Photo: Siddharth Kankaria / Research Matters
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 Organization states that the number of diabetics has quadrupled since 1980 to 422 million adults globally. India has witnessed a dramatic rise in its diabetic population from 11.9 million in 1980 to 69.2 million in 2015. This alarming worldwide rise in the visibility of diabetes has prompted urgent research and intervention to alleviate its potentially catastrophic consequences. Prof. 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.
Diabetes is a chronic disease characterized by either inefficient production of insulin hormone or its ineffective reception by the cells in our body, known as type-1and type-2 diabetes respectively. Insulin is a hormone with multiple functions, one of them being regulating blood glucose levels. Individuals with type-2 diabetes (T2DM), constituting 90% of all cases, are unable to properly use their insulin supply due to insulin resistance, which can be avoided by changes to diet and lifestyle habits. Various therapies and medicines are currently being used to keep a check on the blood glucose levels with the belief that controlling glucose would prevent undesired complications.
Darwinian or Evolutionary medicine (EM) is a branch of medicine that uses evolutionary biology to study diseases and assist treatment. It states that our physiology is a result of several adaptations and maladaptations for natural selection during our ancestry. It explores attributes we have picked during the course of our evolution that may not be best suited in present day conditions, responsible for lifestyle-related diseases. Prof. Watve’s lab favours answering the question of ‘why’ instead of ‘how’ posed by traditional medicine for preventive and therapeutic measures. “EM has a great potential if it comes out of the 'just so ... stories' and uses evolutionary theory more rigorously. Currently the theoretical rigor seen in many other fields of evolutionary theory is not yet seen in EM”, opines Prof. Watve.
Scientists have tried to explain 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 Neel’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 utilization of stored energy or both. Further hypotheses claimed that early life nutritional limitations were to blame for the subsequent development of diabetic i.e. ‘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, applying it to pathophysiology and testing it. 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 in the field too”, comments Prof. Watve on the need for a set of criteria to reject poorly scoring hypotheses and to narrow down to appropriate ones. 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.
Prof. Watve’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 vs. present environment, but in the context of strategic plasticity, choice of coping strategies and trade-offs. It is important to ask the question how and why systems evolved to become what they are, and what are the relative roles of each component in these complex and highly plastic systems? The answer to this question lies in the ecological and social challenges faced by the evolving systems,” says Prof. Watve. The ‘behavioural switch’ hypothesis suggests two tactical behaviours corresponding to different metabolic features - the aggressive hawk (soldier) behaviour characterized 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.
It is widely believed that obesity causes insulin resistance. The β-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. 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. Potential theories explaining inadequate compensation by β cells include oxidative stress, hyper-activation of mTOR pathway or suppression of insulin release via sympathetic nervous system. The first two premises include positive vicious cycles ending in complete β cell destruction that conflicts with post mortem evidence showing substantial β 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 β cells. This generates toxic amyloid which builds up and causes limited damage to the β cell population. Better comprehension of β 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 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. Nevertheless mechanism of glucose regulation is just one of the several changes that fine-tune the system as per its needs.
“We should not make the same mistakes again and again”, warns Prof. Watve. “First people thought diabetes is everything about glucose. They also thought it is all genetic. Both turned about to be false! 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”, he opines. 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. Researchers should avoid focussing on partial picture and classical beliefs; stop disregarding inconvenient facts and evidence and instead should aim to collect empirical data to integrate now known complexities about the disease. Clinical trials based on various hypotheses can also shed some good light on their validity.
And where is the ‘behavioural switch’ hypothesis today? “It has already crossed many milestones on the path but it has 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 Prof. Watve.
“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. Given that, the WHO has estimated diabetes to be the 7th largest global cause of death by 2030, perhaps it is time for a revolution.