A Canadian physiologist, Han Selye, advanced the research on stress and its physiological effects in the body in a series of studies in rats. He found that chronic stress, regardless of the source, would produce characteristic changes in the body, and would, if prolonged, lead to the enlargement of the adrenal cortices, atrophy of the lymphatic organs, and ulcerations in the stomach and duodenum (though, we know now that other organs are involved.)
Broadly stated, stress is ever present, so continual demands are placed on the body requiring ongoing adaptation to maintain physical and chemical balance, as well as the integrative functioning of its parts. When this balance is disturbed, say, when stress is excessive or prolonged, the ability to adapt falters, fails, and, finally, pathology manifests.
In principle, these diseases of stress should be reversible, as long as the metabolic disturbances underlying them are eradicated, and oxygen and nutrients are supplied thereafter. Thus, the exposure to stressors and disease can be conceived to exist on different points of the same continuum. With regard to the interest of diseases, stress isn't the issue, as much as the body's ability to adapt to the stressors that it is continuously exposed to.
Considering the nature of stressors, especially how innocuous many of them seem, and the number of stressors we encounter daily, many of the hormones that execute the stress response can persist in the blood. The damages thereof are cumulative, and can, over time, diminish our ability to adapt, as we had before, leaving us more susceptible to degenerative processes associated with the excessive concentrations of the stress hormones, starting with the excessive mobilization of NEFA.
The regulation of NEFA was first clearly elucidated in the 1950s; and around the same time, the predominant source of NEFA was shown to be the adipose tissue (DOLE, 1956; GORDON & CHERKES, 1956).
With these discoveries, along with the established work on the hormonal control of fuel partitioning, the road was paved for Randle and his colleagues who thereafter demonstrated a so-called glucose-fatty acid cycle (Randle, Garland, Hales, & Newsholme, 1963). Randle and his colleagues’ discovery introduced a new layer of control – a sort of nutrient-mediated fine-tuning of fuel selection.
In addition to cortisol, which was the focus of Selye’s research, the other hormones that execute the stress response include adrenalin/noradrenalin, glucagon, aldosterone, growth hormone, thyroxin, and ADH (Lager, 1991). These hormones stimulate the mobilization of fatty acids, and thus raise blood NEFA concentrations. In diabetes (and old age and obesity), there is a tendency for blood NEFA concentrations to increase.
 |
| (Dole, 1956) |
Of the stress hormones, cortisol is central to the stress response, and its effects are multifaceted. For instance, cortisol increases the sensitivity of the α1-receptors to adrenalin and noradrenalin, potentiating their effects on tissues (Hoen et al., 2005).
Cortisol also interferes with the conversion of T4 to T3. T4 has a permissive effect on adrenalin, and without it, adrenalin couldn’t exert its actions on tissues (e.g., fatty acid mobilization [from adipose tissue]). Adrenalin, in turn, inhibits insulin secretion and stimulates the HPA axis, further reinforcing the inhibition on the conversion of T4 to T3.
Additionally, diabetics have an increase in sympathetic tone, which is also reinforced by angiotensin II – a peptide hormone released during stress on the depletion of sodium, magnesium, and water. The potentiating effects of cortisol and T4 on adrenalin, due to existing high concentrations of adrenalin from an increase in sympathetic tone, are thus even further amplified (Ward et al., 1996).
An increase in the activity of the sympathetic nervous system and the persistence of excessive concentrations of adrenalin, noradrenalin and cortisol in the blood are prominent risk factors for cardiovascular disease – of which diabetics, on average, have a 4- to 10-fold increase in risk for, as compared to non-diabetics.
Interestingly, strong or unrelenting stress weakens cortisol’s effectiveness in executing negative feedback at the hypothalamus; as a result, cortisol’s feedback loop functions from a higher set point, lowering the threshold above which pathology sets in. In diabetes (Alberti et al. 2007), obesity (Sims, Horton 1968), and old age (Deuschle et al. 1998), concentrations and production rates of cortisol are amplified.
Like cortisol, the other previously mentioned stress hormones, by activating the stress metabolism, lead to degenerative changes in the body.
At its core, the stress metabolism entails the oxidation of fat in preference to glucose, and the impairment in the ability to switch from one fuel source (fat) to another (carbohydrate [like after meals]) (Heather & Clarke, 2011). Thus, the stress metabolism implies a high rate of fatty acid oxidation, an energetically inefficient process; a high rate of fatty acid oxidation also leads to ectopic fat deposition (Chavez-Tapia, Rosso, & Tiribelli, 2012) and insulin resistance (through the accumulation of incompletely oxidized lipids inside cells and then, degradation of the insulin receptor).
On stimulation, fatty acids, namely polyunsaturated fatty acids, can decompose – especially against high glucose concentrations – and contribute aldehyde fragments that can form Schiff bases with amino groups on proteins inside and on the surface of cells. This is the initial step in AGE formation.
Glycation and AGE formation are commonly thought to be the prerogative of glucose only, but an in vitro study showed that CML – an AGE derived from fat and sugar – and its precursor, glyoxal, occurred faster in the presence of linoleate and arachidonate than glucose. In fact, about 96 percent more CML was formed from fat than from glucose (Fu et al., 1996).
Fatty acids also, by inhibiting PDH, permit the accumulation of triose phosphates (dihydroxyacetone phosphate and glyceraldehyde 3-phosphate) from sugars, too, resulting in insulin resistance and reactive aldehydes that can glycate proteins (and other lipids [initiating lipid peroxidation processes]) inside cells.
Recent results from 3 large clinical trials further reinforced the possible subsidiary role of glucose in diabetic complications. The trials were set up to determine whether lowering blood glucose concentrations to normal (or near normal) would curtail the risk of heart attacks in obese diabetics. Taken together, more deaths were incurred in those whose blood glucose concentrations were decreased to normality the most (Taubes, 2008).
Although obesity is highly predictive of diabetes – an observation that was first made known in the 1960s – it is not absolutely essential for it. Instead, the pattern of fat accumulation is a greater determinant of diabetes, because visceral fat is pathogenic, whereas subcutaneous fat, per se, is not. That is, on the depletion of visceral fat, by weight loss or surgery, the secretion of inflammatory peptides (e.g., angiotensinogen, leptin, TNF-α, and IL-6) decreases dramatically from subcutaneous fat.
Due to its density of β3 receptors, low density of insulin receptors, and direct access to the liver via the portal vein, on stimulation, fatty acids are shuttled from visceral fat to the liver, initiating all the degenerative effects therein associated with the stress metabolism, as described above.
In summary, because the chronic stressors of a lifetime cause feedback loops to function from a higher set point, the stress hormones persist in the blood longer and at higher concentrations. Fat is exclusively oxidized in preference to glucose as a result, and the rising glucose concentrations can, via oxidative stress, initiate lipid peroxidation processes, that in turn, damage mitochondrial respiratory complexes involved in oxidative metabolism.
In essence, diabetes can be regarded as a condition of unrelenting stress (like the kind Selye subjected his rats to) of which visceral adiposity, promoted by cortisol (and antagonized by progesterone), aggravates. Because he could, Selye carried out his experiments to where there was a progressive loss in adaptation, exhaustion, and breakdown of homeostatic mechanisms. These consequences are preceded by degenerative changes: disorganization of cell cytoplasm, cell swelling, lipid accumulation in cells, and damage to mitochondrial respiratory complexes.
The ability to continuously produce energy, as well as the provision of support for the dysregulated pattern of secretion of the stress hormones, however, short-circuits the progression of these degenerative changes and failure to adapt.
In conclusion, the common perception of diabetes – that it is a disease of too much sugar in the blood – misses the mark in a big way.
Cortisol, itself, can rapidly raise glucose concentrations by increasing the rate of gluconeogenesis in the liver, and by inhibiting the use of glucose by cells in the body. Cortisol also has a permissive effect on adrenalin and glucagon, both of which raise glucose concentrations, too. Hyperglycemia instead should be conceived as our resistance to stress, and as such, pharmacologically decreasing glucose concentrations is misguided, and, in effect, putting the cart before the horse.
Support for diabetics should entail, based on the discussion above, foremost, body fat reduction, rational dietary changes (e.g., eradicating unsaturated oils), calcium and magnesium, suppression of NEFA (e.g., with sugar, glycine, niacinamide, and red light), and restoration of glucose oxidation (e.g., with fructose and T3).
References
Cortisol also interferes with the conversion of T4 to T3. T4 has a permissive effect on adrenalin, and without it, adrenalin couldn’t exert its actions on tissues (e.g., fatty acid mobilization [from adipose tissue]). Adrenalin, in turn, inhibits insulin secretion and stimulates the HPA axis, further reinforcing the inhibition on the conversion of T4 to T3.
Additionally, diabetics have an increase in sympathetic tone, which is also reinforced by angiotensin II – a peptide hormone released during stress on the depletion of sodium, magnesium, and water. The potentiating effects of cortisol and T4 on adrenalin, due to existing high concentrations of adrenalin from an increase in sympathetic tone, are thus even further amplified (Ward et al., 1996).
An increase in the activity of the sympathetic nervous system and the persistence of excessive concentrations of adrenalin, noradrenalin and cortisol in the blood are prominent risk factors for cardiovascular disease – of which diabetics, on average, have a 4- to 10-fold increase in risk for, as compared to non-diabetics.
Interestingly, strong or unrelenting stress weakens cortisol’s effectiveness in executing negative feedback at the hypothalamus; as a result, cortisol’s feedback loop functions from a higher set point, lowering the threshold above which pathology sets in. In diabetes (Alberti et al. 2007), obesity (Sims, Horton 1968), and old age (Deuschle et al. 1998), concentrations and production rates of cortisol are amplified.
Like cortisol, the other previously mentioned stress hormones, by activating the stress metabolism, lead to degenerative changes in the body.
At its core, the stress metabolism entails the oxidation of fat in preference to glucose, and the impairment in the ability to switch from one fuel source (fat) to another (carbohydrate [like after meals]) (Heather & Clarke, 2011). Thus, the stress metabolism implies a high rate of fatty acid oxidation, an energetically inefficient process; a high rate of fatty acid oxidation also leads to ectopic fat deposition (Chavez-Tapia, Rosso, & Tiribelli, 2012) and insulin resistance (through the accumulation of incompletely oxidized lipids inside cells and then, degradation of the insulin receptor).
On stimulation, fatty acids, namely polyunsaturated fatty acids, can decompose – especially against high glucose concentrations – and contribute aldehyde fragments that can form Schiff bases with amino groups on proteins inside and on the surface of cells. This is the initial step in AGE formation.
Glycation and AGE formation are commonly thought to be the prerogative of glucose only, but an in vitro study showed that CML – an AGE derived from fat and sugar – and its precursor, glyoxal, occurred faster in the presence of linoleate and arachidonate than glucose. In fact, about 96 percent more CML was formed from fat than from glucose (Fu et al., 1996).
Fatty acids also, by inhibiting PDH, permit the accumulation of triose phosphates (dihydroxyacetone phosphate and glyceraldehyde 3-phosphate) from sugars, too, resulting in insulin resistance and reactive aldehydes that can glycate proteins (and other lipids [initiating lipid peroxidation processes]) inside cells.
Recent results from 3 large clinical trials further reinforced the possible subsidiary role of glucose in diabetic complications. The trials were set up to determine whether lowering blood glucose concentrations to normal (or near normal) would curtail the risk of heart attacks in obese diabetics. Taken together, more deaths were incurred in those whose blood glucose concentrations were decreased to normality the most (Taubes, 2008).
Although obesity is highly predictive of diabetes – an observation that was first made known in the 1960s – it is not absolutely essential for it. Instead, the pattern of fat accumulation is a greater determinant of diabetes, because visceral fat is pathogenic, whereas subcutaneous fat, per se, is not. That is, on the depletion of visceral fat, by weight loss or surgery, the secretion of inflammatory peptides (e.g., angiotensinogen, leptin, TNF-α, and IL-6) decreases dramatically from subcutaneous fat.
Due to its density of β3 receptors, low density of insulin receptors, and direct access to the liver via the portal vein, on stimulation, fatty acids are shuttled from visceral fat to the liver, initiating all the degenerative effects therein associated with the stress metabolism, as described above.
In summary, because the chronic stressors of a lifetime cause feedback loops to function from a higher set point, the stress hormones persist in the blood longer and at higher concentrations. Fat is exclusively oxidized in preference to glucose as a result, and the rising glucose concentrations can, via oxidative stress, initiate lipid peroxidation processes, that in turn, damage mitochondrial respiratory complexes involved in oxidative metabolism.
In essence, diabetes can be regarded as a condition of unrelenting stress (like the kind Selye subjected his rats to) of which visceral adiposity, promoted by cortisol (and antagonized by progesterone), aggravates. Because he could, Selye carried out his experiments to where there was a progressive loss in adaptation, exhaustion, and breakdown of homeostatic mechanisms. These consequences are preceded by degenerative changes: disorganization of cell cytoplasm, cell swelling, lipid accumulation in cells, and damage to mitochondrial respiratory complexes.
The ability to continuously produce energy, as well as the provision of support for the dysregulated pattern of secretion of the stress hormones, however, short-circuits the progression of these degenerative changes and failure to adapt.
In conclusion, the common perception of diabetes – that it is a disease of too much sugar in the blood – misses the mark in a big way.
Cortisol, itself, can rapidly raise glucose concentrations by increasing the rate of gluconeogenesis in the liver, and by inhibiting the use of glucose by cells in the body. Cortisol also has a permissive effect on adrenalin and glucagon, both of which raise glucose concentrations, too. Hyperglycemia instead should be conceived as our resistance to stress, and as such, pharmacologically decreasing glucose concentrations is misguided, and, in effect, putting the cart before the horse.
Support for diabetics should entail, based on the discussion above, foremost, body fat reduction, rational dietary changes (e.g., eradicating unsaturated oils), calcium and magnesium, suppression of NEFA (e.g., with sugar, glycine, niacinamide, and red light), and restoration of glucose oxidation (e.g., with fructose and T3).
References
Chavez-Tapia, N. C., Rosso, N., & Tiribelli, C. (2012). Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease. BMC gastroenterology, 12, 20. doi:10.1186/1471-230X-12-20
DOLE, V. P. (1956). A relation between non-esterified fatty acids in plasma and the metabolism of glucose. The Journal of clinical investigation, 35(2), 150–4. doi:10.1172/JCI103259
Fu, M. X., Requena, J. R., Jenkins, A. J., Lyons, T. J., Baynes, J. W., & Thorpe, S. R. (1996). The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. The Journal of biological chemistry, 271(17), 9982–6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8626637
GORDON, R. S., & CHERKES, A. (1956). Unesterified fatty acid in human blood plasma. The Journal of clinical investigation, 35(2), 206–12. doi:10.1172/JCI103265
Heather, L. C., & Clarke, K. (2011). Metabolism, hypoxia and the diabetic heart. Journal of molecular and cellular cardiology, 50(4), 598–605. doi:10.1016/j.yjmcc.2011.01.007
Hoen, S., Mazoit, J.-X., Asehnoune, K., Brailly-Tabard, S., Benhamou, D., Moine, P., & Edouard, A. R. (2005). Hydrocortisone increases the sensitivity to alpha1-adrenoceptor stimulation in humans following hemorrhagic shock. Critical care medicine, 33(12), 2737–43. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16352953
Lager, I. (1991). The insulin-antagonistic effect of the counterregulatory hormones. Journal of internal medicine. Supplement, 735, 41–7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2043222
Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963). THE GLUCOSE FATTY-ACID CYCLE ITS ROLE IN INSULIN SENSITIVITY AND THE METABOLIC DISTURBANCES OF DIABETES MELLITUS. The Lancet, 281(7285), 785–789. doi:10.1016/S0140-6736(63)91500-9
Taubes, G. (2008). Diabetes. Paradoxical effects of tightly controlled blood sugar. Science (New York, N.Y.), 322(5900), 365–7. doi:10.1126/science.322.5900.365
Ward, K. D., Sparrow, D., Landsberg, L., Young, J. B., Vokonas, P. S., & Weiss, S. T. (1996). Influence of insulin, sympathetic nervous system activity, and obesity on blood pressure: the Normative Aging Study. Journal of hypertension, 14(3), 301–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8723982