models often suggest new lines of work. The large scale failure of traditional treatments should trigger experimentation on alternative paths.”

Weighing in, Chellaram Diabetes Institute CEO, Dr AG Unnikrishnan, said, “This research brings out an important point — T2DM is multifactorial and complex. The study is consistent with an increasingly accepted current understanding. It is now well known that T2DM cannot just be explained by impaired insulin secretion, insulin resistance or obesity. Multiple factors contribute, including glucagon and other hormones. The study also suggests hypothetical targets for prevention and treatment. Further clinical studies are required to confirm this — only they can clarify if the concepts can be translated into a change in the existing clinical management of diabetes.”