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Rethinking Diabetes : What if glucose and insulin were not central pieces required to solve the puzzle called ‘diabetes’?

Photo : Siddharth Kankaria / Research Matters

India as a nation is no stranger to the epidemic of diabetes. Most of us would know of someone in our extended group of family and friends, who is suffering from this ‘silent killer’ disease. Being the ‘diabetes capital’ of the world, India has had the single largest population of diabetics for years, only to be recently surpassed by China [1,2].  India’s 62 million diabetics is no small number; this figure is set to cross the 100 million mark by 2030, according to the Diabetes Atlas published by the International Diabetes Federation[3]. This rise in the number of India’s diabetics can be attributed to multiple reasons, like the increased genetic predisposition of the Indian population towards diabetes, the growing levels of sedentary lifestyle, and access to more energy-rich food.

For anyone who’s spoken to a diabetic, or even read basic high school biology, it comes as no surprise that diabetes is diagnosed by increased blood glucose levels. Such heightened blood glucose levels may come about due to various reasons. Type 1 diabetes is a consequence of a near-complete lack of production of insulin, the hormone that regulates the body’s glucose levels. Type 2 diabetes, on the other hand, is not caused due to insulin deficiency, but due to 'insulin resistance' or the reduced response of tissues to insulin. Quite naturally, all clinical interventions directed towards treating the symptoms of diabetes have solely been targeted towards regulating the levels of blood glucose, or increasing the insulin production/ absorption in the body.

But, what if this entire understanding of diabetes as a glucose-and-insulin-centric disease was itself flawed? What if, insulin and glucose were not the king and queen in this game of chess called diabetes, but were just two among many other pawns? A research paper by Prof. Milind Watve and his team at the Indian Institute of Science Education & Research (IISER), Pune, raises and tries to address these very questions.

In an email interview with Prof. Watve, he explained that although there has been a lot of research behind the biology of Type II diabetes in the last 25 years, most such endeavours have been very fragmented, especially since everyone has been focussing on smaller and smaller aspects in greater detail. “There was a need to put things together in some unbiased framework, and we tried to do that,” said Prof. Watve, while explaining his group’s motivation behind conducting this study.

In order to achieve this, Prof. Watve and his team took into account a large number of metabolites, hormones, growth factors, neurotransmitters, neuropeptides, and even behaviours linked to diabetes in earlier studies, and constructed a multi-organ, multi-signal network to better understand what happens inside our body during diabetes.

The research team allowed each node of the network to be assigned three states, normal (or 0), up-regulated (or +1) and down-regulated (or -1). They then changed the states of various nodes in isolation and in groups and observed the effects in the network. Each node, by virtue of being connected to other nodes, caused various changes in the state of other nodes. When such perturbations continued for a longer duration, the system was seen to eventually settle into one out of the only two possible stable states.

Their aim was simple: to convincingly demonstrate that an interactive network model of diabetes, which considered many metabolic factors, could explain the inner workings of diabetes much better than a simplistic model solely focussed on the dynamics of insulin and glucose levels in the body.

The most surprising implication of their research was the fact that it might be impossible to prevent diabetic complications by a sole focus on regulating glucose levels in the body. The model also goes on to propose different neuro-endocrine and behavioural interventions that could be promising targets for combating diabetes.  Examples of such interventions include metabolites as diverse as sex hormones like testosterone and oestrogen, neurotransmitters like dopamine and serotonin, hormones like melatonin, ghrelin and growth hormone, and even behaviours like aggression!

“The system attains one of the two states invariably, i.e. either insulin resistance and its correlates or insulin sensitive and its correlates. Both the states are reinforced and stabilized by several mechanisms. That's the meaning of bistability,” explained Prof. Watve. The emergence of bistability in such a system has far-reaching consequences to our understanding of diabetes. “If so many mechanisms have evolved to stabilize the insulin resistant state, there must be some adaptive advantage of this state [evolutionarily] under some or the other context. Without that, we won't expect evolution of multiple mechanisms to stabilize what we call a disease state today,” argued Prof. Watve.

What this means is that an insulin-resistance state of the body – long thought to be the underlying cause of diabetes – is actually not a disease state, but instead an evolutionary adaptation acquired under some environmental circumstances, which have now become obsolete or detrimental. The very fact that diabetes at its core could be an evolutionary adaptation can fundamentally change our outlook towards its treatment and even its prevention.

Their study further focussed on which of these nodes could switch and maintain the body’s stable state from an insulin-resistant to an insulin-sensitive state. Surprisingly, various nodes currently targeted in diabetic treatments such as those involving glucose and insulin production in the body, insulin supplementation, reduction in obesity, reduction in cholesterol, regulating blood glucose levels and even exercise, failed to maintain the body’s systems in an insulin-sensitive state. On the other hand, the transition could be achieved easily by targeting the desired levels of dopamine, testosterone, aggressive behaviour and the likes in isolation, or even more effectively, when used in combinations.

When enquired about the possibility that rigorous control of blood glucose levels in diabetics was not significantly improving the lives of these patients, Dr. Sharada, a medical officer at the Health Centre of the Indian Institute of Science, Bangalore, agreed that “all practicing doctors know that there seems to be only some correlation between health and mortality outcomes and rigorous control of diabetes.” But at the same time, she confessed that she wasn’t sure if it was actually possible to help the body "transition from an insulin resistant state to insulin sensitive state".

If the findings of Prof. Watve’s group hold up to further scrutiny in the field of medicine, they could completely revolutionise the way we think about and treat diabetes. The focus could then soon shift from just regulating insulin and glucose levels, towards a more holistic approach of nudging the body from an insulin resistant state to an insulin sensitive state. Not only would this open up more unconventional and better ways to combat diabetes, but also help remove the unnecessary stigma attached with the dietary and lifestyle restrictions that most diabetics face. Prof. Watve feels that “there is enough evidence by now that the gluco-centric approach to treating diabetes has failed. It’s time to drift away from this line of thinking and look for alternatives.”

When asked about how the medical community is going to react to these findings, Prof. Watve replied by quoting Thomas Kuhn, “A paradigm shift in science is painful.” He further added that in medicine, it was more so because there were more serious conflicts of interest, especially since insulin is a 50-billion-dollar industry today.

Dr. Sharada on the other hand felt that it would take a very long time to change our views in India. She said that “We do not even hold the currently held views from the West. We have our own set of mythologies -- perhaps not more wrong than the "scientific" western ones -- but there is a serious deficit in modern concepts such as the idea of counting calories as opposed to sweetness, irrational beliefs in panaceas and nostrums, severe ignorance of calorific values of foods even among doctors, popularity of unproven Ayurvedic and Unani management, among others.”

Prof. Watve however remained optimistic about the future: “I have started getting positive responses from clinicians and certain classes of diabetes researchers. It will take some more time but a paradigm shift is in the coming,” he signed off.

1.        Facts & Figures from the Asian Diabetes Prevention Initiative, Joint Initiative by Harvard University & National University of Singapore.

2.  Xu Y et al., for the 2010 China Noncommunicable Disease Surveillance Group. Prevalence and Control of Diabetes in Chinese Adults. JAMA. 2013;310(9):948–959. doi:10.1001/jama.2013.168118 .

3.         Whiting, D.R., et al., IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract, 2011. 94(3): p. 311-21.