Metabolism When Stress (Part 2)

Cont.

03 Stress and Glucose Metabolism

• Under normal conditions the gluconeogenesis occurs during starvation to supply glucose to the cells, especially the brain which is dependent on the glucose. Stress increases the hepatic glucose production by increasing the activities of key gluconeogenic enzymes:  phosphoenol pyruvate carboxy kinase  (PEPCK), pyruvate carboxylase, fructose 1,6 bisphosphatase (FBPase) and glucose-6-phosphatase (G6Pase). All these key regulatory enzymes are transcriptionally regulated by glucocorticoids.
• Glucocorticoids also stimulate the expression of pyruvate carboxylase and glucose-6-phosphatase. In addition stress increases the activities of aminotransferases, glutamic pyruvic transaminase (GPT) and glutamic oxaloacetatic transaminase (GOT) which further increase the concentration of substrates like pyruvate and oxaloacetate for gluconeogenesis. 
• Glucocorticoids are known to increase the blood glucose levels under stressful conditions by not only increasing gluconeogenesis but also by reducing insulin sensitivity. The glucocorticoids exert this action by antagonizing insulin stimulated translocation of glucose transporters from intracellular compartments to plasma membrane. 

04 Stress and Weight Gain or Loss

• Weight gain or loss is generally an issue both during and after times of elevated stress. Heightened stress levels tend to cause imbalances in hormones like cortisol, DHEA and adrenaline. Increased stress stimulates our adrenal glands to produce excessive and inadequate amounts of these hormones. When stress subsides, hormone levels should stabilize, but occasionally the irregular hormone levels remain in tact for long periods of time, often having negative effects on our bodies.
• Cortisol in particular is often linked with weight fluctuation. Both an excess and deficiency of cortisol can impact blood sugar levels and thyroid function, trigger weight fluctuation and symptoms of low metabolism.

Cortisol Level Increase

The cells of our body can become resistant to insulin. In turn, this may lead to an increase in blood sugar, weight gain and potentially Type 2 Diabetes. Cortisol decreases TSH, lowering thyroid hormone production. Cortisol inhibits the conversion of T4 (Thyroxine) to active T3 (3,5,3’-tiiodothyronine), and increases the conversion of T4 to reverse T3, causing weight gain.

Cortisol Level Decrease

This is known as adrenal exhaustion. If this occurs, blood sugar levels may decrease, causing hypoglycaemia, linked to weight loss and a low stress tolerance. 

05 Stress and Heart Disease

• Endothelial dysfunction with imbalance of local arterial mediators and resulting loss of functional dilation is one of the earliest signs of atherosclerosis.
• Psychological stress induces cytokines, which, together with the major stress hormones corticosteroids and catecholamines cause endothelial damage. Besides, Endothelial damage can cause by immune/ inflammatory response and increased endothelial reactivity triggered by activation of immune cells.
• Stress-induced immune response also influences the trafficking and infiltration of monocytes and/or lymphocytes. Vascular monocytes can express the highest levels of type II GR (Glucocorticoid Receptor) and it is likely that elevated levels of corticosteroids by stress would especially enhance their migration to vascular wall. 
• At the same time, corticosteroids can induce adhesion molecule synthesis directly, thereby promotting the adhesion of vascular monocytes to these sites.
• Corticosteroids could further facilitate infiltration of monocytes by increasing the expression of IL-1 and IL-6 (Interleukin 1 and 6) receptors on endothelial cells at the affected site. These monocytes and/or lymphocytes, after attaching to such sites, would commence the process of infiltration into the vessel wallsdone of the earliest steps in the progression of atherosclerosis.

• People who are experiencing chronic stress have cortisol levels that are already high, causing the heart to beat more rapidly than normal, blood vessel restriction is quite dangerous. 
• When the supply of oxygenated blood to the heart via coronary artery (which circulates oxygen−rich blood from the lungs to the heart itself)  is not enough to support the heart’s substantial work load, in the worse case, a heart attack may occur. Sometimes the individual may not even be aware of developing ischemia (an interruption in the flow of blood to the heart), in which case it is considered to be “silent.” 
• However, it is thought that silent ischemia can lead to full−blown heart attack, made even more likely by the fact that people who suffer from it, because they are unaware of it, would not seek treatment or make the appropriate changes to their lifestyles to reverse it.

06 Stress and Sleep Disruption

Sleep time vs cortisol

• Sleep and stress interact in a bidirectional fashion, sharing multiple pathways that affect the nervous system and metabolism. Hormones from the hypothalamic –pituitary–adrenal (HPA) axis modulate the sleep–wake cycle, while its dysfunction can disrupt sleep. In turn, sleep loss influence the HPA axis, leading to hyperactivation.
• The secretory activity of the HPA axis follows a distinct 24 h pattern. CRH is released in a circadian-dependent and pulsatile manner from the parvocellular cells of the PVN. In fact, the circadian rhythm of cortisol secretion derives from the connection between the PVN and the central pacemaker, the suprachiasmatic nucleus (SCN)
• Typically, the nadir (time point with the lowest concentration) for cortisol occurs near midnight. Then, cortisol levels increase 2–3 h after sleep on set, and keep rising into to the waking hours. The peak happens in the morning at about 9 a.m. Along the day, there is a progressive decline that is potentiated by sleep, until it reaches the nadir and the quiescent period.

• The misalignment of the sleep–wake cycle has a negative impact on the stress system. Alterations of the HPA axis may play a causative role in sleep disorders such as insomnia. Insomnia is a sleep disorder characterized by difficulties in falling or staying asleep or having restorative sleep, associated with day time impairment or distress. 
• One study did not show any significant differences in urinary cortisol between control and poor sleepers. However, another study presented excessive activation of the HPA axis induces sleep fragmentation, while the sleep fragmentation increases cortisol levels, suggesting that the HPA axis may contribute to the initiation as well as the perpetuation of chronic insomnia. 
• There is still debate whether the activation of the HPA axis found in insomnia is secondary to sleep loss or a marker of CRH activity. 

1. Stress can affect the function of the immune system, the body’s natural means of fighting off infection. Compounds called cytokines, are secreted during the body’s immune response, and increased blood levels of the compounds are a telltale sign that the body is in the process of fighting infection. 
2. Chronic stress has been found to disrupt the normal immune response: now cytokines may be chronically present in the system, but rather than acting to heal the body, chronic inflammation may result instead.
3. Though many people use the term “stressed out” somewhat loosely to describe their state of being at the moment, feeling stressed mentally and physically is a serious concern, as should be evident from the number of complications that can result from chronic stress.
4. Whether feelings of stress are new or have been felt over a long period of time, it’s important to address these concerns, and find ways to relieve the underling stressors for the long term. It may be a good idea to consult with health care provider to discuss the stressors and begin to determine specific approaches to reduce it.

References :

Block, J. P., He, Y., Zaslavsky AM, Ding L, Ayanian JZ. 2009. Psychosocial stress and change in weight among US adults. Am J Epidemiol 170(2): 181−9.

Burg, M.M., 1992, Heart Book (Yale University School of Medicine). Chapter 8: 94−104 http://www.med.yale.edu/library/heartbk/8.pdf

Leproult, R., Copinschi, G., Buxton, O., and Van, C. E., 1997, Sleep loss results in an elevation of cortisol levels the next evening, Sleep 20(10): 865−870.

Hirotsun, C., Tufik, S., and Andersen, M. L., 2015, Interactions between sleep,stress,and metabolism: From physiological to pathological conditions, Sleep Science 8: 143-152.

McEwen B & Krahn D. http://www.thedoctorwillseeyounow.com/content/art1965.html?getPage=2

Nirupama, R., Rajaraman, B., and Yajurvedi, H.N., 2018, Stress and Glucose metabolism: A Review, Imaging Journal of Clinical and Medical Sciences, 5(1): 008-012.

Trentini, D., 2015, Cortisol and Thyroid Hormones, https://hypothyroidmom.com/cortisol-and-thyroid-hormones/.

Vgontzas A.N., Bixler EO, Wittman AM, Zachman D, Lin H.M., 2001, Middle−aged men show higher sensitivity of sleep to the arousing effects of corticotropin−releasing hormone than young men: Clinical implications, J Clin Endocr Metab 86(4): 1489−1495.

Vgontzas, A.N., Bixler, E.O., Lin, H.M., Prolo, P., and Mastorakos, G., 2001, Chronic insomnia is associated with nyctohemeral activation of the hypothalamic−pituitary −adrenal axis: Clinical implications. J Clin Endocr Metab 86(8): 3787−3794.

Wurtman, J.J., 1993, Depression and weight gain: the serotonin connection, Journal ofAffective Disorders, 29: 183-192