Can stress trigger diabetes?
Diabetes often occurs due to stress, poor nutrition and a sedentary lifestyle. In a stressful situation, all the body’s forces are concentrated on the changes taking place. This leads to suppression of the gastrointestinal tract, decreased sex drive and insulin release.
Under stress, a hyperglycemic state and insulin deficiency develop, as it reflexively inhibits basal insulin secretion and promotes the release of sugars.
Chronic stress can cause a decrease in blood glucose, so a person automatically tends to eat foods that can quickly increase sugar. Excessive indulgence in fatty and sugary foods results in weight gain. Against this background, insulin enters the blood in greater quantities than necessary. This negatively affects the condition of the pancreas and can provoke diabetes.
Another factor that proves the relationship between stress and diabetes is increased hormonal release, which provokes increased activity of the thyroid gland. If a person is constantly in a stressful situation, then his level of glucocorticosteroids increases. A complication in this case can be not only diabetes, but even a heart attack or stroke.
Stressful situations can lead to diabetes. In some cases, pathology is provoked by chronic stress, in others – one episode is enough.
Recently, diabetes mellitus (DM) has firmly taken a leading position among diseases that cause disability and mortality. According to WHO data [1], as of January 2010, there were 285 million patients with diabetes, and according to forecasts, by 2030 this number will reach 438 million. Moreover, more than 90% will be people with type 2 diabetes mellitus (T2DM). . In Russia in 2010, 2,822,634 patients with T2DM were registered. The catastrophic increase in the number of cases requires an increasingly detailed study of the pathogenesis of T2DM complications and the development of new approaches to their prevention and treatment.
Formation of oxidative stress in diabetes mellitus
In diabetes, “ideal” conditions arise for the formation of oxidative stress: the content of oxidation substrates (glucose and lipids) increases and the formation and activity of natural antioxidant systems, such as glutathione, superoxide dismutase, catalase and glutathione peroxidase, decreases [2].
Currently, many authors [3] consider oxidative stress as the “universal basis” for the development of all complications in diabetes, caused, in particular, by impaired endothelial function. Moreover, oxidative stress induced by hyperglycemia triggers mechanisms of β-cell damage and thereby accelerates the progression of diabetes [4, 5].
During oxidative stress, free radicals are formed - molecules that have an unpaired electron in the outer orbit, which gives them increased reactivity. Free radicals seek to obtain a second electron from other molecules, leading to disruption of their structure and function [6]. Free radicals are a heterogeneous group, but the largest number of them belong to reactive oxygen compounds. Oxidation of glucose leads to the formation of reactive oxygen species (ROS): superoxide (•O2–), hydroperoxyl (•HRO2–), hydroxyl radical (•OH), peroxyl radical (•RO2). Active nitrogen particles are also formed: nitric oxide (•NO), nitrogen dioxide (•NO2–), peroxynitrite (ONOO–).
Against the background of hyperglycemia, many metabolic pathways are activated, responsible for increasing the formation of ROS and thereby the formation of oxidative stress (Fig. 1):
Figure 1. Effect of hyperglycemia on superoxide production in endothelial cells.
1. Activation of the polyol glucose oxidation pathway, in which glucose is converted to sorbitol, leads to NADPH depletion. This coenzyme is involved in the formation of glutathione, an important antioxidant. A decrease in NADPH levels leads to a decrease in glutathione activity and an increase in oxidative stress [7].
2. Increased conversion of sorbitol to fructose under the action of sorbitol dehydrogenase leads to an increase in the level of diacylglycerol, which in turn activates protein kinase C (PKC) [8]. Under the influence of PKC, the enzyme that forms superoxide NADFH oxidase is induced in endothelial and smooth muscle cells.
3. As a result of non-enzymatic glycation, the end products AGEs are formed, which alone or through the receptor for AGEs (RAGEs) leads to the production of ROS [9, 10]. Advanced glycation end products are also important activators of the NADFH oxidase enzyme.
4. Activation of NADFH oxidase in endothelial and smooth muscle cells is one of the most important sources of ROS. This enzyme is activated by PKC, advanced glycation end products, insulin, and antiotensin II [11].
5. The mitochondrial respiratory chain is also an important site of ROC overproduction. Under normal conditions, almost all oxygen is used in mitochondria for the synthesis of ATP and only 1-2% goes to the synthesis of reactive oxygen species. Under diabetes conditions, this ratio shifts towards superoxide synthesis [12, 13].
Another important component in the development of oxidative stress is a decrease in antioxidant defenses. All tissues are capable of producing reactive oxygen species and each tissue contains a certain amount of antioxidant enzymes. The key enzymes in ROS catabolism are superoxide dismutase (SOD), catalase, glutathione (GSH) and glutathione peroxidase (GP×). SOD-1 and SOD-2 metabolize the superoxide radical to hydrogen peroxide (H2O2). Catalase acts in peroxisomes and metabolizes H2O2 to oxygen and water. Glutathione peroxidase, consisting of 6 isoenzymes, is found in the cytoplasm and mitochondria and metabolizes peroxidized lipids and hydrogen peroxide to water and oxygen. Hyperglycemia causes glycosylation and inactivation of antioxidants, and decreased SOD activity and decreased glutathione availability are indicators of the presence of chronic oxidative stress [14]. in vitro experiments
while maintaining constant activity of SOD and catalase, there was no increase in oxidative stress and damage to endothelial function, even under conditions of hyperglycemia.
The role of oxidative stress in the development of endothelial dysfunction and atherosclerosis
One of the pathogenetic basis of macrovascular complications in diabetes is atherosclerosis. The triggering factor for the development of atherosclerosis is currently considered to be endothelial dysfunction accompanying diabetes [15].
Among the many substances produced by the endothelium, nitric oxide (NO) is especially important. NO not only maintains vascular tone, being one of the most powerful vasodilators, but also performs a number of other important functions, participating in the regulation of physiological processes in the cardiovascular system and preventing atherogenesis. The antiatherogenic properties of nitric oxide are realized by inhibiting the migration and proliferation of smooth muscle cells, i.e. formation of neointima and vascular hypertrophy [16]. NO also blocks the expression of endothelial adhesion molecules - ICAM-1, VCAM-1, E-selectin and monocyte chemotactic peptides; reduces aggregation, adhesion and infiltration of the vascular wall by neutrophils and monocytes. Moreover, NO inhibits platelet aggregation and adhesion. Thus, nitric oxide prevents the development of inflammation and atherosclerotic process in the vascular wall [17, 18].
Increased formation of ROS in diabetes leads to the development of endothelial dysfunction and atherosclerosis (Fig. 2).
Figure 2. The role of reactive oxygen species in the formation of atherosclerosis. The first thing to note is that increased levels of ROS (especially superoxide anion) cause disruption of NO synthesis and activity. Superoxide anion combines with NO to form a strong oxidant, peroxynitrite (ONOO–); as a result, NO loses its biological activity and antiproliferative properties. Peroxynitrite damages cells by nitrating proteins. Nitration inhibits the potassium channels responsible for vasorelaxation. Peroxynitrite can also damage DNA, which is an obligatory stimulus for the activation of the nuclear enzyme PARP [19]. This polymerase depletes the intracellular concentration of NAD+, slowing down glycolysis, electron transport and ATP formation, and blocks the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which leads to endothelial dysfunction and the development of diabetic complications.
Another mechanism for reducing NO synthesis is the uncoupling of eNOS against the background of oxidative stress. Under physiological conditions, eNOS exists as a dimer and produces NO. The synthesis of NO requires the action of a cofactor, tetrahydrobiopterin (BH4). With a lack of this substance, the action of the enzyme shifts towards the synthesis of superoxide. Peroxynitrite (ONOO–) oxidizes BH4, which leads to the uncoupling of eNOS and the production of superoxide anion instead of NO [20–22].
The second aspect of the action of ROS is the induction of the expression of ICAM-1, VCAM-1, which leads to the adhesion of monocytes, lymphocytes to the endothelial wall and to facilitating the penetration of lipid-laden monocytes, lipids and platelets into the subendothelial space [23]. Moreover, excessive production of superoxide and hydroxyl radicals initiates the oxidation of LDL. Due to their toxicity, peroxide-modified LDL damages the endothelial lining of arteries and also accumulates in the subendothelial space [24]. Here they acquire the ability to secrete biologically active compounds (growth factors, chemotoxins, mitogens). These compounds stimulate the migration of smooth muscle cells and fibroblasts from the media to the intima, their proliferation and the synthesis of connective tissue. ROS also regulate the expression of various growth factors and growth proto-oncogenes (c-Myc, c-Fos and c-Jun [25]. This leads to proliferation and migration of smooth muscle cells into the intima of arteries and increased production of collagen and elastin [26, 27]. All of the above mechanisms ultimately lead to atherosclerosis and thrombosis.
The role of reactive oxygen species in the progression of β-cell dysfunction
As noted above, hyperglycemia in diabetes is the main initiator of the development of oxidative stress in many tissues; β-cells are no exception and, moreover, may be particularly susceptible to oxidative stress because they contain extremely low levels of antioxidants [28, 29]. In pancreatic islets, a decrease in the expression of antioxidant genes and an almost complete absence of glutathione peroxidase activity were found [30]. In studies by H. Takahashi et al. D-glyceraldehyde (D-GLIC) has been shown to have dual effects on insulin formation and secretion depending on intracellular concentrations [31]. At low concentrations (<2 mM), D-GLIC improves insulin response to glucose, but at high concentrations inhibits glucose-induced insulin secretion. Administration of the antioxidant NAC (N-acetyl-L-cysteine) blocked the adverse effect of high doses of D-GLIC on insulin secretion. J. Pi et al. [32] came to the surprising conclusion that H2O2 facilitates glucose-dependent insulin secretion and suggested that high levels of antioxidant activity in this situation might reduce insulin secretion. Thus, under conditions of hyperglycemia and oxidative stress in diabetes, the pancreas appears to be less protected compared to surrounding tissues. When exposed to supraphysiological levels of ROS, there is a decrease in insulin mRNA expression, a decrease in insulin secretion, and a decrease in glucose-induced insulin secretion [33]. These changes are associated with a weakening of insulin DNA binding to the transcription factor PDX-1 (the main transcription factor for the formation and differentiation of β-cells) and MafA (a potent transcriptional activator of the insulin gene) [34, 35]. In experiments, the use of antioxidants restored the expression of transcription factors and their binding to DNA. Based on this, we can conclude that chronic hyperglycemia causes a decrease in insulin synthesis and secretion as a result of the damaging effect of ROS on the main transcription factors in the pancreas PDX-1 and MafA. Y. Tanaka et al. [36] studied the effect of antioxidants (NAC and aminoguanidine) in diabetic rats. In HIT-T15 cell culture, an increase in the promoter activity of the insulin gene, an improvement in DNA binding to PDX-1 and MafA, and an increase in the level of insulin mRNA under the influence of antioxidants were detected. Next, the effect of these antioxidants was studied in rats with diabetes mellitus (ZDF). These drugs prevented oxidative stress caused by hyperglycemia and increased insulin gene expression. Similar results were obtained by H. Kaneto et al. [37, 38]: The β-cell mass of mice treated with antioxidants was significantly greater than that of untreated mice. Thus, antioxidant treatment suppresses β-cell apoptosis and prevents oxidative stress-induced loss of β-cell mass without altering cell proliferation.
These data allow us to conclude that oxidative stress caused by chronic hyperglycemia leads to a decrease in the functional mass of β-cells. These cells are very vulnerable because their antioxidant capabilities are extremely low. Reduced expression and binding of MafA and PDX-1 (essential regulators of insulin gene expression) may be the underlying mechanism of glucose toxicity. Antioxidants prevent the progression of β-cell damage in diabetes in animal models and isolated pancreatic islets.
Treatment
Based on the above, it is obvious that the pathogenetic therapy for complications in diabetes mellitus is antioxidant therapy; Moreover, the use of antioxidants in the experiment reduces apoptosis and preserves β-cell mass. Although in experiments large doses of antioxidant vitamins (vitamins C, E) and powerful antioxidants (NAC and aminoguanidine) prevent oxidative stress, this effect cannot be achieved in the clinic. The development of fundamentally new antioxidants (superoxide dismutase mimetics, catalase, PKC blockers) may open a new era in the treatment and prevention of diabetes.
Adjuvant therapy with antioxidants may increase the effectiveness of traditional antidiabetic drug treatment. Considering the fact that all modern hypoglycemic drugs have almost the same effectiveness in terms of reducing HbA1C (by about 1-1.5%), it is necessary to prescribe drugs that additionally affect oxidative stress, improve endothelial function and slow down the development of cardiovascular complications.
One such drug is Gliclazide MB (a second generation sulfonylurea drug), which has a unique structure. In addition to its high hypoglycemic potential, this drug has a number of interesting properties. Investigating its effect on oxidative stress, K. Kimoto et al. [39] found that under conditions of oxidative stress caused by H2O2, it better protects β-cells from death than glibenclamide (55.9% of surviving cells in the gliclazide group and 30% in the glibenclamide group, p < 0.01). In in vitro studies, gliclazide acted as a free radical scavenger [40]. In a 6-month study by P. Jennings et al. [41] patients receiving gliclazide therapy showed lower concentrations of peroxide-modified lipids, higher SOD levels, and a more pronounced decrease in platelet aggregation than patients with diabetes treated with glibenclamide. At the same time, the level of glycated hemoglobin was the same in both groups, which confirms the independence of the effects of the drugs from their hypoglycemic effect. R. Brein [42] studied in vitro the effect of 1 μM gliclazide, glibenclamide, glimepiride, glipizide and tolbutamine on total plasma antioxidant activity (TAA) and LDL oxidation and in vivo assessed the antioxidant effect of gliclazide in a 10-month observation of 44 patients with T2DM. The results obtained in vitro showed an increase in the resistance of LDL to oxidation under the influence of gliclazide; other drugs from the sulfonylurea group did not affect this indicator. Similar results were obtained with respect to PAKP: only gliclazide increased the antioxidant potential of plasma (from 1.09±0.11 to 1.23±0.11 mmol/l; p<0.01). In an in vivo study, levels of isoprostane, OACP, SOD and thiol compounds were determined during gliclazide therapy. Treatment with gliclazide improved all these parameters. Thus, gliclazide has antioxidant properties. The authors suggested that this property is associated with specific features of the molecular formula of gliclazide. The study by A. Desfait [43] included patients with T2DM with unsatisfactory glycemic control while taking glyburide. 3 months after transferring these patients to gliclazide MB therapy, their levels of lipid peroxides decreased, monocyte adhesion decreased, and TNF-α production decreased, which is important in terms of preventing atherosclerosis.
An increase in arterial intima-media thickness is a predictor of the development of myocardial infarction and stroke [44]. In a 3-year study by N. Katakami et al. [45] showed that in patients with T2DM, gliclazide and metformin limit the increase in carotid artery intima-media thickness to a greater extent (p<0.05), regardless of their effect on glycated hemoglobin and blood pressure, than glibenclamide. The authors concluded that taking gliclazide and metformin reduces the progression of the atherosclerotic process in the carotid arteries and suggested that the antiatherogenic effect of metformin is associated with its effect on fibrinolytic activity and ROS formation, while the antiatherogenic effect of gliclazide MB is a consequence of its ability to neutralize free radicals and restore function endothelium and reduce platelet reactivity.
The effect of stress on the diabetic body
The fact that stress influences the possibility of developing diabetes has long been proven. People who have already been diagnosed with this pathology should not be nervous either. Stressful situations in this case can cause complications and deterioration of the condition.
Stress in a diabetic can cause a sharp increase in blood sugar. The critical point can be reached in a matter of minutes. As a result, severe hyperglycemia may develop, and against its background - hyperglycemic coma, which is dangerously fatal.
The concentration of glucose in the blood of a diabetic increases due to the production of stress hormones - cortisol and adrenaline. In a healthy person, cortisol provokes the production of glucose, which provides a surge of energy and is safely absorbed by the body.
In diabetics, carbohydrate metabolism is impaired, so internal tissues do not absorb glucose, which causes its sharp jump. With a high concentration of sugar in the blood, its thickness and viscosity increase, which, against the background of a rapid heartbeat and high blood pressure caused by stress, puts a strain on the cardiovascular system. This negatively affects the condition of the heart and can cause it to stop.
There is another option for the development of the situation. Under severe stress, a person may forget about the usual things: eat, go to the shower, take a glucose-lowering drug. In addition, some people lose their appetite in a stressful situation, while others eat the problem, which is contraindicated in diabetes.
It is important for diabetics to know how much their sugar levels rise in a stressful situation. The higher the glucose jump, the greater the likelihood of various complications.
How to avoid stressful situations?
Due to a serious threat to health, diabetics need to avoid stressful situations, depression, and nervous tension.
The following methods will help with this:
- Sport. You can reduce emotional stress by switching the body's strength to physical activity. A pleasant addition to sports activities is a good figure and lower sugar levels.
- Hobby. Doing what you love is very calming. This could be knitting, drawing, crafts from various materials.
- Aroma and herbal medicine. You can drink teas or decoctions of herbs with a calming effect: peppermint, motherwort, thyme. Another option is essential oils and incense.
- Pets. Some people love cats or dogs, others like exotic things. You can pet the animal, play with it, and this is very calming.
- Walk. It is useful to walk in the fresh air. To calm down, it is better to choose uncrowded places.
- Anti-stress toy or pillow.
- Warm bath. It allows you to relax and calm down. It is useful to combine this option with aromatherapy.
- Vitamins and minerals. They are important for every person, so the diet should be enriched with them. It is not always possible to get enough vitamins from food, so it is useful to take additional vitamin complexes. To combat stress, taking vitamins E and B3, magnesium, and chromium is especially important.
You should choose a calming method that suits you. If this is some kind of thing, then you should carry it with you. If stressful situations are constantly provoked at work, then you should think about changing it, because your own health is more important.
Relaxation techniques
Today there are many relaxation techniques that are useful not only for combating stress, but also for the health of the entire body. Many directions came to us from the East. You can use the following methods:
- Yoga. It is useful as a sport and allows you to find spiritual harmony. According to research, yoga improves diabetes and reduces the risk of complications.
- Meditation. This technique allows you to completely relax your body and mind. As a result, the concentration of cortisol decreases, and with it the level of glucose in the blood.
- Reflexology. This method is often understood as acupuncture, which affects specific points. You can do without needles. At home, reflexology involves self-massage. You can master the technique yourself, the main thing is to choose the right points of influence.
- Self-hypnosis. Stress in diabetics is often caused by illness, the need to constantly take medications, monitor glucose levels, and limit oneself in food. For self-hypnosis, affirmations are used - short phrases-attitudes. They must be repeated 15-20 times in the morning after waking up and in the evening before bed.
- Progressive muscle relaxation. To do this, you should perform special exercises that involve different muscle groups. The essence of the technique is to consistently tense the muscles and relax them.
To relax, it is not necessary to master any technique perfectly. It is enough to understand its basics to learn how to cope with stress.
Stress is contraindicated in diabetes, as it causes an increase in blood sugar and related complications. Healthy people should also avoid stressful situations, as they can lead to the development of diabetes. There are many techniques to combat emotional overload, and anyone can find a suitable option.
Stress control and relief
It is impossible to completely prevent emotional upheavals. But it is quite possible to minimize stress, thus eliminating the factor that triggers the formation of diabetes. Methods for relieving stress include physiological and psychological techniques. Maintaining an active lifestyle, healthy physical activity, and the ability to cope with emotions and “release” them rather than accumulate them help combat the negative impact of stressful situations.
To prevent an increase in blood sugar levels, and subsequently insulin levels, it is important to adhere to the following recommendations:
- practice yoga and conduct meditation exercises;
- try exercises aimed at alternating tension and relaxation of various muscle groups;
- take a contrast shower;
- learn to analyze stressful situations and practice liberation from excess emotions;
- find a relaxing hobby that has a positive effect on your health.
Any form of physical activity helps you cope better with stress. For people already suffering from diabetes and those who are at high risk of developing the disease, it is important to maintain a healthy rhythm of life and cultivate an optimistic outlook on the world. This life position will help diabetic patients smooth out the negative symptoms of the disease and minimize the likelihood of complications. For those who are at risk, this will help avoid the disease. In any case, such a lifestyle will be useful to any person who is conscious about their health.
