(1)
Indian Institute of Science Education and Research Pune (IISER-P), Pune, India
Abstract
A famous musician was once asked how he visualized music after 20 years. He replied, “If I knew, I will be playing it today!”
A famous musician was once asked how he visualized music after 20 years. He replied, “If I knew, I will be playing it today!”
Similar to music, the path of research and development is always difficult to predict. I started an inquiry into the evolutionary origins of type 2 diabetes as a curiosity exercise in evolutionary biology without a slightest idea that it may lead to reinterpretation of the whole phenomenon and that it may have radical implications for clinical practice too. The pursuit of a small but interesting question and some recombination of preexisting ideas led me a long way to challenge the long-standing conceptual foundation of T2D itself. Now I will make an attempt to predict where research would lead us in the near future being completely aware that it is just too difficult to make such predictions.
The Old Versus New Paradigm
Before going to the future, it will be good to summarily state the new paradigm of T2D once again in the form of a logical sequence of statements:
1.
A plurality of behavioral strategies can coexist in a population, and hawk–dove or soldier–diplomat is such a coexisting dichotomy seen in animal and human populations respectively. The difference is mainly in physical strength and aggression (soldier characteristic) versus cognitive abilities and social manipulation (diplomat characteristic).
2.
The two strategies are accompanied by a wide range of physiological adaptations to support the respective behavioral repertoire. In brief, the soldier strategy is marked by strong muscle and bone, more subcutaneous distribution of body fat, low serotonergic activity, low cholesterol and cortisol, low plasma insulin, insulin sensitivity, and protein anabolic bias in metabolism. The diplomat strategy is accompanied by disinvestment from muscle and bone, more visceral accumulation of fat, high serotonergic activity, high plasma levels of cholesterol, cortisol and insulin, insulin resistance, and lipid anabolic bias in metabolism.
3.
Insulin, cholesterol, leptin, and cortisol have important roles in learning, cognitive brain functions, and behavioral modifications. Higher levels of these molecules are involved in aggression suppression, physical risk aversion, and enhancement of cognitive functions, in effect suppression of soldier and facilitation of diplomat behavior.
4.
Aggression anticipates injuries, and a number of mechanisms of combating injuries are activated in anticipation. These include migration of innate immune cells towards the periphery and production of growth factors such as EGF and NGF that are involved in wound healing and regeneration of tissue. Deficiency of physical aggression results in more central distribution of innate immune cells leading to low-grade chronic systemic inflammation and chronic deficiency of many growth factors.
5.
Crowding, a perception of population density, can affect reproductive strategies, aggressive behavior, and energy reserves and thereby overall metabolic and endocrine balance. Crowding is identified as a new potential risk factor for obesity, T2D, and related disorders.
6.
Most of the complications of T2D and related disorders are due to growth factor deficiency, altered dynamics of macrophages and other innate immune cells, oxidative excess, and angiogenesis dysfunction, all of which can arise from behavioral signals independent of hyperglycemia. Hyperglycemia may play a role in aggravating some of these effects, but it is unlikely to be the sole driver of diabetic complications.
7.
Beta cell degeneration is most likely to be due to deficiency of EGF and other growth factors. Beta cells have a high regeneration capacity, and islet degeneration in diabetes is likely to be reversible if we identify the right internal environment required for the regeneration. This would include EGF, gastrin, and possibly a number of other growth factors.
8.
The association of insulin resistance with growth factor deficiency, chronic inflammation, oxidative excess, and endothelial and angiogenesis dysfunction does not appear to be obligate. Insulin resistance can be decoupled from these mechanisms as shown by the Klotho function, and if so decoupled, insulin resistance can promote health and longevity instead of a series of deadly disorders. Therefore insulin resistance may not be central to the pathophysiology of T2D. This necessitates a deviation from the obesity–glucose–insulin-centered paradigm of T2D and expansion of our understanding to a more accommodative picture that simultaneously accounts for all the changes in a wide spectrum of organs and systems.
9.
Along with the insulin–glucagon-driven peripheral mechanisms of glucose homeostasis, central mechanisms appear to play a more important role than previously believed, and there are indications that the rate of glucose transport from the brain capillaries may have a crucial role in determining plasma glucose levels. More research efforts are needed to understand glucose homeostasis in the brain and the interaction between central and peripheral mechanisms in glucose homeostasis. The key to glucose homeostasis is most likely to be found in the brain.
The new paradigm is thus radically different from the orthodox one in that:
1.
Obesity is not considered to be central to T2D and related disorders. It is only one of the risk factors. Obesity is associated with suppression of the soldier set of behaviors with two-way causality, and that is what mediates the association between obesity and metabolic syndrome.
2.
Insulin sensitivity and insulin secretion are affected by a large number of signal molecules including sex hormones, myokines, osteocalcin, BDNF, CCK, endorphins, HISS, serotonin, dopamine, and melatonin among them. The classical view considers only FFAs, triglycerides, and adipokines to affect insulin sensitivity, whereas the new paradigm accounts for the action of almost all the known molecules at proximate and ultimate levels simultaneously.
3.
T2D is not primarily or mainly about insulin and glucose homeostasis. Alterations in insulin and glucose are only a part of the wide variety of changes that take place simultaneously in the body.
4.
All the pathophysiological mechanisms are not driven by hyperglycemia alone, although it may aggravate many of them. As a corollary, glycemic control alone may not be sufficient to prevent all the complications of T2D.
5.
All pathophysiology of T2D originates from brain and behavior rather than diet and energy imbalance.
6.
T2D is not an incurable disorder. With the exception of advanced stages of complications, the baseline alterations in the body systems are not irreversible. Therefore, potentially there should be ways to reverse or “cure” T2D.
7.
A reversal or cure is unlikely to be brought about by medication. Since the origin of the disorders is in behavioral deficiencies, only behavioral supplementation can mediate a reversal. Even complete cure may be possible.
In Chap. 3 we noted five major horse and cart paradoxes that existed on the platform of the orthodox theory. Somewhere in the book, there is a solution to each of the five paradoxes, but let me explicitly relate the solutions once again here to emphasize that the new paradigm is logically sounder and resolves almost all the unresolved paradoxes.
1.
Cart pulls the horse: Insulin resistance first or hyperinsulinemia? This paradox is successfully resolved by the new paradigm with a clear-cut answer that hyperinsulinemia comes first and the hypoglycemic effects of it are avoided by compensatory peripheral insulin resistance. In low birth weight infants, insulin is necessary as a growth hormone to promote catch-up growth. Independent of this, on adopting a diplomat livelihood, insulin is necessary to facilitate cognitive functions for which increased insulin secretion is a primary adaptation. High levels of indigenous insulin are backed up by built-in mechanisms to induce insulin resistance. The orthodox paradigm believed in insulin resistance being primary leading to compensatory hyperinsulinemia. But no mechanism appears to exist by which insulin resistance can stimulate higher insulin secretion without ongoing hyperglycemia. See Chaps. 3 and 7 for more discussion.
2.
Horse moves, cart left behind: In a hyperinsulinemic and insulin-resistant state, if insulin secretion is artificially suppressed, blood sugar should rise if the orthodox view is correct. Experiments show that this does not happen. On suppressing insulin production, insulin resistance comes down and blood sugar is not affected. This paradox is partly resolved by the solution to the first paradox itself. If insulin resistance is a reaction to insulin levels, then reducing insulin would reduce resistance levels automatically. But this is only a partial solution. The other question as to why this does not happen in diabetes needs a separate solution. This is provided by the brain glucose dynamics. If the brain is short of the required sugar levels, it suppresses insulin production, facilitates glucagon production, and stimulates liver glucose production thereby increasing blood sugar until desired brain sugar levels are reached. Insulin, glucagon, liver, and muscle glucose uptakes are only tools that the central mechanisms manipulate. In effect, the blood sugar level is decided by the brain and only executed by insulin, glucagon, and insulin sensitivity. If one of them is changed, others adjust themselves to achieve the desired level. In diabetes, the desired level is increased, and therefore, following insulin suppression, insulin resistance does not drop sufficiently to keep sugar levels to “normal.” See Chaps. 3 and 12 for details.
3.
Horse stops, cart keeps moving: Reducing insulin resistance does not reduce blood sugar: In an early diabetic who has insulin resistance, hyperinsulinemia, and hyperglycemia, if insulin resistance is reduced by exercise or by insulin sensitizing drug, insulin levels drop rapidly but sugar levels do not. This paradox also has the same solution as above. Since desired glucose levels are decided by the brain sugar dynamics, when insulin resistance is forcibly reduced, insulin levels reduce to such an extent that the blood sugar level remains the same. This is an important point that can help us resolve between the old and new interpretations. But currently, data are inadequate here, and more research inputs are needed for a finer scale resolution of the events when insulin resistance is reversed.
4.
Cart starts moving before the horse: By the classical paradigm, raised blood sugar causes oxidative stress leading to endothelial dysfunction. However, early signs of endothelial dysfunction appear before overt diabetes and often without diabetes. So hyperglycemia could not be the or the only horse. On the other hand, vascular pathology can explain hyperglycemia in the new paradigm. Vascular pathology has been shown to reduce blood flow in the brain. If we include reduction in glucose transport across the brain capillaries in vascular defects, the two together cause a reduction in steady-state levels of brain glucose. This is sufficient to increase blood sugar by neuronal manipulation of insulin, glucagon, and liver. See Chaps. 3, 12, and 13 for details.
Somewhat similar is the case of β cell dysfunction and glucotoxicity. Glucotoxicity is unlikely to be the horse since without cell dysfunction, blood sugar is unlikely to rise. Here again, it is possible that the answer lies in brain glucose dynamics which needs to be explored seriously. If glucotoxicity is “real,” the sequence of events could be that hyperglycemia is caused by altered brain glucose dynamics which results in glucotoxicity leading to eventual β cell loss.
5.
Half cart forward, half cart backward: Paradoxical angiogenesis: Research papers on wound healing in diabetes have often blamed impaired angiogenesis for wound healing problems. On the other hand, diabetic nephropathy and retinopathy appear to be caused by excessive angiogenesis. Is angiogenesis reduced or increased in diabetes? The glucocentric paradigm does not explain why and how angiogenesis is affected in diabetes and further why it is affected in opposite directions in different parts of the same body. It is unlikely to be caused by raised blood sugar since the same blood supplies all organs. The new paradigm has a solution in the form of altered macrophage distribution in the body. Since macrophages are important initiators of angiogenetic pathways, wherever there is greater density of macrophages, there is hyperangiogenesis, and where it is less, there is deficient angiogenesis. See Chaps. 8 and 13 for details.
Does the new theory fulfill the expectations from an evolutionary theory? At the beginning of Chap. 4, I had expressed my expectations from a theory of evolutionary origins of diabetes. Does the emerging theory fulfill these expectations? What stand does it take on each of these issues? Let us see one by one. (1) Why a sudden rise? The sudden rise in the population in 1–2 generations is because of altered physical and social behavior. Behavioral deficiencies developed and reached an extreme only in the modern urban life, and therefore, these disorders are specific to modern life. (2) Polymorphism: When alternative behavioral strategies have negative frequency dependence, stable polymorphism is achieved. This need not always happen at the genetic level. The same principle may work at the phenotypic level too. (3) The strong association between birth weight and metabolic syndrome is explained by the new theory by the developmental constraints laid by intrauterine growth retardation. Since the growth retardation is unequal and brain is spared, diplomat strategy is a better option after IUGR. (4) An evolutionary theory should not stop at explaining the origins of obesity but also explain why obesity is associated with insulin resistance and its consequences with both proximate and ultimate components of reasoning. The emerging theory is unique in this respect since all the prior theories have talked about why a tendency to accumulate fat may be adaptive but do not proceed to explain the downstream effects of obesity, insulin resistance, and other pathophysiological processes. The new theory deals with why insulin resistance is adaptive independent of obesity, why obesity is associated with (but not the only cause of) insulin resistance, and why insulin resistance is associated with (but not necessarily causal to) other pathophysiological processes. Almost every aspect of the multitude of changes in the body is accounted for by the new theory at both ultimate and proximate level simultaneously. (5) We have seen above how almost every paradox has a plausible solution in the light of the neurobehavioral way of interpreting diabetes. (6) The new theory has raised the possibility that T2D is actually not irreversible and cure may be reasonably possible by treating behavioral deficiencies. Only carefully designed long-term studies will be able to put this claim to test. (7) Testable predictions are abundant all over the book, and many of them are simple and practicable. Researchers with different set of expertise need to work in concert to test these ideas. (8) Lastly, beyond being an evolutionary theory, it has many implications which may change clinical practice in the future if careful trials support the possible implications. Thus the neurobehavioral origins appear to fulfill all the expectations from an evolutionary theory of T2D, but more work is certainly needed to fill in the gaps in the picture and ultimately come out with strategies that will help the current-generation diabetics and prevent diabetes in the next generation.
A few questions that were not explicitly answered so far need to be answered now. First is about the age dependence of T2D. Readers might have worked out the answer already since it is implicit in Chaps. 5–9. To state it more explicitly, aggression, sex, and reproduction, the three main determinants of metabolic states, are certainly affected by age. The optimum strategies for sex and reproduction change with changing marital status, parity status, and reproductive capacity. Accompanying the change in reproductive strategy and capacity, a change in physical aggression is natural. Risk-taking behavior should decrease after having offspring at various stages of dependence. In humans, grandparental status induces further behavioral changes. It is no surprise therefore that behavioral as well as metabolic states change simultaneously with age. The rate of change is dependent on lifestyle though. In women, menopause is a major transition, and the risk of obesity, CVD, and T2D increase after menopause is consistent with this logic. Even more dramatic is the metabolic change following hysterectomy. Loss of sex hormones is an important risk factor. In men, although there is no well-defined condition comparable to menopause, a slow andropause-like condition marked by loss of testosterone is a well-recognized risk factor. It is perceivable therefore that loss of sex and aggression hormones may not be only correlated to the increased risk of T2D and related disorders, it may have a causal role.
The other possible FAQ is about the apparent heritability of diabetes. Although attempts to find a gene for T2D have failed and GWA studies have demonstrated the near impossibility of obesity and T2D being genetic, one cannot deny familial tendency in the susceptibility to T2D. This is likely to be due to epigenetic to some extent, but the possibility of extragenetic or nongenetic biological inheritance cannot be denied. For example, maternal EGF has an important role in fetal development [1–4]. We have already seen that EGF secretion is behaviorally triggered. This raises the possibility that maternal behavior affects her growth hormone levels which influences the developmental pattern of the fetus. We know that fetal development has lifetime programming effects. This can influence behavioral strategies of the progeny and when it reproduces its hormonal and growth factor levels further influence the third-generation phenotype. The EGF case is interesting because EGF specifically affects branching morphogenesis of fetal submandibular glands that are the sources of adult EGF secretion [5]. This can make EGF deficiency transgenerational. Therefore a transgenerational biological inheritance without involving genetic or epigenetic mechanisms is possible which we may call extragenetic or nongenetic inheritance. It is not impossible that there are other mechanisms with similar heritable programming effects. This inheritance, unlike true genetic inheritance, can be changed by environment or behavior within a generation or two. Such a mechanism could have evolved to support adaptive behavioral programming for social status since social hierarchies are at least partially heritable. Good correlation exists between maternal and progeny social status, and therefore, transgenerational transmission of behavioral strategies through fetal programming would be adaptive. Further, behavioral traits are passed on culturally from parents to offspring, which does not need a biological mechanism but may have biological effects. A vertical cultural inheritance mimics genetic inheritance in certain aspects. Therefore there are a number of alternative possible mechanisms that lead to familial tendencies that are not genetic. The implication of understanding that obesity and T2D are not genetic is extremely important. Blaming genes for T2D reduces the motivation for controlling or reversing the condition. When patients are given the impression that your diabetes is genetic, it is implied that it is inevitable and needs to be accepted as it is. If it is not genetic, the implication is that it can be reversed since behavioral patterns can be at least partially changed by conscious efforts.
There is one more question that is not adequately answered by either the old or the new school. That is regarding why there is a need for acute-phase insulin response (AIR). Since there are neural mechanisms involved in inducing AIR [6], it would be safe to conclude that AIR must have been a response evolved for some specific function. But what function did it evolve for? There would be a temptation to argue that it serves the function of keeping the GTT “normal.” It needs to be realized that if AIR was not there, the “normal” would have been different. Absence of AIR leads to an increase in the area under the curve of both glucose and late-phase insulin, but there is no evidence that this by itself leads to any pathological consequences. Therefore we may have considered that curve as “normal” if AIR had not evolved. There are more riddles associated with AIR for which I have no definitive answers currently. Since AIR is launched even before absorption of digested food begins, an acute insulin response should lead to a transient hypoglycemia but that does not seem to happen for some unknown reason. I suspect that AIR evolved for behavioral rather than metabolic reasons. Insulin affected rodent behavior in open-field test [7] as well as elevated plus maze test [8]. Animals administered insulin avoided being in the open and exploring. This is a sensible response from a behavioral ecology point of view. During hunting or foraging, risk-taking and exploring may be needed. The hormonal composition of the body therefore needs to be that of a risk-taker. However once some rich food is obtained, it is better to hide and be inconspicuous to avoid aggressive competitors. This is particularly true for species that can carry food to a safer place and eat. This needs a sudden change in mood, and the acute insulin response may be instrumental in mediating this change. Feeding-induced corticosteroids serve a similar purpose. If AIR evolved to serve a behavioral purpose, I presume mechanisms will have evolved to avoid accompanying hypoglycemia.
I am sure there will be more unanswered questions than the ones that have been answered so far. Certainly the new school has answered more questions than the old one, and this process has not ended.
The new paradigm is not “complete” at this stage. We can at the best say that it looks far more promising than the old one, but a number of gaps in data can still be visualized. This is not surprising. Research is driven by hypotheses. If a line of thinking does not exist, experimenters are most unlikely to collect any data to support or reject it. Very surprising is the fact that although completely new, the theory already has much evidence in support. One way available evidence can be used is to know all the existing evidence and then try to make a coherent picture out of it. But this is not how this concept evolved. Rather it evolved like the way experimental research evolves. One has a hypothesis, based on which testable predictions are defined, and then experiments are designed and performed to test the predictions. During the evolution of this theory, I made certain predictions and then looked into literature to see whether there were any data already available to test that prediction, and to my surprise, most frequently, data already existed and the predictions turned out to be true. To cite a few examples, in the very beginning of this effort, when I learned that insulin-resistant mothers have larges babies, I interpreted it as an increased investment in a fetus and following the theory of r and K selection predicted that by some mechanism the offspring number must be coming down. It could be reduced ovulation or failure of implantation or something else. At this time, I was completely unaware of the link of PCOS to insulin resistance. I was amazed to find from literature that anovulatory disorders like PCOS are commonly associated with insulin resistance. One of my students attempted a meta-analysis carefully going through literature with an expectation that all molecular signals positively correlated with aggression should have antiobesity and antidiabetic action and vice versa. This association turned out to be highly significant [9]. One of the antiobesity antidiabetes signals for which we did not find any relation to aggression was adiponectin. Here I thought if adiponectin was not related to aggression, it must be related to regulating r and K strategies of reproduction. Specifically it should increase fecundity and decrease transplacental nutrient flow. To my great amazement, some experimenters had looked at these relations, and both of them turned out to be true (Chap. 9). Thus the journey of the theory so far has happened with a hypothesis testing approach. But a large number of predictions are yet to be tested, and here I will briefly outline what I feel are the important predictions that need to be tested and also the areas where data are conspicuously missing.
It is likely that some of the data needed already exists in unpublished studies. I am aware of some unpublished results that support the new paradigm. They remained unpublished because either the investigators did not understand the relevance of the results or they found it hard to publish. One such study showed that the insulin resistance of youngsters doing nonaggressive exercise was not different from those doing no exercise. A third group doing aggressive exercise was substantially insulin sensitive as compared to both no exercise and nonaggressive exercise groups. In another study, diabetics with poor glycemic control were found to be more extrovert and socially dependent as compared to those with excellent glycemic control. The latter were significantly introvert and socially independent. A study of maternal and early childhood nutrition in relation to cognitive development reveals that after correcting for birth weight, children with higher insulin levels are better at certain cognitive tasks as compared to the ones with low insulin levels and higher insulin sensitivity. A study in Drosophila demonstrates that crowding in the larval stages gives rise to adults that are less aggressive than those coming from uncrowded environments. When I started publishing and talking about my hypotheses, I found people saying, “Oh, we did observe something like this, but we did not (or could not) publish it.” If an experimental result does not make sense in the prevalent paradigm, it is most unlikely to be published. My small sample size might be an indication that there are many more unpublished results that are of relevance to and make sense in the light of the new paradigm. We can expect that they would be published sooner or later. Much more research is nevertheless needed to fill in the existing gaps.
Major Areas of Data Voids
1.
The multidimensionality of aggression: Aggression is a very complex phenomenon, and all dimensions of it are not yet quite explored. Throughout this book, we have used aggression more or less as a black box. The reason why all aspects of the aggression syndrome are not yet clear is that aggression has been handled by behavioral ecologists, psychologists, physiologists, and neurobiologists in different ways and with different perspectives. In physiology and neurobiology experiments, often, aggression is reduced to simple stereotyped behaviors such as a resident–intruder test. In real life, there are several different contexts of aggression, and accordingly, there are several types of aggressions. All types and all contexts of aggressions are unlikely to have identical effects. Although some aggression-related physiological changes would be common, there can be substantial difference in a few others. Our understanding of such subtleties is still in the infancy. I made an attempt in Chap. 7 to account for some of the complexities of aggression physiology, but reality is bound to be much more variable and complex.
A particularly worrying information void is female aggression mechanisms. Most of our knowledge related to the physiology of aggression is based on male aggression. Aggression researchers have not paid sufficient attention to female aggression. This bias needs to be removed as fast as possible. Female aggression and dominance are important in deciding female social ranks. Maternal aggression is a female specific form of aggression. But unlike the testosterone story of male aggression where there is abundant literature, female aggression is largely a literature void.
2.
Interaction between diet, behavior, peripheral, and central mechanisms affecting insulin sensitivity and other metabolic alterations: It is adequately clear by now that neither peripheral nor central mechanisms alone are likely to give us a complete understanding of insulin resistance syndrome. There is evidence that peripheral changes such as glucose transporter levels that were thought to originate peripherally are under neuronal control [10], and the central systems take cues continuously from peripheral systems. There have been some indents into the interaction between peripheral and central mechanisms [11–17], but so far, there have not been enough insights into how the CNS modulates insulin sensitivity and other aspects of metabolism. Diet is closely linked to behavior, but this area is largely neglected so far [18]. The behavior-centric paradigm is likely to give some insights into how and why neurobehavioral mechanisms should be involved. There is a cross talk between neuronal mediators of insulin sensitivity and those involved in anxiety, exploratory behavior, aggression, and other behaviors. A study of such interactions is likely to give many leads in research, and this I presume would be an active and most fruitful field of research in the near future.
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