Diabetes mellitus is one of the prevalent non-communicable diseases in the world, with India being infamously called the diabetes capital. A report by World Health Organisation states that the number of diabetics globally has risen from 108 million in 1980 to 422 million in 2014. This alarming rise has prompted urgent research and intervention to alleviate its potentially catastrophic consequences.
Professor Milind Watve’s lab at the Indian Institute of Science, Education and Research (IISER), Pune, is adding a new dimension to this research by studying the underlying pathogenesis of diseases like diabetes from an evolutionary perspective. Evolutionary medicine (EM) is a branch of medicine that uses evolutionary biology to study diseases and assist treatment. It explores attributes we have picked during the course of our evolution that may not be best suited in present day conditions and may be responsible for lifestyle-related diseases.
‘Behavioural switch’ hypothesis
Scientists have tried to explain type-2 diabetes (T2DM) from an evolutionary standpoint since the 1960s, when James Neel first proposed his ‘thrifty’ gene hypothesis. He alleged the ‘thrifty’ gene conferred a selective advantage during famine on expressing a thrifty metabolic attribute, and when food was abundant resulted in high insulin levels and obesity. However, no strong genetic link was established to substantiate James’s hypothesis and scientists attributed obesity to insulin resistance, leading to T2DM. Hence, this theory was disregarded. Moreover, there was no clarification if the concept of thrift implied higher food intake or reduced utilisation of stored energy or both. Further hypotheses claimed that early life nutritional limitations were to blame for the subsequent development of a diabetic, that is, ‘obese and thrifty’ phenotype later in life.
These theories pose key questions like what concepts constitute our understanding of T2DM and how much of them are backed by evidence, what are some of the recent discoveries about T2DM which may contradict or support existing beliefs and what aspects are looked into to formulate a hypothesis that adequately explains and accommodates the existing empirical data. “Rigorous norms are necessary for building any hypothesis. Once the path is highlighted, it is easier to take steps in that direction. So far, there has been great confusion in the field as to where to go and what to achieve. Now, hopefully, our work would be helpful to others too,” says Professor Milind. For instance, one major drawback of classical hypotheses is their sole focus on energy metabolism revolving around insulin, glucose and obesity while failing to account for other organ systems, now known to be involved in T2DM pathophysiology.
Professor Milind’s ‘behavioural switch’ hypothesis addresses these limitations by considering fundamental concepts of natural selection without claiming genetic propensity towards T2DM. It elaborates on the evolution of behavioural, metabolic and neuro-endocrine plasticity and its contribution to most lifestyle-related disorders today. “Our hypothesis considers the mismatch in ancestral versus the present environment, but in the context of strategic plasticity, choice of coping strategies and trade-offs,” he says.
The ‘behavioural switch’ hypothesis suggests two tactical behaviours corresponding to different metabolic features — the aggressive hawk (soldier) behaviour characterised by insulin sensitivity, higher fertility and shorter life span, and the docile dove (diplomat) behaviour exhibiting insulin resistant metabolism, low reproductive potential and longevity. Diplomat personalities are more prone to T2DM than warrior personalities according to this hypothesis. This is supported by evidence in the form of over 70 signalling molecules and processes linking behaviour to metabolism and immunity.
Probing a dual system
It is widely believed that obesity causes insulin resistance. The beta-islet cells of the pancreas compensate insulin resistance by overproducing insulin, a condition called hyperinsulinemia. But, insufficient compensation results in excess glucose in the bloodstream and related complications over a prolonged period. These classical beliefs regarding T2DM have been disputed by several paradoxes, thanks to recent evidence. The belief that obesity causes insulin resistance has neither been substantiated nor refuted. A few studies even show that many obese people do not suffer from T2DM, whereas lean individuals do. This inconsistency prompts the need to establish a clear direction of causality between the variables using better approaches.
The beta cell dysfunction puzzle needs to be explored too, by considering options to uncorroborated exhaustion theory. The first two premises include positive vicious cycles ending in complete βbeta cell destruction that conflicts with post-mortem evidence showing substantial beta cell mass in long term diabetic patients. Alternatively, the model put forth by ‘behavioural switch’ hypothesis clues at suppression of insulin release by the sympathetic nervous system and its prolonged retention of the protein amylin in beta cells. This generates toxic amyloid which builds up and causes limited damage to the beta cell population. Better comprehension of beta cell dynamics will help in resolving among these diametrically opposite theories to gain better perspective.
Some studies have probed a dual system involving peripheral insulin dependent and central insulin independent mechanisms in regulation of blood glucose levels. The behavioural switch hypothesis concurs by suggesting that labour intensive lifestyle depends predominantly on the peripheral mechanism when energy supply to muscle is the priority, as opposed to a sedentary existence largely reliant on brain activity, hence central regulation. “Diabetes is not only about a change in glucose regulation; it is about a change in all the systems. All these changes are not triggered by glucose. They are triggered independently by an individual’s chosen behavioural strategies. Increased glucose is only a minor symptom in the big set of changes,” opines Professor Milind. A good evolutionary hypothesis for T2DM should therefore be able to explain the cross talk between multiple systems in a complex network, interspecies similarities and differences in metabolic adaptations and population variation in susceptibility to the disease.
And where is the ‘behavioural switch’ hypothesis today? “It has already crossed many milestones on the path but it is yet to clear the acid test of clinical trials. That should be the goal. We have clarity about what needs to be tested and how to test it. We are in a process of establishing partnership with clinical groups, hoping to get sufficient support for what perhaps would be the first clinical trial based on evolutionary medicine,” explains Professor Milind. “Sound theoretical development, quantitative reasoning as well as an evidence base, can make evolutionary medicine a potential revolution, but we are yet far from it,” he signs off.
(The author is with Gubbi Labs, a Bengaluru-based research collective)