EVOLVING CONCEPTS ARTICLE
Over the last century insulin resistance has been found in many physiological and disease states. A few examples are diabetes mellitus, obesity, infection, sepsis, different types of arthritis (including rheumatoid arthritis), systemic lupus erythematosus, ankylosing spondylitis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, and mental stress (reviewed in Ref.1).
Thus, insulin resistance seems to be present in many disease states outside the field of diabetology (although it was mainly investigated by scientists of this particular field). When considering these diseases and disease states, one observes two major clusters of clinical entities that are linked to insulin resistance: 1) inflammation with an activated immune/repair system, and 2) increased mental activation. At this point it is important to try and understand the question of how the overall background and pathophysiology of insulin resistance is related to the two disease clusters linked to insulin resistance.
There are many available theories of insulin resistance; i.e. the glucose-fatty acid cycle theory, thrifty genotype hypothesis, starvation-related insulin resistance, thrifty phenotype hypothesis, fight infections theory of insulin resistance, central nervous resistance model, breakdown of robustness theory, cellular pathogen- and nutrient-sensing pathway theory [metaflammation], and good calories – bad calories theory, but none fully explain the two clusters . Inflammation-related insulin resistance is briefly described in Box 1. In order to get a broader understanding of the two clusters, the publication includes aspects of energy regulation and evolutionary medicine .
The model of energy regulation suggests that the central nervous system and the immune system are the two main areas which actually benefit from insulin resistance-related hyperglycemia because they do not become insulin-resistant. In addition, the immune system receives an added benefit from insulin because it is an important growth factor for leukocytes. Insulin resistance-related hyperglycemia offers approximately 900 kJ (215 kcal) per 24 hours to the two systems. While insulin resistance is most often regarded as a pathological state to be treated, these numbers and the fact that insulin resistance is linked to so many diseases and disease states are indicative of a beneficial role of insulin resistance.
This helps explain the valuable role insulin resistance plays in the brain and immune systems, but the model of energy regulation also identifies an important number of controllable amount of energy (CAEN), which can be distributed between different organs. The so-called minimal metabolic rate of an 80 kg and 180 cm person is approximately 8500 kJ/d , and it is not up for ‘negotiations’ between different organs. The delta between 8500 kJ/d and the maximum of daily energy uptake in the gut (20.000 kJ/d) is 11.500 kJ/d. In this example, the 11.500 kJ/d is the controllable amount of energy (CAEN) because allocation of CAEN to different organs is controlled by the interplay of these organs. This amount of energy is up for ‘negotiations’. The question appears to be, which organs are dominant in regulating CAEN?
Currently, aspects of evolutionary medicine are included in the theory. For example, if a paleolithic hunter experiences tissue trauma with infection, the immune/repair system becomes strongly activated. In this type of life-threatening situation, regulation of CAEN allocation to the immune/repair system must be independent of other organs and immediate (hierarchically, the highest level of control to survive). Circulating cytokines and activated sensory nerve fibers would be responsible for the immediate re-allocation of CAEN to the activated immune system that increases energy consumption. I refer to this as an “energy appeal reaction” . Likewise, if a paleolithic hunter needs to escape from a severe dangerous threat, the brain must control CAEN. In life-threatening situations, the control of CAEN by the brain must be independent of other organs (again, the highest level of control to survive).
With trauma/infection or the fight-or-flight response, the activity of most organs depend on either the immune/repair system or the central nervous system, respectively. From these theoretical considerations, it becomes clear that either the immune/repair system or the central nervous system are dominant regulators of CAEN. One recognizes two independent organs: 1) the “selfish immune system”, and 2) the “selfish brain” (expression introduced by Achim Peters of Lübeck, Ref. 3), related to the above-mentioned clusters of 1) inflammation with an activated immune/repair system, and 2) increased mental activation.
Another important explanation that comes from the model of energy regulation and evolutionary medicine says that a highly activated immune/repair system or central nervous system cannot be switched on for a long time because this would be very energy-consuming. For example, a highly activated immune system is accompanied by sickness behavior and anorexia, which prevents adequate food intake and necessitates life on stored reserves (inflammation-induced anorexia).
Under systemic inflammatory conditions, break down of all reserves takes 19-43 days . If alterations of homeostasis lead to marked energy consumption, the situation cannot be chronic – it must be acute. In contrast, if mutations were helpful to protect energy reserves, they were positively selected during evolution. This is true for memory responses because immediate reaction of an educated system can spare energy reserves (immune memory, neuronal memory, energy memory or energy stores).
Networks that lead to insulin resistance serve the acute activation of the selfish immune system or the selfish brain, but do not belong to networks that protect energy stores. In contrast, insulin resistance leads to loss of energy-rich substrates because it is a catabolic process (energy-rich fuels are consumed by non-insulin-dependent organs or simply excreted). If the hypothesis of the “acute insulin resistance program” is correct, then chronic insulin resistance in chronic inflammation and in chronic mental activation or mental disease is a misguided acute program.
Figure 1. Pathophysiology of insulin resistance according to the new theory
UPPER BOX: Acute activation programs were positively selected for short-lived activation of either the brain or the immune system. Hierarchically, brain and immune system are on the same level. Activation of the brain mainly stimulates stress axes hormones and activates the sympathetic nervous system (SNS). This is supported by a mild inflammatory process that is paralleled by mental activation (A). Activation of the immune system induces cytokines, chemokines, and danger signals. In addition, the inflammatory process uncouples the locally inflamed area from the control of the brain by cytokine-induced hormone /neurotransmitter production in the periphery independent of superordinate stress pathways. This leads to hepatic cortisol secretion, ACTH-independent cortisol secretion, and production of leukocyte hormones and leukocyte neurotransmitters. The activation of the immune system is accompanied by a mild stimulation of the HPA axis (albeit inadequately low in relation to inflammation) and a somewhat stronger stimulation of the SNS (B). Despite activation of the SNS, anti-inflammatory neurotransmitters of sympathetic nerve fibers do not reach the uncoupled inflamed tissue. Inflammatory and mental activation are often accompanied by anorexia and sickness behavior, which aggravates energy shortage.
LOWER BOX: Chronic energy storage and memory programs were positively selected. The major storage organs are fat tissue (glycerol, free fatty acids) and muscles (proteins). The liver is more of a switchboard to interchange and renew energetic substrates. The main storage factor is insulin so that insulin resistance can be seen as a catabolic program induced by catabolic pathways (upper box). The numbers in red give the typical time of energy provision by the respective organ (amino acids from muscle are spared from day 3 onwards). Storage is mainly supported by a positively selected program of foot intake / foraging behavior and memory. Memory is outstandingly important to spare energy-rich fuels (brain, immune system). The dashed black arrows in the lower box demonstrate real and hypothetical connections between respective organs. The black numbers give a typical figure of stored energy in the respective organs. The dashed black line between upper and lower boxes separates the programs positively selected for acute (catabolic) versus chronic states (storage and memory). Abbreviations: CAEN, controllable amount of energy (this is the energy that is regulated and negotiated between organs); HPA, hypothalamic-pituitary-adrenal axis; 11βHSD1, 11beta-hydroxy steroid dehydrogenase type 1.
With all this information, one can generate a new model of insulin resistance that builds upon the existing theories: The new model includes four new aspects: 1) immune/repair system plays a larger role than previously known due to its enormous energy requirements , 2) it juxtaposes selfish brain and selfish immune system on a similar hierarchical level in terms of energy demand and requirements, 3) it respects that energy requirements convey an evolutionary pressure (highly energy-consuming states are acute [negative selection pressure], energy-storage is beneficial [positive selection pressure]), and 4) it accepts that either immune system activation or mental activation are equally important in inducing insulin resistance. On the basis of these elements a new model of insulin resistance is presented in Figure 1. This model states that insulin resistance is a beneficial acute catabolic program to serve the selfish immune system or the selfish brain, positively selected 1) for inflammation with an activated immune/repair system, and 2) for increased mental activation.
In conclusion, insulin resistance makes sense in acute alterations of homeostasis in the context of short-lived diseases but it is a misguided program in chronic inflammatory and mental activation.
Rainer H Straub – Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine, University Hospital Regensburg, Germany;
Corresponding author: Rainer H. Straub, MD; Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Division of Rheumatology, Department of Internal Medicine, University Hospital, 93042 Regensburg, Germany; Phone: +49 941 944 712, Email: firstname.lastname@example.org
The contents of this article were adapted from: Straub RH. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Research & Therapy 2014, 16 (Suppl 2):S4; published online in Arthritis Research & Therapy under the Creative Commons Attribution License 4.0.
Box 1. Inflammation-mediated insulin resistance
Currently, inflammation-mediated insulin resistance is the important explanatory platform of insulin resistance in adipocytes, myocytes and hepatocytes [5-8]. Disruption of insulin signaling at the level of insulin receptor substrate (IRS)-1 and IRS-2 and further downstream by TNF signaling, toll-like receptor signaling, NF kB and Ikk, and FoxO1 activation are key elements of inflammation related insulin resistance [7,9,10]. Crucial cytokines in insulin resistance are TNF, IL-1β, IL-6, IL-18, and adipokines. A relatively new aspect is nutrient-induced inflammation that leads to endoplasmic reticulum stress, activation of jun-N-terminal kinase (JNK), and inhibition of insulin receptor substrate 1(IRS-1) and AKT (v-akt murine thymoma viral oncogene homolog 1) and, thus, insulin resistance in liver and adipose tissue .
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