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When we blame obesity exclusively on insulin, we are being radically simplistic. Not only because we are ignoring, for example, the satiating effect that this hormone can have or the implication at the muscular level that it induces, since it will cause the muscle tissue to store glucose, up to 80%, but of course, if we do something to deplete these glycogen deposits, such as caloric restriction or exercise. In addition, insulin will help to conserve this muscle mass, not so much for its anabolic effect (which it also has) but above all for its powerful effect on muscle catabolism. Thus, physical activity, physical exercise and muscle tissue have a lot to say about this problem. In fact, the feared de novo lipogenesis will not be a fact that occurs (at least substantially) in active people and/or athletes. So, apart from all the above, where we mostly go wrong when simplifying this story, is in the context of the subject.

And it is towards this subject that I want to continue this text…. let’s continue…

Both obesity and its associated comorbidities are the consequence of the disparity between human biology and the contemporary human environment. Increasing evidence shows that current social conditions promote chronic sedentary lifestyles, with many hours a day spent in a seated position.

This relative inactivity coupled with unhealthy nutrition is metabolically toxic: it distorts body composition and alters glucose homeostasis.

The public has been told ad nauseam that exercise and weight control are essential to prevent Obesity and diabetes, but has not been provided with comprehensive information that convinces them. An evolutionary perspective, along with the concept of insulin receptor competence, may fill that need.

THE “SELFISH” BRAIN AND ENERGY REALLOCATION

Our sensitivity to develop insulin resistance can be traced back to our rapid brain growth over the past 2.5 million years. An inflammatory reaction jeopardizes our brain’s high glucose needs, triggering several adaptations, such as insulin resistance, functional reallocation of energy-rich nutrients, and change in serum lipoprotein composition.

Systemic inflammation causes insulin resistance and compensatory hyperinsulinemia that strives to keep glucose homeostasis in balance. Our glucose homeostasis ranks high in the hierarchy of energy balance, but is ultimately compromised in ongoing inflammatory conditions through glucotoxicity, lipotoxicity, or both, leading to the development of beta-cell dysfunction and eventually type 2 diabetes mellitus.

Insulin resistance has a bad name. The ultimate goal of this survival strategy is, however, deeply anchored in our evolution, during which our brain has grown enormously. The goal of reduced insulin sensitivity is, among others, the reallocation of energy-rich nutrients due to an activated immune system, the limitation of the immune response and the repair of inflicted damage.

Homo sapiens and present-day chimpanzees share a common ancestor, who lived in Africa about 6 million years ago. Since about 2.5 million years ago, our brains have grown strongly from an estimated volume of 400 ml to the current volume of approximately 1400 ml. This growth was made possible by the discovery of a high quality dietary source, which was easy to digest and contained an ample amount of nutrients, necessary for the construction and maintenance of a larger brain.

Our brain consumes 20-25% of our basal metabolism and is therefore, together with the liver (19%), our gastrointestinal tract (15%) and skeletal musculature (15%) one of the quantitatively most important organs in energy consumption. Due to the high energy expenditure of a large brain, it was necessary to make several adjustments in the size of other organs. There is a linear relationship between body weight and basal metabolism among terrestrial mammals. This seemingly dogmatic relationship predicts that, due to the growth of our brain, other organs with high energy consumption had to be reduced in size. As a consequence, our intestines, among others, had to be reduced in size. The trigger for this process was the consumption of easily digestible high-quality food. Also our muscle mass adapted, as its current size is relatively small compared to our body weight. For example, compared to the chimpanzee, we are definitely weak. On the other hand, we have a relatively large fat mass, which probably serves as a guarantee for the high energy requirement of our brain.

The energy consumption of our brain is quite stable and occupies a high place in the functional hierarchy and must be provided with the necessary energy at all times.

Under normal circumstances, our brain runs almost entirely on glucose, consuming up to 130 g/day. Compared to the seemingly unlimited storage capacity of fat, we have only a small reserve of glucose that is stored as glycogen in the liver (up to 100-120 g, mobilizable) and muscles (360 gr-500gr “for local use”). With the exception of glycerol, we cannot convert fat into glucose. The reduced carbohydrate intake that arose during evolution with the transition from vegetarians to omnivores made us very dependent on amino acid gluconeogenesis. This was possible because we simultaneously consumed more protein from meat and fish, which is also known as the “carnivore connection” . After depletion of our glycogen stores, for example after an overnight fast, we obtain the glucose necessary for our brain through gluconeogenesis from glycerol and amino acids. Under normal conditions, these amino acids are derived from our dietary proteins after a meal, but during starvation, they are extracted from our tissues by catabolism of functional proteins, at the expense of our lean body mass, i.e., at the expense of our muscle. Under such circumstances of severe glucose deficit, the energetic need of our brain becomes more and more covered by fat ketone bodies.

A glucose deficit leads to competition between organs for the available glucose. As mentioned above, this occurs during fasting, but also during pregnancy and infection/inflammation, and in my opinion, this fact makes a ketogenic diet not optimal for muscle mass gain, since after training-induced damage, a physiological inflammatory response occurs which is key in muscle regeneration. The cells of the immune system involved in this muscle regeneration are among others neutrophils and macrophages, which have a highly glycolytic system and therefore depend to a large extent on glucose.

Fasting is characterized by a generalized shortage of glucose (and other macronutrients), but in case of inflammation, we deal with active compartments competing with the brain for the available glucose, i.e. the activated immune system. During inter-organ competition for glucose, we meet the high glucose needs of the brain by a reallocation of energy-rich nutrients, and for this we need to become insulin resistant, i.e. drift glucose to these cells.

During infection/inflammation we deal with the metabolic needs of an activated immune system for acute survival. The quiescent immune system consumes approximately 23% of our basal metabolism, of which up to 50% is derived from glucose and the amino acid glycogen glutamine (25%), the remainder being fatty acids and ketogenic bodies. After activation, the energy requirement of our immune system may increase with about 9-30% of our basal metabolic rate. In multiple fractures, sepsis and extensive burns, we deal with increases of up to 15-30, 50 and 100% of our basal metabolic rate, respectively.

Well, the way we save glucose for our brain during starvation or ketosis and for the immune system during infection/inflammation is by causing insulin resistance in certain insulin-dependent tissues. These tissues are forced to switch to fat burning. Due to insulin resistance, the adipose tissue compartment will be encouraged to distribute free fatty acids, while the liver will be encouraged to produce glucose through gluconeogenesis and distribute triglycerides through very low density lipoproteins (VLDL).

Glucose intolerance and insulin resistance have been reported in caloric restriction, extreme fasting and anorexia nervosa, and may even cause, in these circumstances, type 2 diabetes mellitus, especially in subjects sensitive to its development.

Insulin resistance refers especially to a markedly reduced decrease in circulating glucose concentration by insulin. However, insulin has many functions, and therefore exerts different effects on the various organs carrying the insulin receptor. This compensatory increase in circulating insulin levels is aimed at preventing a disturbance of glucose homeostasis and thus the onset of type 2 diabetes mellitus. The persistence of compensatory hyperinsulinism is responsible for most, if not all, of the abnormalities that belong to the metabolic syndrome.

In muscle and fat cells, insulin resistance induces decreased glucose uptake and thus reduced storage of glucose as glycogen and triglycerides. In fat cells, it causes decreased uptake of circulating lipids, increased hydrolysis of stored triglycerides and their mobilization as free fatty acids and glycerol. In liver cells, insulin resistance induces the inability to suppress glucose production and secretion, in addition to decreased glycogen synthesis and storage. The reallocation of energy-rich substrates (glucose to the brain and immune system) and compensatory hyperinsulinemia are intended for short-term survival and their persistence as a chronic state underlie the later changes we recognize as the symptoms of metabolic syndrome, including:

-Reduction of insulin sensitivity (glucose and lipid redistribution, hypertension).

-Increased sympathetic nervous system activity (stimulation of lipolysis, gluconeogenesis and glycogenolysis)

-Increased activity of the HPA axis (hypothalamus-pituitary-adrenal gland axis), i.e. stress.

-Increased cortisol, gluconeogenesis, with cortisol resistance

-Decreased activity of the HPG (hypothalamo-pituitary-gonadal) axis

-Resistance to IGF-1 (insulin-like growth factor-1)
-In addition to sarcopenia, androgen/estrogen imbalance, inhibition of sexual activity and reproduction, the appearance of “sickness behavior” (energy saving, sleep, anorexia, minimal activity of muscles, brain and intestine).

Summarizing so far, humans are extremely sensitive to glucose deficits, because our large brain runs mainly on glucose. During starvation and infection/inflammation, we become insulin resistant, along with many other adaptations. The goal is the reallocation of energy-rich substrates to save glucose for the brain and our activated immune system which also runs primarily on glucose. Under these conditions, insulin-resistant tissues are supplied with fatty acids.

Glucose regulation is thus an ancestral process that has operated in the context of body composition (muscle tissue to adipose tissue ratios) as observed in free-living wild-type animals. However, agriculture and social stratification among humans led to the emergence of elite groups and nobility in whom food acquisition and physical exertion became dissociated. This promoted obesity among the wealthy. More recently, the social impact of industrialization has further increased this fact, which has further altered the proportions of fat and muscle in many humans, rich or not, and also in some of their household pets.

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