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Metabolic syndrome – A truly psychosomatic disorder? A global hypothesis
Medical Hypotheses 97 (2016) 46–53
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Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Metabolic syndrome – A truly psychosomatic disorder? A global hypothesis Shrikant Madhukar Ghike ME [Chem Engg] CE & PD Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
a r t i c l e
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Article history: Received 28 April 2016 Revised 5 September 2016 Accepted 19 October 2016
Keywords: Clinical psychiatry Metabolic syndrome Cardio vascular disease Hyperglycaemia Type 2 diabetes mellitus Lactic acidosis
a b s t r a c t Exact cause of the metabolic syndrome [MS], a global epidemic, is still unclear. Man has same fundamental needs to live as animals but modern man’s life-style compels him to acquire certainty of resources for all his needs in a complex social network. Today money has become the sole life essential need. Contrarily none of the animals needs to earn money. Brain is also an organ of the human body with a unique thought process to define logical actions to achieve a person’s goals. This way life is a flow of desires followed by logical actions. The person struggles to attain desired goals via the allostatic load but a perceived insurmountable threat can make his flow of life stalled to freeze him. Published data from varied branches of medical science indicates role of hormones in overall homeostasis. Particularly multifaceted role of serotonin is well documented. Adrenalin being the primary mediator of Cori cycle is also well known. From the integration of observations from published data with reference to common human’s modern lifestyle, it is hypothesized that a perceived trapped situation in life creates acute chaos of thoughts in brain, which results in acute excess of stress hormones and concurrent depletion of resting hormones, which in turn triggers MS. In global terms, MS indicates an acute imbalance of a few hormones and implies psychosomatic roots of the disorder. This may pave a better way in deciding a personalized holistic protocol with combination of counter regulatory psychoactive medications. Ó 2016 Elsevier Ltd. All rights reserved.
Introduction World Health Organization (WHO) celebrated its birthday on 7 April 2016 – World Health Day, with a call to action to beat diabetes. As per the fact sheet on WHO website [1], the global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014, corresponding to a huge 422 million population. The collection of metabolic abnormalities including central obesity, decreased high-density cholesterol (HDL-C), elevated low-density cholesterol [LDL-C] and triglycerides, hypertension (BP), hyperglycaemia/insulin resistance, inflammatory response is known as the metabolic syndrome [MS]. Associated with a three fold and 2-fold increase in type 2 diabetes and cardiovascular disease (CVD), respectively, it is thought to be a driver of the modern day epidemics of diabetes and CVD and has become a major public health challenge around the world [2]. Across many theories and postulates still a confusion exists on exact cause-effect diagram for MS. Unambiguous evidence on the
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initial stages of disease is missing, making it difficult to pin down the causes at the cellular and molecular level. Some consider it as impaired glucose metabolism while some consider it impaired lipid metabolism [3]. Therefore the treatment protocols only aim to manage the disorder over a lifetime and reversal is yet quite difficult.
The hypothesis I propose an overall hypothesis that during his intense struggle under allostatic load, today’s man faces a ‘‘freeze” or ‘‘doomed to failure” life situation in which both fight and flight response can pose similarly severe threats and loss. However, the person’s intense battle to remove the stressor results in an acute chaos of alternating thoughts of fight or flight in his brain. This causes great confusion and an acute imbalance of hormones, which triggers MS. This directly indicates psychosomatic roots of MS. I further hypothesize that it is not just the measurable and observable individual hormones but also the ratio of resting hormones to that of stress hormones and their correlation with body symptoms like blood
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pressure and blood glucose levels, which can play a key role in understanding the homeostatic/allostatic, or MS status of an individual. The first step is a brief review of homeostasis, risk factors and hormones followed by multiple pathways of some hormones. Then I present the supporting data/information from select references on known risk factors for MS. This is followed by a comparison of natural animals’ life with that of modern man to arrive conceptually at the stress he suffers during his intellectual struggle in today’s money-centred socio-economic setup. The collective observations from this overall background lead to the main hypothesis. Then I have discussed the implications in terms of apparent symptoms and their correlation with observable hormone levels to arrive at the homeostatic/allostatic status of individual patient. Evaluation of hypothesis Homeostasis & risk factors for MS In general, we know that man’s diet, physical activity profile and various hormones play a key role in maintaining the homeostasis of his body. The risk factors widely recognized for MS are a) Obesity indicating unhealthy diet & lack of physical activity, b) Cholesterol: High concentration of Low density lipids [LDL] compared to high density lipids [HDL] in blood, c) Stress, d) Heredity and e) Genetic predisposition. Heredity & genetic predisposition are not in control of any human so; I have sidelined it for this study. Diet, exercise & cholesterol Role of diet in health is very well proven. A diet rich in fibre appears to reduce the cholesterol [4]. O’Connor et al., demonstrated that including dairy products in diet appear to reduce the insulin resistance [5]. A study has found that young, overweight adults who consume high amounts of dairy products have a reduced risk of developing insulin resistance syndrome (IRS) [6]. Role of exercise in homeostasis does not need more elaboration. Human micro biota Millions of microbes live inside and on the surface of each person; with some estimates suggesting that microbes outnumber human cells about 10 to 1 [7]. Researchers demonstrated that colonizing germ-free mice with the intestinal micro biome from obese mice led to an increased total body fat in the recipient mice without change in diet [8]. Individuals with a low bacterial richness were characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals [9]. Hormone pathways in human body Human body has a precise self regulatory fuel [food] consumption and energy production mechanism governed automatically by the hormones and neurotransmitters in the autonomic nervous system [ANS]. The sympathetic and parasympathetic branches of autonomic nervous system continuously regulate complete heart/ breathing function as well as the energy homeostasis in a healthy body. The gastrointestinal tract is the largest endocrine organ in
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the body which controls the digestive function. At cellular level the body maintains glucose-homeostasis through a slow but highly efficient aerobic respiration creating almost 30 mol of ATP per glucose molecule. Major hormones, which regulate the metabolism as well as mood and behavioural aspects of a human, are Oxytocin, Vasopressin, Serotonin, Dopamine, Norepinephrine, Epinephrine, Cortisol/Glucocorticoids and Acetylcholine. Off these, Serotonin [Anger & mood modulator], Oxytocin & Vasopressin [Bonding] and Acetylcholine [Slow down body processes] are pleasure and rest providing hormones while, Dopamine [Motivator], Norepinephrine [Excitement inducer], Epinephrine [Main fight /flight response inducer] and Cortisol [released in response to stress and low blood-glucose concentration.] are stress hormones. We know that all these hormones, steroids, neuropeptides etc work as a harmonious orchestra in a healthy human body. Hormones’ dual pathways Some critical hormones appear to express multiple pathways in brain and body. For instance, Oxytocin improves trust and faith. [10]. Intranasal administration of oxytocin increases envy and gloating [11], Plasma oxytocin enhances glucose uptake by skeletal muscles [12]. Dopamine can activate either reward seeking or punishment expecting neuronal network in the brain [13]. Dopamine D2like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion [14]. Acute dopamine depletion reduces peripheral insulin sensitivity in healthy men [15]. Serotonin It was best known as a neurotransmitter that modulates brain’s neural activity and a wide range of neuropsychological processes like mood, perception, reward, anger, aggression, appetite, memory, sexuality, etc. However, 90% of total serotonin is found outside the central nervous system. The advances now clearly indicate that in addition to the neuropsychiatric processes, serotonin plays a major role in almost all of the functions of the body [16]. For instance, serotonin mediates control of vascular resistance, blood pressure, haemostasis and platelet function [17]. Therefore selective serotonin reuptake inhibitors [SSRIs] treatment may enhance serotonin transporter activity from plasma into the platelets leading to prevention of thrombosis in arteries and so the acute MI [18]. Paulmann et al., conducted animal studies to show that serotonylation of intracellular proteins in pancreatic beta cells modulate insulin secretion [19]. Serotonin’s role in glucose metabolism via a 5HT-4 receptor agonist [20], and 5-HT2C [21] is also known. Stress hormones All the stress hormones are synthesized from normal dietary precursor Phenylalanine by route [22] as shown in Fig. 1 In terms of chemistry, whole reaction pathway has the nature of a classical sequential series reaction, which implies that concentration of these in body will depend on the rates of these individual reactions. Stress factor Surwit and Schneider have indicated that ‘‘Stress” has long been suspected to have major effects on metabolic activity [23]. Stress is a potential contributor to chronic hyperglycemia in diabetes,
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Fig. 1. Catecholamines biosynthesis route, [22].
although its exact role is unclear. They have inferred from studies that behavioural or pharmacologic intervention to manage stress may contribute significantly to the treatment of patients already suffering from diabetes. Batch et al. have provided an excellent review with various stress studies on animal as well as human subjects but has concluded that although pharmacological and behavioural therapies can be useful in management of established diabetes, there is little convincing evidence that stress contributes directly to the pathophysiology of the disease [24]. Lustman et al., concluded in a pharmacological intervention with Alprazolam treatment of anxious patients with poorly controlled diabetes may result in decreased anxiety and improved glucose regulation through independent mechanisms [25]. Fink, has provided an elaborate review of the term ‘‘Stress”[26]. Right from Hans Selye’s pioneering efforts on stress and Generalized Adaptation Syndrome [GAS] followed by Eustress and Destress, we find the work of Sterling and Eyer [27], McEwen [28], and McEwen and Wingfield [29] who laid the foundation of the allostasis and allostatic load theories. Allostasis proposes a reset on all body parameters to a new set point outside the normal. The main hormonal mediators of the stress response in this situation are cortisol and epinephrine (adrenaline). McEwen and Wingfield have also proposed a chronic allostatic overload of type 2, which results in different pathophysiologies [29]. Stress studies on different species of monkeys – the social animals- clearly indicate that the most dominated of them [subordinates] undergo a psychosocial stress of subordination leading to increased consumption of calorically dense foods [30]. Wilson et al. demonstrated that such monkeys show reduced glucocorticoid negative feedback and higher frequencies of anxiety-like behaviour [31]. They hyper secrete cortisol. Shivley et al., have concluded that chronic, low-intensity social stress may result in depression in susceptible individuals [32].
Man & animal’s life Since MS is a ‘‘Life-Style Disorder”, it becomes imperative to review the ‘‘life style” of the modern man. Man being primarily an animal; let us first compare the life of natural animals with man. Human beings are a part of the animal kingdom on this earth. Basic needs of any animal to live are air, water, food, sleep, reproduction and the ‘‘threat” induced alertness to either fight or flight. Man has very similar needs to live. Historically we can imagine that man started living in groups of people and later invented farming. Division of labour resulted into interdependence of humans in the family as well as social setup. Man’s unique intellect and curiosity brought the technological advances and an excellent level of comfort. The civilization has substantially reduced direct threat to his life from wild animals, and many other external dangers. At the same time, modern man’s life is a cascade of desires followed by intellectual/logical to result in physical struggle to fulfil those. [Here, even brainwork also can be termed as physical struggle.] The family setup not only provides the man the emotional security but also provides him a social identity and stability. Normally a human grows up under the care of parents. Then he gets married and settles his own family, grows his own children and the cycle continues from generation to generation indefinitely. In today’s socio-economic system, life essential needs namely air, water are almost free and the emotional needs like love, affection, care, in a family setup are priceless. However, the resources to fulfil all the other needs and desires must be bought only by money. Man has to continuously struggle to earn requisite money to buy resources for essential needs first and then for a better living.
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His struggle involves a race with stringent targets and deadlines resulting either in rewards or punishment-again in terms of money. Many a times, just maintaining the current job/cash inflow itself is a reward. Even an inkling of an uncertainty in his primary source of bread and butter, can generate a huge surge of worry, anxiety, and panic in a man’s life. Man & animals – Difference None of the other animal needs to earn money. The modern man lives a ‘‘money-centred” & logical/intellectual life otherwise quite secured from external threats while, all animals still live the natural life and struggle for just life-essential needs. Most critically, the animals spontaneously express their feelings physically. For instance, a lion instantaneously roars to warn that encroacher in his territory. His next step is a natural physical assault. But, at any extent of anger [for Fight] as well as fright [for Flight], contrarily the civilized man is taught to suppress emotions and to utilize only logical means to resolve the issues, involving neither physical attack nor physical runaway. In all situations of struggle, any animal’s body parameters must reset as a part of his reaction to the threat in terms of flight or fight. [Both situations need a sudden surge of energy in the skeletal muscles.] Even if the lion/tiger looses, it will let go that deer, relax/ regain its body parameters and would restart its hunt for another prey for its need of food with a new hope. Same can be expressed from the side of that deer. As such, no scientific proof is available, as to what happens to these parameters of a deer’s body at the moment it is trapped/ immobilized by a tiger. In this event, the deer can neither fight nor can it run away. It has to normally accept its end of life. Modern man’s social existence Since the interdependence of man within today’s complex social network is inevitable, every modern man must adapt to a chain of command primarily for his life essential needs and adapt to family’s, other peoples’, organizations’, society’s as well as government’s demands/objectives. This also creates dominance. And each individual within this chain is dominated by somebody and also dominates somebody. For instance, today’s man is compelled to accept working in shifts at factories, airports, railways, etc, only to earn his life-essential needs. Herochova elaborates the influence of shift-work on human physiology and suggests good methods to adapt to this stress on his circadian rhythm. [33]. Man’s emotions and feelings McEwen & Wingfield in a review [29] have pointed out very well documented references on influence of man’s emotions like anger/hostility and depression on CVD and Myocardial Infarction (MI) [34–37]. When his struggle ends on a success, man experiences positive emotions like happy, joyful, bliss, calm, tranquil, relaxed, contented, affection, love, security, excitement, empathy, sense of some achievement etc. While when his struggle ends up on a failure against his desires, he feels one or more of the negative emotions like worry, tension, anxiety, apathy, agony, disgust, fear, guilt, embarrassment, defeat, pity, panic, nervousness, and helplessness. Negative events either in family situations, or in job & financial situations or in social situations can result in various negative emotions in a human. All these events relate directly with certainty and stability. After a cooling off period, he is compelled to first logically identify the cause, then either struggle to remove that bottleneck or to follow
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an alternative path to regain his efforts or adapt to the situation and change his own life-style suitably. A ‘‘freeze” or ‘‘stalled life” situation However, no human really loves to lose his liberties of free will. Against this, he adapts to various hierarchies with a hope that he, by some way he would still fulfil the desire to exercise his free will. This fact well validates the allostatic load theory. During this chronic struggle, just like an immobilized deer, modern man also can face such an event in his life, which is extremely unfavourable against his critical aims. In such a lock in, he can neither fight nor flight! He senses that he is trapped in such a ‘‘doomed to failure” mess that, a) His goal is now unreachable. b) Any more struggle is futile and useless or has a corresponding stark threat. c) He has to now just accept the biggest defeat in his struggle. d) Now he has to adapt to a new life style against his own will and compulsorily live just suffering until his end. Considerable progress has been made over the past 20 years in relating specific circuits of the brain to emotional functions. The major conclusion from studies of fear conditioning is that the amygdala plays critical role in linking external stimuli to defence responses [38]. The amygdala’s influence on episodic memory is also tied to physiological arousal. [39]. All memories arouse respective emotions of the man. My own experience 1. I took up a research project in 2010. I anticipated a reward of promotion with certainty of resources for my family in the end from the success. Almost 300 experiments in a series until June 2011 completely failed. During this period my weight increased from 65 kg to 82 kg, the routine medical checkups indeed branded me to be overweight with low HDL-C, and high LDL-C/triglycerides, but absolutely normal BP and blood sugar levels. Thus, I was living in an allostatic load state. On last failure the I perceived the legal trap of contractual commitments and anticipated the stark threat of the repercussions on my future as: Punishment-1: To adapt to a thankless strenuous routine of court visits to address legal issues anticipated from client. Punishment-2: Anticipated negative appraisal and loss of promotion Punishment-3:To get distracted from own desired life Huge sense of defeat and loss of confidence. At this juncture, my weight reduced from 82 kg to 72 kg within just about a week. During the logical adaptation stage, I reviewed and identified the causes to conclude that I must fulfil the commitment. But, on the other hand, I had just run out of all options to do so. Here I experienced extreme anger, panic-stricken anxiety as well as helplessness at a time in this ‘‘No Go” situation. I experienced all those symptoms like hypertension, proteinurea [a slimy albuninous discharge in urine], dizziness, confusion, swollen and painful feet and hot impacts in head etc. My blood glucose levels shot to 357 mg/dl Fasting and 467 mg/dl Post meal along with hypertension to the extent of 150/110 mmHg. 2. My 75-year-old mother suffered from chronic type-2 diabetes mellitus. Concurrent observation of her life-style and behaviour led me towards a hypothesis that she also suffered from Obses-
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sive Compulsive Disorder [OCD] and a perennial anxiety on status of her body parameters-namely Low OR High?-Blood Pressure & Blood Sugar.
Observations 1. All dairy products are rich in tryptophan, the precursor to well known serotonin. . .the primary resting hormone. 2. Since the microbial life cycle depends on the pH of its environment, particularly the abnormal hyper-acidic environment would directly grow an unhealthy microbiota. 3. The hormones like Dopamine and Oxytocin show dual pathways while the data on Serotonin clearly reflects that it works in the body at intracellular levels too in addition to brain, and appears to play a critical role in counterbalancing processes of the body as well as protein serotonylation process’s ‘‘ant platelet” role to prevent clot formation within blood vessels. 4. Epinephrine is widely recognized as main contributor to the flight & fight response. In a stressed condition, the reaction [22] may accelerate forward towards more of epinephrine, depleting the body of dopamine and norepinephrine successively. 5. Thus it appears that a human’s homeostasis is predominantly governed by the three main stress hormones namely dopamine, norepinephrin, epinephrine; cortisol and the counterbalancing hormone serotonin. 6. Stress studies on monkeys show that the obese monkeys are at much lower steps of the social hierarchy- dominated, poor, helpless, inferior-most in the group. Since the interdependence of man within today’s complex social network is inevitable, every modern man must adapt to a chain of command in social, professional as well as family life. Thus, almost everybody in this setup simultaneously dominates somebody as well as is dominated by somebody. 7. None of the animals need to earn money. Money is now the life-essential need of modern man. 8. Today’s man’s life revolves around the steps as ‘‘Desire” followed by ‘‘Logical thought process” to select an option to fulfil the desire followed by ‘‘Efforts and actions” to gather resources to fulfil that desire. And this process continues for whole life as desires are endless. It can be stated with reasonable confidence that man struggles to achieve a basic level of certainty to fulfil essential needs of his life and when this is achieved, he desires to live his life as per his free will. Since money is life essential, this pursuit becomes a marathon behind a goal perpetually racing forward. Thus, modern man is under a constant threat of fear/anxiety/tension etc mainly about the certainty and sustainability of earning resources to live. 9. Animal’s life involves physical struggle while modern man’s life involves extreme logical-intellectual struggle across varied aspects of his existence. In principal, the man first feels happiness/sadness of a real event in his life, and the surge of emotions follow as a result and logic follows as the last process. Since interdependence inhibits the free expression of feelings, the chronically inhibited emotions of the man in social as well as family setup may be the most critical and fundamental cause of stress. 10. It can be expected that any surge of emotions would primarily activate the Amygdala in brain followed by a logical thought process to activate HPA axis and right parts of CNS/PNS downstream to release all corresponding primary hormones.
Therefore all these diseases should have a direct connection with man’s emotions. In short, the hormones are the same but their action in the body’s biochemical pathways changes as per the man’s experience/emotions/feelings and resultant thought process/behaviour/attitude. Discussion The integrated information from this literature and modern man’s struggle directly points out to the role of hormone balance in the human body. Going back to basics of our endocrinal physiology, we have agonistic as well as antagonistic pairs of hormones, meaning one hormone stimulates the production of a second; the second suppresses the production of the first. Or hormone secretion is increased (or decreased) by the same substance whose level is decreased (or increased) by the hormone. The above information indicates that right concentration of resting and optimism-inducer hormones would balance all catecholamines [dopamine, norepinephrin & adrenalin] and cortisol. Thus, the same few hormones would mediate the right signalling pathways in the body towards normal homeostasis or a stable allostasis for a temporary period. Conversely, the absence/deficiency of the same resting and enthusiasm inducer hormones would cause hyperactivity of the catecholamines and create havoc in the metabolism leading to metabolic syndrome. Compared to other pacifying hormones like Acetylcholine, serotonin is much more abundant in the body. Therefore, presence of Serotonin in right concentration may slow down the reaction pathway [22] leading to secretion of adrenalin, and improve dopamine and norepinephrine availability. Implications of hypothesis From the above information, we can state that inhibited negative emotions arouse the thought process in brain, which activates the HPA axis to prepare the body for fight or flight. The data clearly indicates that acute excess of adrenalin and cortisol, and concurrent depletion of Serotonin, Dopamine and Epinephrine should be the root cause of MS. Thus in addition to the concentration of individual hormones in serum/ urine and cerebrospinal fluid [CSF], the observable hormone ratios like a) b) c) d) e) f)
Serotonin to Dopamine Serotonin to Norepinephrin Serotonin to Epinephrine, Serotonin to Cortisol Dopamine to Epinephrine Epinephrine to Lactic Acid etc
And their correlation with observed body parameters like blood pressure, plasma glucose etc can become the root biomarkers for MS. We can link the most probable chain of events, respective emotions and stress which lead to the trigger of various facets of MS as follows: Obesity Nobody likes continued domination/imposition against own will. Recurrently dominated person realizes that he cannot fight. Such a man would apparently adapt but be prepared to fight or flight at an opportune time just like the poorest monkey. Such person’s continuous alert state with anxiety induced by fear, and desperate search for an opportunity would cause excessive cortisol
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and would activate anabolism to store energy in the form of fat to be used in such opportunity, thus making the person obese. During this allostatic state, all hormones would increase but with their ratios would show within normal range. Individually Cortisol, dopamine and norepinephrine as well as epinephrine will be in high excess. But he would show normal glycaemic levels. Hypertension Initial recurrent failures and domination accrue negative memories. The unexpressed anger, lost trust on dominating people/system and man’s ambitions to remove the threats result into hostility. Continuous alertness with disbelief/doubt on system/ people but concurrent self-confidence and desperate motivation to remove the threat would cause excessive but inhibited anger, anxiety and alertness. So all catecholamines would enhance, the ratio of epinephrine to serotonin would increase while oxytocin and dopamine would mediate negative pathways in brain. The excessive catecholamines in this condition would cause hypertension but normal glycaemic levels.
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brain the body would start using more energetic proteins and fats from the body’s storage. Lactic acidosis Although both fight and flight is not feasible, the whirlpool of thoughts in brain prepares the body for a sprint type action anticipated any moment. This would activate the HPA axis to follow hyper secretion of epinephrine, which in turn would invoke the Cori cycle [40]. Human body is not quite accustomed to the presence of high concentrations of glucose as well as the lactic acid. However, in such a perceived trapped situation, lactic acid gets continuously recycled and reused for a much longer time period. Such acidic environment must be irritating the cell walls, it may be evoking the inflammatory response and accumulation of mucous at cellular level with all inflammation markers, which naturally foul the mitochondria retarding the normal aerobic cellular respiration cycle at large. Current treatment protocol
Heart attack, stroke Further, during the day time man’s logic and intellect prevails over emotions but some events in life can renew the bad memories stored in brain. When such person comes out of deep NREM sleep, the frustrating memories surface up and the emotional brain takes over the logical brain. That can be the reason why many times the fatal emergencies like stroke & myocardial infarction occur during early morning hours. The person would experience an acute surge of anger along with acute frustration. This state would deplete the serotonin/dopamine while making adrenaline excess. Adrenalin constricts arteries and platelets release serotonin to clump leading to a clot. Such fatal emergency can also occur anytime in the day as well. Hyperglycaemia, insulin resistance, diabetes type-2 If the man is subjected to recurrent failures against his struggle for his critical desires, one day he finds that he is in a freeze situation and a trap. The first shock of this revelation that now he just cannot fight as well as flight, immediately induces a freeze on the body. This should be a period of resultant adrenocorticoid deficiency. The next phase of adaptation through logic follows. However, he is trapped. Contrary to the rewards, he perceives a harsh punishment. In such an event, his own life-style is about to change drastically against his expectations and so the man concurrently experiences some extreme emotions concurrently like a) Hyper-anxiety on how to escape from the trap [Flight] b) Acute panic and desperate thought process to overcome the obstacle. [Fight] c) Detachment/depression as both ways are blocked. d) Deep feeling of defeat. During this logical adaptation phase man wishes to get rid of this stressor instantaneously, making him acutely panicky with a typhoon or utter chaos of thoughts in his brain resulting in acutely excessive and abnormal energy demands by brain. The epinephrine levels would rise beyond the allostatic state to mediate Cory cycle [40] depicted in Fig. 2. Concurrently dopamine, norepinephrine and serotonin levels would deplete resulting into quite unhealthy ratios of these hormones in the body. In such a panic and anxious state cortisol levels also would rise and when Cory cycle also becomes insufficient to fulfil energy demand of
Advances in identification of body’s thousands of biochemicals, hormones, genes and DNA sequence, their interactions, microbial species in gut and precision of even picogram [10–12] level measurement achieved by the modern science is therefore commendable. The medical research has definitely given the modern man many life saving drugs and a variety of treatment protocols for management of metabolic syndrome over the lifetime as well as the interventional emergency procedures to remove blockages from arteries for ischemic myocardial infarction [MI]/stroke. However, there is no guaranteed way to prevent recurrence of those in future. The physician, immediately after diagnosis of MS, starts up the proven pharmacological treatment comprising anti-hypertensive, anticholesterol, clot-preventives and oral hypoglycaemic drugs as per the clinical case. He advices an active and tension-free life style with strict restrictions on the diet. He also warns about complications like kidney failure, silent heart attack, stroke and diabetic-foot/ amputation etc to induce the patient to improve upon his aerobic respiration system. However, in contrast this additional shock of all these stark threats and imposition of living with these disorders for whole life in the cage of all these restrictions adds to more distress of the man. Current protocol neither helps solve the emotional issue nor does it remove the chaos of panic-stricken thoughts in patient’s brain. The acidic environment by lactic acid in plasma at cellular level, concurrent depletion of resting hormones, the pessimistic approach [negative pathways of dopamine and oxytocin], excessive anxiety and excessive catecholamines in the body must be depleting the body of many critical nutrients. Loss of selfconfidence would deplete oxytocin. Excessive depression and loss of enthusiasm would deplete serotonin/dopamine. This should stop concurrent repair process of not only blood vessels but also whole body at cellular level. This physical damage to body continues for whole life. McEwen [41] has rightly urged the politicians and business leaders to change their policies in order to make food affordable and to induce changes in lifestyle and behaviour of people instead of just using drugs, which help, control the metabolic and neurologic consequences of being stressed out. However, with the existing protocol, the cost of managing these diseases for whole life, along with management of fatal emergencies like stroke/MI etc is huge and the patient becomes more
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Fig. 2. Cori cycle, [40].
stressed in gathering additional money for this purpose alone. The dosage of hypoglycaemic drugs and insulin shots do not show a linear relation with patient’s blood glucose levels. Rather the dose progressively increases leading to even hyperinsulinemia as well. Proposed methodology Instead of waiting for the government/businesses to change their policies, using same science, I questioned if we can restore hormone balance in a holistic manner? Science knows that an injection of Cholecystokinin induces nausea and anxiety. Similarly, serotonin-norepinephrin agonists and benzodiazepines counterbalance and provide artificial rest. Since balance of all hormones is essential, use of non selective serotonin-norepinephrine reuptake inhibitors [SNRIs] to induce enhancement in the concentration of serotonin, dopamine and norepinephrine and short term anxiolytics [aimed at counter regulation of corticotropin releasing hormone] to kill the anxiety respectively may be a better pharmacological option to restore the balance of all these hormones together. Further instead of rigid restrictions on diet & exercise routine, if the patient gets such first line psychoactive treatment to stop the chaos of thoughts in his brain, along with protein rich diet, water soluble vitamin supplements and cognitive behavioural counselling by the physician with critical assurance that there is no threat to the patient’s life, it may provide the patient a cooling off time to revisit the issue to logically resolve it in an easy state of mind and brain. This would also reinstate the normal aerobic respiration cycle at cellular level in his body. Thus we may be able to convert the distress into eustress or a type 1 allostatic load for a temporary period. This would not only facilitate better management of the acute MS but also avert the fatalities like MI/Stroke via enhanced protein serotonylation. We also may possibly reverse it completely if patient finds an option to resolve/sideline the stressor or adapt to it, and restarts his life.
with individual stress hormones along with their individual concentration in body fluids as diagnostic markers to enable the clinical practitioners to arrive at a holistic personal protocol for first line treatment of MS. I hope that particularly the combination of counter balancing psychoactive drugs with existing protocol and behavioural counselling will, 1. Restore hormone balance. 2. Provide artificial rest and peace of mind to the patient to slow down the chaotic thought processes in his brain. 3. This would in turn improve the protein serotonylation process in the body, replace anaerobic cellular respiration with healthy aerobic respiration. 4. Prove to be very useful to avert the fatal consequences like MI/ Stroke and to improve the quality of life of such patients. 5. Such holistic treatment option may also reverse the entire MS through a short-term therapy in many cases. I urge all researchers and practitioners to integrate these aspects from varied branches of medical science and collectively conduct randomized and statistically controlled trials to lead to right protocols for holistic treatment of MS across the world.
Conflict of interest I did not receive any funding from either National Chemical Laboratory or any other organization for this work. I also declare that I am not financially associated with any business organization engaged in manufacture/marketing of drugs and medicines.
Sources of support in form of grants None.
Conclusion
Acknowledgements
I propose that MS is an acute chaos of derailed balance of a few hormones in the body and it is a truly psychosomatic disorder. I also propose to introduce the ratios of individual resting hormones
I thank the management of National Chemical Laboratory for the library resources made available for compiling various references cited in this article.
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[20] Ueno N, Inui A, Asakawa A, et al. Mosapride, a 5HT-4 receptor agonist, improves insulin sensitivity and glycaemic control in patients with Type II diabetes mellitus. Diabetologia 2002;45:792–7. [21] Miller Keith J, Azzara Anthony V. An old dog learns a new trick: Regulation of peripheral glucose homeostasis by the Serotonin (5-HT)2C receptor. Mol Interventions 2008;8:73–7. [22] Walker Dr. Edward B., Chemistry Site at Weber State University, Web-book, VII. Drugs That Stimulate Adrenergic Mechanisms, 2016,. [23] Surwit Richard S, Schneider Mark S. Role of stress in the etiology and treatment of diabetes mellitus. Psychosomatic Med 1993;55:380–93. [24] Batch BC, Kincaid B, Surwit RS. The role of stress in the development and management of diabetes mellitus. Int Diabetes Monit 2009;21(4):124–34. [25] Patrickj Lustman, Linda Griffith, Ray Clouse, et al. Effects of Alprazolam on glucose regulation in diabetes. Diabetes Care 1995;18(8):1133–9. [26] Fink G. Stress: Definition and History. In: Squire Larry R, editor. In encyclopedia of neuroscience. Elsevier Ltd; 2009. p. 549–55. ISBN: 978-0-08045046-9, 2009. [27] Sterling P, Eyer J. Allostasis: A new paradigm to explain arousal pathology. In: Fisher S, Reason JT, editors. Handbook of life stress, cognition, and health. NY: Wiley: Chicester; 1988. [28] McEwen Bruce S. Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 2000;22:108–24. [29] McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm Behav 2003;43(1):2–15. [30] Marilyn Arce, Vasiliki Michopoulos, Shepard Kathryn N, et al. Diet choice, cortisol reactivity, and emotional feeding in socially housed rhesus monkeys. Physiol Behav 2010;101(4):446–55. [31] Wilson Mark E, Fisher Jeff, Fischer Andrew, et al. Quantifying food intake in socially housed monkeys: Social status effects on caloric consumption. Physiol Behav 2008;94(4):586–94. [32] Shively CA, Laber-Lard K, Anton RF. Behavior and physiology of social stress and depression in female cynomolgus monkeys. Biol Psychiatry 1997;41 (8):871–82. [33] Herichova I. Changes of physiological functions induced by shift work. Endocr Regulations 2013;47(3):159–70. [34] Suarez EC, Kuhn CM, Schanberg SM, Williams RB, Zimmermann P. Neuroendocrine, cardiovascular, and emotional responses of hostile men: the role of interpersonal challenge. Psychosom Med 1998;60:78–88. [35] Williams RB, Chesney MA. Psychosocial factors and prognosis in established coronary artery disease. JAMA 1993;270:1860–1. [36] Kop WJ. Acute and chronic psychological risk factors for coronary syndromes: moderating effects of coronaryartery disease severity. J Psychosom Res 1997;43:167–81. [37] Musselman DL, Tomer A, Manatunga AK, Knight BT, Porter MR, Kasey S, et al. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996;153:1313–7. [38] LeDoux J. The Emotional Brain, Fear, and the Amygdala. Cell Mol Neurobiol 2003;23(4/5). [39] cGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Ann Rev Neurosci 2004;27:1–28. doi: http://dx.doi.org/10.1146/annurev.neuro.27.070203.144157. PMID 15217324. [40] Ophardt Charles E, In Virtual Chembook, Elmhurst College, , 2003. [41] McEwen BS. Protective and damaging effects of stress mediators: central role of the brain. Dialogues Clin Neurosci 2006;8(4).
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Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Metabolic syndrome – A truly psychosomatic disorder? A global hypothesis Shrikant Madhukar Ghike ME [Chem Engg] CE & PD Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
a r t i c l e
i n f o
Article history: Received 28 April 2016 Revised 5 September 2016 Accepted 19 October 2016
Keywords: Clinical psychiatry Metabolic syndrome Cardio vascular disease Hyperglycaemia Type 2 diabetes mellitus Lactic acidosis
a b s t r a c t Exact cause of the metabolic syndrome [MS], a global epidemic, is still unclear. Man has same fundamental needs to live as animals but modern man’s life-style compels him to acquire certainty of resources for all his needs in a complex social network. Today money has become the sole life essential need. Contrarily none of the animals needs to earn money. Brain is also an organ of the human body with a unique thought process to define logical actions to achieve a person’s goals. This way life is a flow of desires followed by logical actions. The person struggles to attain desired goals via the allostatic load but a perceived insurmountable threat can make his flow of life stalled to freeze him. Published data from varied branches of medical science indicates role of hormones in overall homeostasis. Particularly multifaceted role of serotonin is well documented. Adrenalin being the primary mediator of Cori cycle is also well known. From the integration of observations from published data with reference to common human’s modern lifestyle, it is hypothesized that a perceived trapped situation in life creates acute chaos of thoughts in brain, which results in acute excess of stress hormones and concurrent depletion of resting hormones, which in turn triggers MS. In global terms, MS indicates an acute imbalance of a few hormones and implies psychosomatic roots of the disorder. This may pave a better way in deciding a personalized holistic protocol with combination of counter regulatory psychoactive medications. Ó 2016 Elsevier Ltd. All rights reserved.
Introduction World Health Organization (WHO) celebrated its birthday on 7 April 2016 – World Health Day, with a call to action to beat diabetes. As per the fact sheet on WHO website [1], the global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014, corresponding to a huge 422 million population. The collection of metabolic abnormalities including central obesity, decreased high-density cholesterol (HDL-C), elevated low-density cholesterol [LDL-C] and triglycerides, hypertension (BP), hyperglycaemia/insulin resistance, inflammatory response is known as the metabolic syndrome [MS]. Associated with a three fold and 2-fold increase in type 2 diabetes and cardiovascular disease (CVD), respectively, it is thought to be a driver of the modern day epidemics of diabetes and CVD and has become a major public health challenge around the world [2]. Across many theories and postulates still a confusion exists on exact cause-effect diagram for MS. Unambiguous evidence on the
E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2016.10.015 0306-9877/Ó 2016 Elsevier Ltd. All rights reserved.
initial stages of disease is missing, making it difficult to pin down the causes at the cellular and molecular level. Some consider it as impaired glucose metabolism while some consider it impaired lipid metabolism [3]. Therefore the treatment protocols only aim to manage the disorder over a lifetime and reversal is yet quite difficult.
The hypothesis I propose an overall hypothesis that during his intense struggle under allostatic load, today’s man faces a ‘‘freeze” or ‘‘doomed to failure” life situation in which both fight and flight response can pose similarly severe threats and loss. However, the person’s intense battle to remove the stressor results in an acute chaos of alternating thoughts of fight or flight in his brain. This causes great confusion and an acute imbalance of hormones, which triggers MS. This directly indicates psychosomatic roots of MS. I further hypothesize that it is not just the measurable and observable individual hormones but also the ratio of resting hormones to that of stress hormones and their correlation with body symptoms like blood
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pressure and blood glucose levels, which can play a key role in understanding the homeostatic/allostatic, or MS status of an individual. The first step is a brief review of homeostasis, risk factors and hormones followed by multiple pathways of some hormones. Then I present the supporting data/information from select references on known risk factors for MS. This is followed by a comparison of natural animals’ life with that of modern man to arrive conceptually at the stress he suffers during his intellectual struggle in today’s money-centred socio-economic setup. The collective observations from this overall background lead to the main hypothesis. Then I have discussed the implications in terms of apparent symptoms and their correlation with observable hormone levels to arrive at the homeostatic/allostatic status of individual patient. Evaluation of hypothesis Homeostasis & risk factors for MS In general, we know that man’s diet, physical activity profile and various hormones play a key role in maintaining the homeostasis of his body. The risk factors widely recognized for MS are a) Obesity indicating unhealthy diet & lack of physical activity, b) Cholesterol: High concentration of Low density lipids [LDL] compared to high density lipids [HDL] in blood, c) Stress, d) Heredity and e) Genetic predisposition. Heredity & genetic predisposition are not in control of any human so; I have sidelined it for this study. Diet, exercise & cholesterol Role of diet in health is very well proven. A diet rich in fibre appears to reduce the cholesterol [4]. O’Connor et al., demonstrated that including dairy products in diet appear to reduce the insulin resistance [5]. A study has found that young, overweight adults who consume high amounts of dairy products have a reduced risk of developing insulin resistance syndrome (IRS) [6]. Role of exercise in homeostasis does not need more elaboration. Human micro biota Millions of microbes live inside and on the surface of each person; with some estimates suggesting that microbes outnumber human cells about 10 to 1 [7]. Researchers demonstrated that colonizing germ-free mice with the intestinal micro biome from obese mice led to an increased total body fat in the recipient mice without change in diet [8]. Individuals with a low bacterial richness were characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals [9]. Hormone pathways in human body Human body has a precise self regulatory fuel [food] consumption and energy production mechanism governed automatically by the hormones and neurotransmitters in the autonomic nervous system [ANS]. The sympathetic and parasympathetic branches of autonomic nervous system continuously regulate complete heart/ breathing function as well as the energy homeostasis in a healthy body. The gastrointestinal tract is the largest endocrine organ in
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the body which controls the digestive function. At cellular level the body maintains glucose-homeostasis through a slow but highly efficient aerobic respiration creating almost 30 mol of ATP per glucose molecule. Major hormones, which regulate the metabolism as well as mood and behavioural aspects of a human, are Oxytocin, Vasopressin, Serotonin, Dopamine, Norepinephrine, Epinephrine, Cortisol/Glucocorticoids and Acetylcholine. Off these, Serotonin [Anger & mood modulator], Oxytocin & Vasopressin [Bonding] and Acetylcholine [Slow down body processes] are pleasure and rest providing hormones while, Dopamine [Motivator], Norepinephrine [Excitement inducer], Epinephrine [Main fight /flight response inducer] and Cortisol [released in response to stress and low blood-glucose concentration.] are stress hormones. We know that all these hormones, steroids, neuropeptides etc work as a harmonious orchestra in a healthy human body. Hormones’ dual pathways Some critical hormones appear to express multiple pathways in brain and body. For instance, Oxytocin improves trust and faith. [10]. Intranasal administration of oxytocin increases envy and gloating [11], Plasma oxytocin enhances glucose uptake by skeletal muscles [12]. Dopamine can activate either reward seeking or punishment expecting neuronal network in the brain [13]. Dopamine D2like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion [14]. Acute dopamine depletion reduces peripheral insulin sensitivity in healthy men [15]. Serotonin It was best known as a neurotransmitter that modulates brain’s neural activity and a wide range of neuropsychological processes like mood, perception, reward, anger, aggression, appetite, memory, sexuality, etc. However, 90% of total serotonin is found outside the central nervous system. The advances now clearly indicate that in addition to the neuropsychiatric processes, serotonin plays a major role in almost all of the functions of the body [16]. For instance, serotonin mediates control of vascular resistance, blood pressure, haemostasis and platelet function [17]. Therefore selective serotonin reuptake inhibitors [SSRIs] treatment may enhance serotonin transporter activity from plasma into the platelets leading to prevention of thrombosis in arteries and so the acute MI [18]. Paulmann et al., conducted animal studies to show that serotonylation of intracellular proteins in pancreatic beta cells modulate insulin secretion [19]. Serotonin’s role in glucose metabolism via a 5HT-4 receptor agonist [20], and 5-HT2C [21] is also known. Stress hormones All the stress hormones are synthesized from normal dietary precursor Phenylalanine by route [22] as shown in Fig. 1 In terms of chemistry, whole reaction pathway has the nature of a classical sequential series reaction, which implies that concentration of these in body will depend on the rates of these individual reactions. Stress factor Surwit and Schneider have indicated that ‘‘Stress” has long been suspected to have major effects on metabolic activity [23]. Stress is a potential contributor to chronic hyperglycemia in diabetes,
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Fig. 1. Catecholamines biosynthesis route, [22].
although its exact role is unclear. They have inferred from studies that behavioural or pharmacologic intervention to manage stress may contribute significantly to the treatment of patients already suffering from diabetes. Batch et al. have provided an excellent review with various stress studies on animal as well as human subjects but has concluded that although pharmacological and behavioural therapies can be useful in management of established diabetes, there is little convincing evidence that stress contributes directly to the pathophysiology of the disease [24]. Lustman et al., concluded in a pharmacological intervention with Alprazolam treatment of anxious patients with poorly controlled diabetes may result in decreased anxiety and improved glucose regulation through independent mechanisms [25]. Fink, has provided an elaborate review of the term ‘‘Stress”[26]. Right from Hans Selye’s pioneering efforts on stress and Generalized Adaptation Syndrome [GAS] followed by Eustress and Destress, we find the work of Sterling and Eyer [27], McEwen [28], and McEwen and Wingfield [29] who laid the foundation of the allostasis and allostatic load theories. Allostasis proposes a reset on all body parameters to a new set point outside the normal. The main hormonal mediators of the stress response in this situation are cortisol and epinephrine (adrenaline). McEwen and Wingfield have also proposed a chronic allostatic overload of type 2, which results in different pathophysiologies [29]. Stress studies on different species of monkeys – the social animals- clearly indicate that the most dominated of them [subordinates] undergo a psychosocial stress of subordination leading to increased consumption of calorically dense foods [30]. Wilson et al. demonstrated that such monkeys show reduced glucocorticoid negative feedback and higher frequencies of anxiety-like behaviour [31]. They hyper secrete cortisol. Shivley et al., have concluded that chronic, low-intensity social stress may result in depression in susceptible individuals [32].
Man & animal’s life Since MS is a ‘‘Life-Style Disorder”, it becomes imperative to review the ‘‘life style” of the modern man. Man being primarily an animal; let us first compare the life of natural animals with man. Human beings are a part of the animal kingdom on this earth. Basic needs of any animal to live are air, water, food, sleep, reproduction and the ‘‘threat” induced alertness to either fight or flight. Man has very similar needs to live. Historically we can imagine that man started living in groups of people and later invented farming. Division of labour resulted into interdependence of humans in the family as well as social setup. Man’s unique intellect and curiosity brought the technological advances and an excellent level of comfort. The civilization has substantially reduced direct threat to his life from wild animals, and many other external dangers. At the same time, modern man’s life is a cascade of desires followed by intellectual/logical to result in physical struggle to fulfil those. [Here, even brainwork also can be termed as physical struggle.] The family setup not only provides the man the emotional security but also provides him a social identity and stability. Normally a human grows up under the care of parents. Then he gets married and settles his own family, grows his own children and the cycle continues from generation to generation indefinitely. In today’s socio-economic system, life essential needs namely air, water are almost free and the emotional needs like love, affection, care, in a family setup are priceless. However, the resources to fulfil all the other needs and desires must be bought only by money. Man has to continuously struggle to earn requisite money to buy resources for essential needs first and then for a better living.
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His struggle involves a race with stringent targets and deadlines resulting either in rewards or punishment-again in terms of money. Many a times, just maintaining the current job/cash inflow itself is a reward. Even an inkling of an uncertainty in his primary source of bread and butter, can generate a huge surge of worry, anxiety, and panic in a man’s life. Man & animals – Difference None of the other animal needs to earn money. The modern man lives a ‘‘money-centred” & logical/intellectual life otherwise quite secured from external threats while, all animals still live the natural life and struggle for just life-essential needs. Most critically, the animals spontaneously express their feelings physically. For instance, a lion instantaneously roars to warn that encroacher in his territory. His next step is a natural physical assault. But, at any extent of anger [for Fight] as well as fright [for Flight], contrarily the civilized man is taught to suppress emotions and to utilize only logical means to resolve the issues, involving neither physical attack nor physical runaway. In all situations of struggle, any animal’s body parameters must reset as a part of his reaction to the threat in terms of flight or fight. [Both situations need a sudden surge of energy in the skeletal muscles.] Even if the lion/tiger looses, it will let go that deer, relax/ regain its body parameters and would restart its hunt for another prey for its need of food with a new hope. Same can be expressed from the side of that deer. As such, no scientific proof is available, as to what happens to these parameters of a deer’s body at the moment it is trapped/ immobilized by a tiger. In this event, the deer can neither fight nor can it run away. It has to normally accept its end of life. Modern man’s social existence Since the interdependence of man within today’s complex social network is inevitable, every modern man must adapt to a chain of command primarily for his life essential needs and adapt to family’s, other peoples’, organizations’, society’s as well as government’s demands/objectives. This also creates dominance. And each individual within this chain is dominated by somebody and also dominates somebody. For instance, today’s man is compelled to accept working in shifts at factories, airports, railways, etc, only to earn his life-essential needs. Herochova elaborates the influence of shift-work on human physiology and suggests good methods to adapt to this stress on his circadian rhythm. [33]. Man’s emotions and feelings McEwen & Wingfield in a review [29] have pointed out very well documented references on influence of man’s emotions like anger/hostility and depression on CVD and Myocardial Infarction (MI) [34–37]. When his struggle ends on a success, man experiences positive emotions like happy, joyful, bliss, calm, tranquil, relaxed, contented, affection, love, security, excitement, empathy, sense of some achievement etc. While when his struggle ends up on a failure against his desires, he feels one or more of the negative emotions like worry, tension, anxiety, apathy, agony, disgust, fear, guilt, embarrassment, defeat, pity, panic, nervousness, and helplessness. Negative events either in family situations, or in job & financial situations or in social situations can result in various negative emotions in a human. All these events relate directly with certainty and stability. After a cooling off period, he is compelled to first logically identify the cause, then either struggle to remove that bottleneck or to follow
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an alternative path to regain his efforts or adapt to the situation and change his own life-style suitably. A ‘‘freeze” or ‘‘stalled life” situation However, no human really loves to lose his liberties of free will. Against this, he adapts to various hierarchies with a hope that he, by some way he would still fulfil the desire to exercise his free will. This fact well validates the allostatic load theory. During this chronic struggle, just like an immobilized deer, modern man also can face such an event in his life, which is extremely unfavourable against his critical aims. In such a lock in, he can neither fight nor flight! He senses that he is trapped in such a ‘‘doomed to failure” mess that, a) His goal is now unreachable. b) Any more struggle is futile and useless or has a corresponding stark threat. c) He has to now just accept the biggest defeat in his struggle. d) Now he has to adapt to a new life style against his own will and compulsorily live just suffering until his end. Considerable progress has been made over the past 20 years in relating specific circuits of the brain to emotional functions. The major conclusion from studies of fear conditioning is that the amygdala plays critical role in linking external stimuli to defence responses [38]. The amygdala’s influence on episodic memory is also tied to physiological arousal. [39]. All memories arouse respective emotions of the man. My own experience 1. I took up a research project in 2010. I anticipated a reward of promotion with certainty of resources for my family in the end from the success. Almost 300 experiments in a series until June 2011 completely failed. During this period my weight increased from 65 kg to 82 kg, the routine medical checkups indeed branded me to be overweight with low HDL-C, and high LDL-C/triglycerides, but absolutely normal BP and blood sugar levels. Thus, I was living in an allostatic load state. On last failure the I perceived the legal trap of contractual commitments and anticipated the stark threat of the repercussions on my future as: Punishment-1: To adapt to a thankless strenuous routine of court visits to address legal issues anticipated from client. Punishment-2: Anticipated negative appraisal and loss of promotion Punishment-3:To get distracted from own desired life Huge sense of defeat and loss of confidence. At this juncture, my weight reduced from 82 kg to 72 kg within just about a week. During the logical adaptation stage, I reviewed and identified the causes to conclude that I must fulfil the commitment. But, on the other hand, I had just run out of all options to do so. Here I experienced extreme anger, panic-stricken anxiety as well as helplessness at a time in this ‘‘No Go” situation. I experienced all those symptoms like hypertension, proteinurea [a slimy albuninous discharge in urine], dizziness, confusion, swollen and painful feet and hot impacts in head etc. My blood glucose levels shot to 357 mg/dl Fasting and 467 mg/dl Post meal along with hypertension to the extent of 150/110 mmHg. 2. My 75-year-old mother suffered from chronic type-2 diabetes mellitus. Concurrent observation of her life-style and behaviour led me towards a hypothesis that she also suffered from Obses-
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sive Compulsive Disorder [OCD] and a perennial anxiety on status of her body parameters-namely Low OR High?-Blood Pressure & Blood Sugar.
Observations 1. All dairy products are rich in tryptophan, the precursor to well known serotonin. . .the primary resting hormone. 2. Since the microbial life cycle depends on the pH of its environment, particularly the abnormal hyper-acidic environment would directly grow an unhealthy microbiota. 3. The hormones like Dopamine and Oxytocin show dual pathways while the data on Serotonin clearly reflects that it works in the body at intracellular levels too in addition to brain, and appears to play a critical role in counterbalancing processes of the body as well as protein serotonylation process’s ‘‘ant platelet” role to prevent clot formation within blood vessels. 4. Epinephrine is widely recognized as main contributor to the flight & fight response. In a stressed condition, the reaction [22] may accelerate forward towards more of epinephrine, depleting the body of dopamine and norepinephrine successively. 5. Thus it appears that a human’s homeostasis is predominantly governed by the three main stress hormones namely dopamine, norepinephrin, epinephrine; cortisol and the counterbalancing hormone serotonin. 6. Stress studies on monkeys show that the obese monkeys are at much lower steps of the social hierarchy- dominated, poor, helpless, inferior-most in the group. Since the interdependence of man within today’s complex social network is inevitable, every modern man must adapt to a chain of command in social, professional as well as family life. Thus, almost everybody in this setup simultaneously dominates somebody as well as is dominated by somebody. 7. None of the animals need to earn money. Money is now the life-essential need of modern man. 8. Today’s man’s life revolves around the steps as ‘‘Desire” followed by ‘‘Logical thought process” to select an option to fulfil the desire followed by ‘‘Efforts and actions” to gather resources to fulfil that desire. And this process continues for whole life as desires are endless. It can be stated with reasonable confidence that man struggles to achieve a basic level of certainty to fulfil essential needs of his life and when this is achieved, he desires to live his life as per his free will. Since money is life essential, this pursuit becomes a marathon behind a goal perpetually racing forward. Thus, modern man is under a constant threat of fear/anxiety/tension etc mainly about the certainty and sustainability of earning resources to live. 9. Animal’s life involves physical struggle while modern man’s life involves extreme logical-intellectual struggle across varied aspects of his existence. In principal, the man first feels happiness/sadness of a real event in his life, and the surge of emotions follow as a result and logic follows as the last process. Since interdependence inhibits the free expression of feelings, the chronically inhibited emotions of the man in social as well as family setup may be the most critical and fundamental cause of stress. 10. It can be expected that any surge of emotions would primarily activate the Amygdala in brain followed by a logical thought process to activate HPA axis and right parts of CNS/PNS downstream to release all corresponding primary hormones.
Therefore all these diseases should have a direct connection with man’s emotions. In short, the hormones are the same but their action in the body’s biochemical pathways changes as per the man’s experience/emotions/feelings and resultant thought process/behaviour/attitude. Discussion The integrated information from this literature and modern man’s struggle directly points out to the role of hormone balance in the human body. Going back to basics of our endocrinal physiology, we have agonistic as well as antagonistic pairs of hormones, meaning one hormone stimulates the production of a second; the second suppresses the production of the first. Or hormone secretion is increased (or decreased) by the same substance whose level is decreased (or increased) by the hormone. The above information indicates that right concentration of resting and optimism-inducer hormones would balance all catecholamines [dopamine, norepinephrin & adrenalin] and cortisol. Thus, the same few hormones would mediate the right signalling pathways in the body towards normal homeostasis or a stable allostasis for a temporary period. Conversely, the absence/deficiency of the same resting and enthusiasm inducer hormones would cause hyperactivity of the catecholamines and create havoc in the metabolism leading to metabolic syndrome. Compared to other pacifying hormones like Acetylcholine, serotonin is much more abundant in the body. Therefore, presence of Serotonin in right concentration may slow down the reaction pathway [22] leading to secretion of adrenalin, and improve dopamine and norepinephrine availability. Implications of hypothesis From the above information, we can state that inhibited negative emotions arouse the thought process in brain, which activates the HPA axis to prepare the body for fight or flight. The data clearly indicates that acute excess of adrenalin and cortisol, and concurrent depletion of Serotonin, Dopamine and Epinephrine should be the root cause of MS. Thus in addition to the concentration of individual hormones in serum/ urine and cerebrospinal fluid [CSF], the observable hormone ratios like a) b) c) d) e) f)
Serotonin to Dopamine Serotonin to Norepinephrin Serotonin to Epinephrine, Serotonin to Cortisol Dopamine to Epinephrine Epinephrine to Lactic Acid etc
And their correlation with observed body parameters like blood pressure, plasma glucose etc can become the root biomarkers for MS. We can link the most probable chain of events, respective emotions and stress which lead to the trigger of various facets of MS as follows: Obesity Nobody likes continued domination/imposition against own will. Recurrently dominated person realizes that he cannot fight. Such a man would apparently adapt but be prepared to fight or flight at an opportune time just like the poorest monkey. Such person’s continuous alert state with anxiety induced by fear, and desperate search for an opportunity would cause excessive cortisol
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and would activate anabolism to store energy in the form of fat to be used in such opportunity, thus making the person obese. During this allostatic state, all hormones would increase but with their ratios would show within normal range. Individually Cortisol, dopamine and norepinephrine as well as epinephrine will be in high excess. But he would show normal glycaemic levels. Hypertension Initial recurrent failures and domination accrue negative memories. The unexpressed anger, lost trust on dominating people/system and man’s ambitions to remove the threats result into hostility. Continuous alertness with disbelief/doubt on system/ people but concurrent self-confidence and desperate motivation to remove the threat would cause excessive but inhibited anger, anxiety and alertness. So all catecholamines would enhance, the ratio of epinephrine to serotonin would increase while oxytocin and dopamine would mediate negative pathways in brain. The excessive catecholamines in this condition would cause hypertension but normal glycaemic levels.
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brain the body would start using more energetic proteins and fats from the body’s storage. Lactic acidosis Although both fight and flight is not feasible, the whirlpool of thoughts in brain prepares the body for a sprint type action anticipated any moment. This would activate the HPA axis to follow hyper secretion of epinephrine, which in turn would invoke the Cori cycle [40]. Human body is not quite accustomed to the presence of high concentrations of glucose as well as the lactic acid. However, in such a perceived trapped situation, lactic acid gets continuously recycled and reused for a much longer time period. Such acidic environment must be irritating the cell walls, it may be evoking the inflammatory response and accumulation of mucous at cellular level with all inflammation markers, which naturally foul the mitochondria retarding the normal aerobic cellular respiration cycle at large. Current treatment protocol
Heart attack, stroke Further, during the day time man’s logic and intellect prevails over emotions but some events in life can renew the bad memories stored in brain. When such person comes out of deep NREM sleep, the frustrating memories surface up and the emotional brain takes over the logical brain. That can be the reason why many times the fatal emergencies like stroke & myocardial infarction occur during early morning hours. The person would experience an acute surge of anger along with acute frustration. This state would deplete the serotonin/dopamine while making adrenaline excess. Adrenalin constricts arteries and platelets release serotonin to clump leading to a clot. Such fatal emergency can also occur anytime in the day as well. Hyperglycaemia, insulin resistance, diabetes type-2 If the man is subjected to recurrent failures against his struggle for his critical desires, one day he finds that he is in a freeze situation and a trap. The first shock of this revelation that now he just cannot fight as well as flight, immediately induces a freeze on the body. This should be a period of resultant adrenocorticoid deficiency. The next phase of adaptation through logic follows. However, he is trapped. Contrary to the rewards, he perceives a harsh punishment. In such an event, his own life-style is about to change drastically against his expectations and so the man concurrently experiences some extreme emotions concurrently like a) Hyper-anxiety on how to escape from the trap [Flight] b) Acute panic and desperate thought process to overcome the obstacle. [Fight] c) Detachment/depression as both ways are blocked. d) Deep feeling of defeat. During this logical adaptation phase man wishes to get rid of this stressor instantaneously, making him acutely panicky with a typhoon or utter chaos of thoughts in his brain resulting in acutely excessive and abnormal energy demands by brain. The epinephrine levels would rise beyond the allostatic state to mediate Cory cycle [40] depicted in Fig. 2. Concurrently dopamine, norepinephrine and serotonin levels would deplete resulting into quite unhealthy ratios of these hormones in the body. In such a panic and anxious state cortisol levels also would rise and when Cory cycle also becomes insufficient to fulfil energy demand of
Advances in identification of body’s thousands of biochemicals, hormones, genes and DNA sequence, their interactions, microbial species in gut and precision of even picogram [10–12] level measurement achieved by the modern science is therefore commendable. The medical research has definitely given the modern man many life saving drugs and a variety of treatment protocols for management of metabolic syndrome over the lifetime as well as the interventional emergency procedures to remove blockages from arteries for ischemic myocardial infarction [MI]/stroke. However, there is no guaranteed way to prevent recurrence of those in future. The physician, immediately after diagnosis of MS, starts up the proven pharmacological treatment comprising anti-hypertensive, anticholesterol, clot-preventives and oral hypoglycaemic drugs as per the clinical case. He advices an active and tension-free life style with strict restrictions on the diet. He also warns about complications like kidney failure, silent heart attack, stroke and diabetic-foot/ amputation etc to induce the patient to improve upon his aerobic respiration system. However, in contrast this additional shock of all these stark threats and imposition of living with these disorders for whole life in the cage of all these restrictions adds to more distress of the man. Current protocol neither helps solve the emotional issue nor does it remove the chaos of panic-stricken thoughts in patient’s brain. The acidic environment by lactic acid in plasma at cellular level, concurrent depletion of resting hormones, the pessimistic approach [negative pathways of dopamine and oxytocin], excessive anxiety and excessive catecholamines in the body must be depleting the body of many critical nutrients. Loss of selfconfidence would deplete oxytocin. Excessive depression and loss of enthusiasm would deplete serotonin/dopamine. This should stop concurrent repair process of not only blood vessels but also whole body at cellular level. This physical damage to body continues for whole life. McEwen [41] has rightly urged the politicians and business leaders to change their policies in order to make food affordable and to induce changes in lifestyle and behaviour of people instead of just using drugs, which help, control the metabolic and neurologic consequences of being stressed out. However, with the existing protocol, the cost of managing these diseases for whole life, along with management of fatal emergencies like stroke/MI etc is huge and the patient becomes more
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Fig. 2. Cori cycle, [40].
stressed in gathering additional money for this purpose alone. The dosage of hypoglycaemic drugs and insulin shots do not show a linear relation with patient’s blood glucose levels. Rather the dose progressively increases leading to even hyperinsulinemia as well. Proposed methodology Instead of waiting for the government/businesses to change their policies, using same science, I questioned if we can restore hormone balance in a holistic manner? Science knows that an injection of Cholecystokinin induces nausea and anxiety. Similarly, serotonin-norepinephrin agonists and benzodiazepines counterbalance and provide artificial rest. Since balance of all hormones is essential, use of non selective serotonin-norepinephrine reuptake inhibitors [SNRIs] to induce enhancement in the concentration of serotonin, dopamine and norepinephrine and short term anxiolytics [aimed at counter regulation of corticotropin releasing hormone] to kill the anxiety respectively may be a better pharmacological option to restore the balance of all these hormones together. Further instead of rigid restrictions on diet & exercise routine, if the patient gets such first line psychoactive treatment to stop the chaos of thoughts in his brain, along with protein rich diet, water soluble vitamin supplements and cognitive behavioural counselling by the physician with critical assurance that there is no threat to the patient’s life, it may provide the patient a cooling off time to revisit the issue to logically resolve it in an easy state of mind and brain. This would also reinstate the normal aerobic respiration cycle at cellular level in his body. Thus we may be able to convert the distress into eustress or a type 1 allostatic load for a temporary period. This would not only facilitate better management of the acute MS but also avert the fatalities like MI/Stroke via enhanced protein serotonylation. We also may possibly reverse it completely if patient finds an option to resolve/sideline the stressor or adapt to it, and restarts his life.
with individual stress hormones along with their individual concentration in body fluids as diagnostic markers to enable the clinical practitioners to arrive at a holistic personal protocol for first line treatment of MS. I hope that particularly the combination of counter balancing psychoactive drugs with existing protocol and behavioural counselling will, 1. Restore hormone balance. 2. Provide artificial rest and peace of mind to the patient to slow down the chaotic thought processes in his brain. 3. This would in turn improve the protein serotonylation process in the body, replace anaerobic cellular respiration with healthy aerobic respiration. 4. Prove to be very useful to avert the fatal consequences like MI/ Stroke and to improve the quality of life of such patients. 5. Such holistic treatment option may also reverse the entire MS through a short-term therapy in many cases. I urge all researchers and practitioners to integrate these aspects from varied branches of medical science and collectively conduct randomized and statistically controlled trials to lead to right protocols for holistic treatment of MS across the world.
Conflict of interest I did not receive any funding from either National Chemical Laboratory or any other organization for this work. I also declare that I am not financially associated with any business organization engaged in manufacture/marketing of drugs and medicines.
Sources of support in form of grants None.
Conclusion
Acknowledgements
I propose that MS is an acute chaos of derailed balance of a few hormones in the body and it is a truly psychosomatic disorder. I also propose to introduce the ratios of individual resting hormones
I thank the management of National Chemical Laboratory for the library resources made available for compiling various references cited in this article.
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References [1] World Health Organization, Geneva, 2016
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[20] Ueno N, Inui A, Asakawa A, et al. Mosapride, a 5HT-4 receptor agonist, improves insulin sensitivity and glycaemic control in patients with Type II diabetes mellitus. Diabetologia 2002;45:792–7. [21] Miller Keith J, Azzara Anthony V. An old dog learns a new trick: Regulation of peripheral glucose homeostasis by the Serotonin (5-HT)2C receptor. Mol Interventions 2008;8:73–7. [22] Walker Dr. Edward B., Chemistry Site at Weber State University, Web-book, VII. Drugs That Stimulate Adrenergic Mechanisms, 2016,