The protein insulin and its equivalents are widespread in the animal world including vertebrates and invertebrates. Since impairment of insulin signaling or insulin resistance is believed to be central to a cluster of deadly diseases in humans, it would be useful to look at what happens when there is impairment of insulin signaling in other animals. And here lies a very fundamental paradox. In widely different taxa of animals, including both invertebrate and vertebrates, impairment of insulin signaling has no adverse effects on health; on the contrary, it increases life span. This is one very fundamental and perplexing fact reviewed very well by Kaletsky et al. [1].

Over 20 years ago, it was discovered that mutations in daf-2 and age-1 double the life span of a nematode worm model Caenorhabditis elegans [2, 3]. Subsequent cloning of these genes uncovered the importance of the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway in aging regulation. daf-2 encodes the only insulin/IGF-1 receptor expressed in worms, and age-1 is the catalytic subunit of the downstream phosphoinositide 3-kinase (PI3K) [4, 5]. Mutations in these genes interfere with the normal insulin signaling pathway and therefore are equivalents to insulin resistance in humans. These “insulin-resistant” worms have a substantially longer life span. In addition to the overall life span extension, worms bearing either of these mutations, i.e., the insulin-resistant worms, are highly resistant to oxidative stress [6], hypoxia [7], heat [8], heavy metals [9], and bacterial pathogens [10].

The insulin/insulin-like growth factor signaling (IIS) pathway also acts as a food and stress sensor during development. When food is abundant, worms develop rapidly and uninterrupted through four larval stages to reach adulthood. If worms develop in food-limited or overcrowded conditions, they enter an alternative long-lived larval state called dauer in which reproductive maturity is delayed but resistance to environmental challenges increases. Favorable nutritional conditions promote exit from dauer which is again mediated by changes in insulin signaling pathway and development to reproductive adults [11]. The daf-2 mutants are dauer phenotype by default [12]. Both the long-lived and dauer phenotypes of daf-2 worms are dependent on the downstream forkhead transcription factor DAF-16 [2, 12, 13]. Briefly speaking, signaling through DAF-2 activates PI3K, which leads to the phosphorylation of DAF-16 and its inactivation by nuclear exclusion [14]. In the absence of IIS or in daf-2 or age-1 mutants, DAF-16 enters the nucleus and enacts a transcriptional program that doubles worm life span [10, 15–17]. Loss of daf-2 or age-1 also slows the age-related declines; thus, the insulin signaling pathway regulates longevity through its modulation of processes and pathways leading to aging.

This is not a worm story alone. Insulin signaling is an evolutionarily conserved pathway that regulates life span across many species. Drosophila melanogaster has a single insulin-like receptor (dInR) that, when mutated, extends life span in a manner that is dependent on its daf-16 homolog dFOXO or simply foxo [18]. Overexpression of dFOXO in the fat body [19] or mutation of the insulin receptor substrate protein chico extends life span in the fly [20, 21]. Mammals encode several daf-2 homologs including IGF-1 receptor (IGF-1R) and insulin receptor (IR)-A [22]. Despite these differences in insulin receptor expression, the functional consequences are similar, as reduced insulin/IGF signaling extends life span in multiple mammalian species [23, 24]. Longevity in dogs is inversely proportional to body size [25]. Interestingly, a single nucleotide polymorphism in IGF-1 is associated with small size and long life, suggesting that IIS influences aging in dogs [26]. Heterozygous IGF-1R knockout mice are long lived [27], and adipose tissue-specific insulin receptor knockout (FIRKO) mice also exhibit increases in life span [28, 29].

In mammals, there are some counterexamples where low insulin production and insulin sensitivity are associated with long life. Naked mole rats, known for their exceptionally long life spans, are insulin sensitive [30]. Recent studies suggest that IIS and aging are linked processes in mammals and specifically humans as well. But there appears to be a contradiction in the direction of the association. It is well known that insulin resistance is associated with a large cluster of disorders, many of which are fatal and therefore should reduce life span. Insulin sensitivity is a common feature of centenarians. Mutations in a human daf-16 homolog, FOXO3a, are linked to increased longevity [31–33]. Long-lived men who are homozygous for the FOXO3a GG genotype also display greater insulin sensitivity [31]. Therefore it may appear that insulin sensitivity rather than insulin resistance is the key to longevity in humans. We may conclude that sometime in evolution, the relationship might have turned upside down.

But unfortunately this inference is not so straightforward. Other pieces of evidence point to the possibility that similar to worms and flies, insulin resistance increases life span in humans too. IGF-1R mutations are highly represented in populations of centenarians [34] indicating impaired IIS associated with long life. Of particular importance is the gene called Klotho known to be a longevity gene in mammals [35]. Klotho, the gene coding for a transmembrane enzyme, was discovered in 1997. Overexpression of this gene increases life span, and mutants with impaired expression age prematurely. It was therefore named after one of the three Greek Moirae or fate called Clotho that weaves the thread of life. It was soon discovered that Klotho increases life span by inducing insulin resistance. Klotho induces adipocyte differentiation [36], lipogenesis [37], and insulin resistance [38, 39]. Contrasting with this stands out the fact that Klotho increases life span substantially. There are two different paradoxes here. First is that although almost every model of longevity extension involves insulin signaling, the direction appears confusing. In some examples longevity is associated with increased insulin sensitivity and in other models insulin resistance. The emerging solution to the paradox is that it is reduction in insulin signaling at a subcellular level that increases life span. This can be achieved either by lower levels of insulin or by reducing the sensitivity to insulin. If this turns out to be true, no real paradox is left since in long-lived phenotypes that are insulin sensitive such as naked mole rat, insulin production is indeed very low.

The concept of insulin resistance increasing life span is actually theoretically very sound at both proximate and ultimate levels. We have argued before that insulin resistance is a mechanism of modifying reproductive strategies to adapt to the demography and environment. Typical r reproductive strategy is insulin sensitive, and K reproductive strategy is insulin resistant. As a broad generalization across species, K-selected species are generally long lived as compared to r-selected species. We do not know whether this would be true for reproductive strategies within a species as well. But theoretically it should and therefore insulin-resistant individuals should be long lived as expected by life history theories. It is interesting to note that although the Klotho protein is essential for fertility, as demonstrated by infertility of Klotho knockouts [40], Klotho overexpression actually reduces fecundity [41]. Also note that placenta produces Klotho protein [42] which by inducing insulin resistance can draw more glucose through the placenta. Therefore Klotho appears to be the ideal K reproduction mechanism, one that increases longevity, reduces fecundity, and increases transplacental investment in the fetus through insulin resistance.

Insulin is a growth hormone during developmental period [43, 44]. Insulin has modulating effects on reproductive strategies [45–48], and insulin is an important modulator of life span as seen above. All three are important parameters of life history evolution. This means that insulin is the chief mediator of life history strategies. Being a fine-tuner of aggressive behavior, it also serves the function of selecting behavioral strategies for an individual. Aggression cannot be separated from life history strategies. Presence of predators is well known to shape life history strategies. Having aggressive competitors would play a role similar to predators. Since both predation and aggression increase the probability of death, life histories will tend more towards r and away from K. Therefore, insulin’s role in aggression cannot be separated from its role in life history strategies. This appears to be the main role of insulin conserved across simple to complex animal taxa. Insulin’s role in glucose homeostasis is only a small part of this bigger role. Just because insulin’s role in glucose homeostasis was discovered earlier, medicine believed that that was the primary function of insulin. An evolutionary perspective shows that this is a grossly incomplete and biased view. Understanding insulin’s function on a broader canvas can certainly deepen our understanding about insulin and thereby give us greater insights into diabetes too. Without understanding life history strategies and life sustenance strategies, it is impossible to understand insulin. Traditional medicine has been doing precisely this mistake so far and that must have contributed to the overall failure to prevent, control, or cure diabetes.

This leads us to the other paradox. How is insulin resistance associated with increased life span when it leads to so many deadly disorders? Here, once again, Klotho shows the way out. The paradox gets resolved when we look at the other metabolic and endocrine effects of Klotho. Klotho has anti-inflammatory effect [49], proangiogenic action [50], proendothelial function [51], and antioxidant activity [52]. We have seen earlier and will elaborate once again below that inflammatory changes, endothelial dysfunction, angiogenesis dysfunction, and oxidative damage are the main pathophysiological mechanisms of T2D. The prevalent perception is that insulin resistance or hyperglycemia is the driver of these pathological effects. Since in diabetes insulin resistance and/or hyperglycemia is invariably coupled with its pathophysiological mechanisms, the association has been assumed to be mandatory. A fundamental conceptual revision that Klotho has necessitated is that the association is not mandatory. Here is a mechanism in the form of Klotho protein that can decouple obesity and insulin resistance from the true pathological mechanisms of systemic inflammation, endothelial and angiogenesis dysfunction, and oxidative damages. Having thus decoupled, insulin resistance appears to increase longevity.

The inference that one can draw from Klotho research is that insulin resistance is not sufficient to drive the pathophysiological mechanisms of T2D. The real pathological drivers are different. In fact insulin resistance may be good for health if there is a way to decouple it from the true pathological drivers. Klotho is certainly an effective decoupler, but perhaps there can be other mechanisms too. Once we know that such a decoupling is possible in principle, researchers can speci­fically look for other mechanisms. The decoupling also means that if the pathophysiological mechanisms are not targeted, targeting insulin resistance will be ineffective as a strategy for the treatment of T2D. It may appear to normalize blood sugar temporarily but is most unlikely to cure diabetes because insulin resistance is not central to the pathophysiology of diabetes at all. Insulin resistance is the target for the mainstream pharmacological R&D in search of a wonder drug against T2D. A generation of insulin-sensitizing drugs is already in the market and being used commonly, but T2D remains an “incurable” disorder. This is because all our efforts are not only beating around the bush but beating around the wrong bush. Although insulin resistance is central to the behavioral transition from soldier to diplomat, it is not likely to be the root cause of T2D and related pathology, and therefore, targeting insulin resistance will never cure diabetes.

The orthodox paradigm has revolved only around glucose and insulin and as a result may have completely misled medicine for decades together. Plasma glucose is an important parameter in diagnosis, and it will remain so for some more time. However, doubts can be raised about its value as an indicator of the effect of treatment and a predictor of pathological complications. First of all one should differentiate between hyperglycemia and diabetes. Hyperglycemia is only one of the symptoms of diabetes. The current treatment regime has the sole aim of normalizing plasma glucose, and therefore, it does not really treat diabetes. All that it can control is hyperglycemia. There is a strong prevalent belief that controlling sugar levels are sufficient to prevent all types of diabetic complications. Evidence is not completely in favor, and therefore, this postulate needs to be critically reexamined as we have discussed earlier (Chap. 3).

The paradigm that hyperglycemia is the root of all pathophysiology of T2D is an old one and has been there with us for several decades. Interestingly, in spite of decades of research, the mechanisms by which glucose can bring about wound-healing problems, peripheral neuropathy, endothelial dysfunction, and erectile dysfunction have never been clearly and completely worked out. All that we have are some incompletely worked out mechanisms, some other hypotheses that were never put to test, and some prevalent beliefs that are not even worth calling hypotheses. As a good example of the latter, it was believed that increased sugar encourages bacterial growth, and therefore, wound healing is difficult and infections are more common in diabetes. However, honey has been traditionally used as a wound-healing agent, and a number of careful studies have reproducibly demonstrated the wound-healing properties of honey [53, 54]. Here is an example of high sugar concentration not interfering in wound healing. Why should sugar interfere in wound healing only in diabetes? But this is a story that is popularly believed in the layman’s circle, and even some practicing physicians seem to subscribe to it though fortunately not many researchers.

Glucose is proposed to cause a series of pathological changes through proposed mechanisms that we saw in Chap. 2. This is the current mainstream thinking. But the Klotho story suggests something else. Impaired Klotho pathway can give rise to a phenotype which is lean, insulin sensitive, and normoglycemic but shows rapid age-related degenerative changes including oxidative damage, chronic systemic inflammation, and vascular problems similar to those in diabetes. Since the pathological components of T2D such as inflammatory changes, oxidative excess, and endothelial and angiogenesis dysfunctions can be demonstrably decoupled from glucose homeostasis mechanisms, they are likely to have origins independent of glucose levels. This could imply that these pathological processes could also be ameliorated without worrying about glycemic control.

In order to elaborate on the possibility of glucose-independent origins of diabetic pathology, I will put together several pieces of evidence for the same set of pathological changes being caused by behavior-driven pathways. These alternative pathways work independent of sugar but are not incompatible with the sugar-driven pathways. We will see the alternative pathways first and then think of any convergence or contradiction between the behavior-driven and glucose-driven pathways.

This new landscape of behavior-driven pathology is more complex than the orthodox picture but much more realistic and evidence based. Although there are still some loose ends left where more research is needed, it is much more detailed than the orthodox one. Here the root of all pathophysiology lies in brain and behavior, not blood sugar. The brain and endocrine systems of a soldier-deficient or supernormal diplomat phenotype send independent signals that bring about simultaneous changes in (1) sex and aggression signals; (2) insulin secretion; (3) fat accumulation; (4) immune redistribution; (5) disinvestment from wound healing and angiogenesis mechanisms; (6) deficiencies of EGF, NGF, BDNF, and many other growth factors; and (7) deficiency of erythropoietin (Fig. 13.1). We have already seen the origin of these alterations at both ultimate and proximate levels, but a brief reiteration would be appropriate. Long-term absence of aggressive encounters reduces levels of aggression signals including testosterone. Higher insulin levels are needed by the brain to provide for the greater demand for cognitive functions. This is mediated by the parasympathetic stimulation of pancreas. High insulin activity induces fat accumulation. The reduced frequency as well as reduced anticipation of injuries leads to disinvestment from wound healing and angiogenesis mechanisms as well as accumulating deficiency of erythropoietin and growth factors. Reduced injuries along with increased levels of adipokines mediate redistribution of macrophages. The seven primary changes are partially independent but have interactions and mechanisms reinforcing each other. For example, testosterone deficiency facilitates adiposity and arrests EGF synthesis. Adipose tissue facilitates altered distribution of macrophages and so on. However I will still call all seven processes primary since they can also originate independently in the absence of others.

These half a dozen primary processes stemming independently from a common neurobehavioral origin trigger a chain of processes downstream (Fig. 13.1). Downstream to hyperinsulinemia, signals from adipose tissue, pancreas, and perhaps brain induce compensatory insulin resistance. Disinvestment from angiogenesis reduces capillary density which also reduces glucose uptake by muscle and other tissues contributing to insulin resistance. Immune redistribution leads to vascular and systemic inflammatory changes as well as oxidative excesses. Deficiency of EGF and other growth factors leads to progressive β cell loss [55, 56]. Reduced insulin levels lead to disinvestment from muscle on the one hand and increased plasma glucose on the other. As a result of disinvestment from muscle, soldier behavior becomes increasingly impossible, and this reinforces diplomat behavior completing the circle and thereby stabilizing the state.

The emerging alternative picture can explain each of the diabetic complications with a sound logic and substantial support from available evidence, although these hypotheses still remain to be tested directly.

All the glucose-independent pathophysiological pathways proposed above are evidence based in the sense that every component of these processes has been demonstrated in the cited references. So far this work was piecemeal, and I have tried to put the pieces together to construct a coherent picture. Admittedly evidence for every step is not necessarily evidence for a ladder. But this is where more research is needed.

Agreeably there is evidence for hyperglycemia-driven pathology too. These pathways mainly involve alterations in NO expression, oxidative damages, and AGE-RAGE pathways (see Chap. 2 for details). If two alternative pictures explain the same pathology, we need some ways to resolve between the two. For example, oxidative state is implicated in both but the proposed origin of free radicals is different. This can possibly help us in resolving between the two hypotheses. By the glucose-driven view, oxidative state originates from glucose loading of cell respiratory mechanisms. Glucose loading is unlikely to happen in insulin-resistant cells but can happen in insulin-independent cells. On the other hand macrophage-driven oxidative stress will be distributed according to the distribution of macrophages. This suggests a differential testable prediction. If glucocentric hypothesis is true, insulin-independent tissues such as brain and endothelium should generate almost all the free radicals. If the macrophage hypothesis is true, origin of free radicals should be in tissues where macrophages accumulate. Macrophages accumulate in adipose tissue and vascular endothelium. Since vascular endothelium is common for both, it does not help in resolving. Adipose tissue-related predictions are in the opposite directions and therefore would be useful. Since adipose tissue is insulin dependent, it will not experience intracellular glucose excess and thereby a respiratory burst leading to free radical generation if the glucose hypothesis is correct. However since adipose tissue attracts macrophages in large numbers, it will have macrophage-generated free radicals if the alternative hypothesis is correct. If adipose tissues in T2D generate little free radicals, glucocentric hypothesis would be supported, and if adipose tissue generates larger amounts of free radicals, the macrophage hypothesis gets greater support. As we know today adipose tissue does generate substantial oxidative excess from an early stage and arresting oxidative stress in adipose tissue prevents shift of the adipokine imbalance towards proinflammatory state [114, 115]. Therefore oxidative stress in adipose tissue seems to matter, but a sound quantitative experimental comparison across different tissues would be more helpful. I expect in reality both the pathways could be contributing to pathology, but it is important to evaluate their relative roles since that can have important clinical implications.

There is another possible way in which the behavior-driven and glucose-driven pathways could be interacting. The hyperglycemia-driven pathways lead to oxidatively damaged proteins and cells, accumulation of AGEs, and AGE-driven protein damage. However, there is a rate at which damaged proteins and cells are being replaced in normal life. The effects of these damages need to be weighed against the rate of replacement of damaged components. In diabetes there is evidence that the rate of replacement is reduced. For example, the rate of formation of endothelial progenitor cells is reduced in diabetes [116]. This overall reduction is likely to be behavior driven since testosterone [117–119], estrogens [120–123], erythropoietin [124–129], and other behavioral signal molecules play a role in proliferation and mobilization of endothelial progenitor cells. EGF and other growth factors are needed for tissue regeneration. Testosterone, oxytocin, and some other behavioral signals promote protein synthesis. Therefore it is likely that these pathways stimulated by physical activity and aggression may effectively compensate the hyperglycemia-induced damages by replacing damaged cell components, cells, or tissues. Similarly even if we assume that hyperglycemia is the only source of oxidative radicals, antioxidant activity triggered by aggression can take care of it at least partially. Since aggression anticipates injuries and macrophages activated by injuries produce free radicals to kill bacteria, it is necessary to increase antioxidant capacity in anticipation. Therefore aggression should streng­then antioxidant defenses. Not surprisingly testosterone and estradiol have antioxidant actions [130–133], and physical exercise and aggression appears to have some testosterone-independent effect on antioxidant capacity [134–136]. If this is true it may be possible to prevent and perhaps reverse the hyperglycemia-induced pathophysiological processes by aggressive exercise even without tight glycemic control. This is a theoretical possibility currently but is testable and needs to be put to test sooner.

The two most important possible implications of the alternative pathophysiological pathways are that (1) even if raised blood sugar is demonstrated to cause some of the pathological effects, that is not sufficient to say that controlling sugar will eliminate them. Since the rise in blood sugar is associated with disinvestment from muscle and thereby loss of aggression, one would see an apparent effect of raised sugar on the behavior-driven pathophysiological mechanisms. But now, if sugar is controlled but behavior remains the same, we may not expect a mitigation of the pathophysiology. (2) If behavior is corrected appropriately, then even if sugar levels remain moderately higher, pathology can be prevented.

Partial support to the latter exists in literature on the effects of exercises. Exercises can bring about improvements in a number of functions without, before or independent of, improvement in glycemic control. Exercise increases growth factor and neurotrophin levels [137–142], improves angiogenesis [143], increases antioxidant enzymes in muscle [135, 144, 145], and enhances endothelial function [146], all independent of blood sugar levels.

The emerging alternative picture implies the need to drift away from glucocentric thinking. This is the basic inferential difference between the two models. In the orthodox model, since all pathologies are rooted in hyperglycemia, treating hyperglycemia is all that one needs to do. This is not so in the alternative picture. According to the alternative picture too, hyperglycemia can lead to pathological effects since it affects behavior and the behavioral change can result into downstream pathologies. However, in this model, controlling sugar will not mitigate complications if the behavior remains unchanged. On the other hand if the behavior is corrected or supplemented appropriately, as we will discuss in the coming chapter, pathological effects can be prevented even without normalizing glucose levels.

I have no intention to state that it is not important to control sugar, but the important point is that sole emphasis on sugar control is not sufficient. To be conservative, treatment aimed towards moderate control of glucose should continue until we have a proven alternative effective therapy against the true pathological processes of diabetes. At the same time research should focus on understanding and arresting the true pathological mediators of diabetes.

Finally we need to address the question of “incurability” of T2D here. The major depressive factor of diabetes for a patient is the understanding that he or she is a patient for life. One can never come out of diabetes. What one can do at the most is to prevent it from escalating. Unfortunately this too does not work in all cases. Glycemic control keeps on deteriorating slowly even in patients with good compliance to treatment.

A disease can be incurable for two reasons. One being that the disease causes some irreversible changes. There are many examples of this. Mammals have lost retinal regeneration capacity which lower vertebrates have. Therefore, in mammals, retinal damage is irreversible. In poliomyelitis, the viral infection can be cured but paralysis caused by the infection is irreversible and leads to lifetime disability. Is diabetes incurable because of some such irreversible changes?

It has been believed for a long time that β cell loss is irreversible. Therefore, by the popular belief, insulin resistance can be reversed, but once the progressive β cell loss begins, it cannot be reversed. However, unlike retina, we have not lost the capacity to regenerate β cells. There have been clear and reproducible demonstrations that β cells have good regeneration capacity, and this can happen by two alternative means. The β cells themselves can replicate or they can be generated from the acinar and ductal endothelial cells [147–152]. This means that as long as pancreatic tissue exists, β cells can regenerate. There is some evidence that even in autoimmune type 1 diabetes, β cells are continuously being regenerated [153, 154], although the rate of autoimmune destruction supersedes the rate of regeneration. In streptozotocin-treated rats, at least partial regeneration of β cells has been successfully brought about under the influence of EGF and gastrin [155, 156]. Therefore it is unlikely that β cell loss is irreversible. Perhaps we have failed to identify the appropriate internal environment needed for the growth of β cells. Although research on in vitro propagation of β cells for generation of functional islets from stem cells has not given us viable therapy options, it played an important role in recognizing the complex growth factor requirement for β cell growth.

Apart from EGF, a large number of other growth factors are now known to be required for β cell growth. The list may not be complete as yet, but interestingly, all the factors listed so far also have active roles in wound healing too. Insulin, IGF1, and IGF2 are important in β cell proliferation and preventing apoptosis [157–161], both IGFs are active in wound healing and also synthesized locally at the wound site [162–165]. Insulin itself has a beneficial action in wound healing [166]. Other growth factors that are involved in both β cell regeneration and wound healing are PDGF and FGF [167–169], HGF [148, 170–174], NGF [175–177], growth hormone [178–180], prolactin and placental lactogen [147, 180, 181], PTHrP [147, 182–184], gastrin [155, 156, 185], GRP [186], glucagon-like peptide [187–189], activin [190, 191], and betacellulin [148, 192]. Not only are these factors required in wound healing, most of them are synthesized systemically or locally at the site of wound after injury [172]. For the factors that are synthesized locally, some spillover in circulation is inevitable. It makes sense for the wound-healing growth factors to help β cell function since insulin itself is needed for wound healing. This raises the possibility that a chronically non-injury-prone lifestyle creates a deficiency of one or more of these factors affecting β cell regeneration. Interestingly two immunosuppressive agents that were used in the Edmonton protocol to prevent immune damage to transplanted β cells have now been shown to prevent natural β cell regeneration [150]. This is very likely to be related to the suppression of wound-healing mechanisms that the two agents are known to bring about [193–196]. Therefore the causes of impairment of wound healing and failure of effective β cell regeneration in diabetes appear to have much in common. This raises the possibility that the factors that would normalize β cell regeneration in diabetes will be identified in the near future, and a growth factor cocktail might turn out to be effective. But it is equally or perhaps more likely that behavioral intervention to stimulate growth factors and wound-healing mechanisms may work better. It is already known that two behaviors, namely, aggression and adventure, that anticipate injuries induce secretion of some of the growth factors. There are no studies on whether there is behavioral stimulation of all other growth factors, but one should expect it logically. If that is true, the right cocktail could be internally generated, and islet degeneration might be substantially reversed. If β cell loss can be reversed, then except for extremely advanced stages of diabetic complications, particularly retinopathy and nephropathy, there do not appear to be any truly irreversible changes involved in diabetes.