PresentationEndocrinology

The Effects of Acute and Chronic Stress on Diabetes Control

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Science Signaling  23 Oct 2012:
Vol. 5, Issue 247, pp. pt10
DOI: 10.1126/scisignal.2003508
A Presentation from the European Society for Paediatric Endocrinology (ESPE) New Inroads to Child Health (NICHe) Conference on Stress Response and Child Health in Heraklion, Crete, Greece, 18 to 20 May 2012.

Abstract

Stress is an important contributor to pathological conditions in humans. Hormonal changes that occur during acute and chronic stress situations can affect glucose homeostasis in both healthy people and in those with diabetes. Several studies have reported a negative effect of acute stress on maintenance of blood glucose concentrations in patients with type 1 and type 2 diabetes. The effect of stress on glycemic control in people with diabetes may be related to a direct effect of stress hormones on blood glucose levels and an indirect effect of stress on patient behaviors related to diabetes treatment and monitoring and meal and exercise plans. In contrast, there is no clear evidence that stressful life events promote the development of diabetes in children or in adults. Stress hyperglycemia, the development of hyperglycemia during acute illness, represents another interesting connection between the stress system and glucose homeostasis. A large body of evidence supports an association between stress hyperglycemia and increased morbidity and mortality in critically ill patients. Interestingly, there is some evidence supporting a beneficial effect of insulin in reducing morbidity and mortality in patients admitted to intensive care units. Finally, stress can influence the development of type 2 diabetes indirectly by promoting obesity and metabolic syndrome.

Presentation Notes

Slide 1: Science Signaling logo

The slideshow and notes for this Presentation are provided by Science Signaling (http://www.sciencesignaling.org).

Slide 2: The effects of acute and chronic stress on diabetes control

Stress is an important contributor to pathological conditions in humans. During acute and chronic stress situations, several hormonal changes occur, and these can affect glucose homeostasis, both in healthy people and in those with diabetes.

Slide 3: Outline of this Presentation

This Presentation offers an overview on the effect of stress on glucose homeostasis and glucose control in people with known diabetes, as well as on the potential role of acute and chronic stress on the onset of diabetes. In addition, the concept of stress hyperglycemia, diabetes in people with Cushing syndrome, and the relationship between stress and obesity or metabolic syndrome are also reviewed.

Slide 4: Effects of stress hormones on glucose metabolism

During acute and chronic stress situations, several hormonal changes occur, and these can affect glucose homeostasis, both in healthy people and in patients with dia­betes (1). Hormones released during stress conditions (stress hormones) are defined as counter-regulatory in the context of glucose metabolism because they can induce hyperglycemia. These hormones include norepinephrine, epinephrine, cortisol, β-endorphin, and growth hormone. As shown in this table, these hormones can influence several mechanisms implicated in glucose homeostasis. The majority stimulate insulin release, hepatic glucose production, glucose utilization, and lypolysis, as well as increase plasma blood glucose (2, 3).

Slide 5: Stress and glucose metabolism

During stress situations, insulin sensitivity is generally reduced, mainly due to signaling defects downstream of the insulin receptor that reduce GLUT-4–mediated glucose transport in insulin-sensitive tissues such as liver, muscle, and fat. Storage of glycogen in muscle is also reduced. In contrast, glucose production is higher as a consequence of increased hepatic gluconeogenesis. Glucose utilization within all cells of the body is also impaired due to increased oxidative metabolism and reduced nonoxidative metabolism (3).

Slide 6: Role of counter-regulatory hormones in modulating glucose metabolism in healthy subjects

Several experimental studies have shown that, in nondiabetic subjects, stress hormones exert a negative effect on glucose homeostasis. Gelfand et al. assessed the effect of increased circulating counter-regulatory hormones on metabolic alterations during major injury or illness (4). The endocrine milieu of major stress was simulated by simultaneous infusion of cortisol, glucagon, epinephrine, and norepinephrine into healthy adult human subjects for 3 days. As shown in this figure, hormone infusion was associated with a rise in glucose concentrations and increased plasma insulin concentration. These effects were stronger when the combination of four stress hormones was infused as compared with the infusion of cortisol alone.

Slide 7: Psychological stress and blood glucose in nondiabetic subjects

A study by Wing et al. addressed the effect of psychological stressors on blood glucose concentrations in nondiabetic subjects participating in both stress and nonstress sessions (5). During each session, subjects were fed a liquid carbohydrate load, and blood glucose responses were measured after the load. On nonstress days, subjects relaxed after drinking the load; on stress days, subjects participated in 30 min of competitive tasks immediately after the drink. Whereas blood glucose levels peaked 30 min after consuming the load on nonstress days, the peak blood glucose response was delayed until 60 min after the drink on stress days. These results suggest an impaired glucose metabolism under stress conditions.

Slide 8: Effects of stress on serum glucose in rats

A similar effect of stress on glucose concentrations has also been reported in animal models. Radahmadi et al. assessed serum glucose levels in nondiabetic and diabetic male rats under normal and stress conditions (6). As expected, glucose levels were higher in diabetic rats overall. Interestingly, there was a statistically significant increase in glucose levels in both normal and diabetic rats under stress conditions compared with nonstress conditions.

Slide 9: Effect of stress on diabetes control

These observations suggest that stress may affect glycemic control in patients with diabetes.

Slide 10: Effect of acute psychological stress on glucose control in patients with type 1 diabetes

Several studies have assessed the effect of acute stress on glucose concentrations in patients with type 1 and type 2 diabetes. A study from Wiesli et al. measured the effect of acute psychosocial stress on glucose concentrations in adult patients with type 1 diabetes, both in fasting and in postprandial states, during a normal day or a stress day (7). Patients were exposed to moderate psychosocial stress by means of the Trier Social Stress Test. Interestingly, whereas in the fasting state, glucose concentrations did not change between the stress and normal day, in the postprandial period, there was a delay in the gradual decrease of glucose concentrations after the onset of stress (time 0). These results suggest that, in the postprandial period, acute psychological stress can delay the normal postprandial decrease of plasma glucose.

Slide 11: Effect of acute psychological stress on glucose control in patients with type 2 diabetes

A similar study was performed in 30 adult patients with type 2 diabetes (8). Again, the effect of acute psychological stress was assessed on glucose concentrations in the fasting and postprandial state. The results were very similar to the previous study in adults with type 1 diabetes. When the Trier Social Stress Test was applied in the postprandial state, glucose concentrations were statistically significantly higher compared with the control nonstress day. In the fasting state, glucose concentrations decreased slightly during the control day but remained stable on the stress-test day.

Slide 12: Association between stress and glycemic control in adults with type 1 diabetes

Further support for stress affecting glycemic control comes from a study by Lloyd et al., in which the relationship between stressful life events and changes over time in hemoglobin A1c (HbA1c) was assessed in 55 adults with type 1 diabetes (9). The main study results were that HbA1c deteriorated over time or remained poor in subjects reporting severe personal stressors (SPS) in the month before the HbA1c measurements. In contrast, HbA1c remained fair or improved in subjects reporting only positive life events during the same time period. SPS was independently associated with poor glycemic control [odds ratio 95% confidence interval 49.6 (46.9 to 52.3)], highlighting the negative influence of recent stress events on glycemic control.

Slide 13: Relation between HbA1c at time of questionnaire and Family Inventory of Life Events score

The association between glycemic control and stress has been also assessed in the pediatric population. Viner et al. performed a crosssectional study in 43 children and adolescents with type 1 diabetes and their families, exploring the relationship between family life stress, family social support, and metabolic control (10). As shown in this figure, there was a statistically significant correlation between a high Family Inventory of Life Events score (FILE) and HbA1c at the time of the questionnaire administration (Hb-Q).

Slide 14: Mechanisms by which stress can influence glycemic control

These studies support a clear role for stress in altering glycemic control in people with both type 1 and type 2 diabetes. This may involve two mechanisms. First, there is a direct effect of stress hormones on blood glucose concentrations. Second, patients with diabetes may pay less attention to their diabetes treatment and monitoring and may be less compliant with meal and exercise plans under stress conditions.

Slide 15: Changes in HbA1c in psychological intervention group compared with control group

These results suggest that psychological therapies for reducing stress might improve glycemic control in diabetes patients. A systematic review and meta-analysis of 25 previous published trials was performed to assess the effectiveness of psychological therapies in improving glycemic control in patients with type 2 diabetes (11). In 12 of the trials, the mean HbA1c was lower in people assigned a psychological intervention than in the control group, defined as patients receiving usual care, education, waiting list, or attention control. Psychological interventions included counseling and cognitive, behavioral, and family systems therapy. As shown in this forest plot, the pooled mean difference was –0.32 (95% confidence interval –0.57 to –0.07), equivalent to an absolute difference of –0.76%.

Slide 16: Effects of psychological intervention on glycemic control (HbA1c)

A systematic review and meta-analysis has also been performed on data from studies in people with type 1 diabetes in order to determine whether psychological interventions have any effect on glycemic control in these patients (12). The systematic review included 29 trials, and the meta-analysis included 21 trials. In the 10 studies of children and adolescents that were included in the meta-analysis, the mean HbA1c was statistically significantly decreased in those who had received a psychological intervention compared with those in the control group [standardized mean difference −0.35 (−0.66 to −0.03)], equivalent to a 0.48% (0.05% to 0.91%) absolute reduction in HbA1c. In the 11 studies of adults, the pooled standardized mean difference was −0.17 (−0.45 to 0.10), equivalent to 0.22% (−0.13% to 0.56%) absolute reduction in HbA1c. Therefore, the overall result was that psychological treatments can slightly improve glycemic control in children and adolescents with diabetes but have no effect in adults.

Slide 17: Role of stress in the onset of diabetes

Another important question to answer is whether stress plays a role in the onset of diabetes.

Slide 18: Do stressful life events cause type 1 diabetes?

Cosgrove performed a systematic review of the literature in order to assess whether stressful life events might play a causative role in type 1 diabetes. Nine studies from the published literature were analyzed (13).

Slide 19: Stressful life events and type 1 diabetes: Results from a systematic review I

Older literature provides some support for a link between stressful life events and diabetes. However, these studies were based on small sample sizes and made no distinction between type 1 and type 2 diabetes. Unexpectedly, one study showed fewer stressful events in people developing diabetes (13).

Slide 20: Stressful life events and type 1 diabetes: Results from a systematic review II

More recent studies, in particular from Scandinavia, failed to show a link between the number or the severity of stressful life events in the year before the diagnosis of diabetes and the onset of the disease itself (13).

Slide 21: Stress hyperglycemia

Another interesting topic in the context of the relationship between the stress system and glucose homeostasis is the concept of “stress hyperglycemia,” which is the development of hyperglycemia during acute illness (3).

Slide 22: Multifactorial causes of hospital-related hyperglycemia

Factors implicated in the development of stress hyperglycemia can be related to preexisting conditions in the patient him/herself, such as the pancreatic insulin reserve and insulin sensitivity, or to the illness itself, in terms of the metabolic, hormonal, and cytokine changes associated with the illness. Another potentially important contributor is the specific treatment for the active pathological condition, especially if it involves administration of hormones such as glucocorticoids (3).

Slide 23: Hyperglycemia and mortality in the ICU

A large body of evidence has shown an association between stress hyperglycemia and an increased morbidity and mortality in critically ill patients. This figure shows the progressive increase in mortality risk associated with increasing levels of plasma glucose in patients in intensive care units (ICUs) (14). However, these associations do not necessarily prove causation, and further studies are required to clarify whether there is a direct causative role for high glucose levels in determining mortality.

Slide 24: Intensive insulin infusion in critically ill hospitalized patients

The negative effect of hyperglycemia on patient outcome during critical illnesses has inspired studies investigating the potential beneficial effect of insulin treatment in intensive care patients to prevent stress hyperglycemia. Interestingly, there is some evidence supporting a beneficial effect of insulin, in terms of reduction in mortality and morbidity due to infections, acute renal failure, or transfusions in critical ill patients, particularly in those with a long stay in ICUs (14, 15).

Slide 25: Cushing syndrome and diabetes

Chronic stress is associated not only with increased levels of counter-regulatory hormones but also with activation of the hypothalamic-pituitary adrenal (HPA) axis (16). This latter effect may explain several of the negative effects of chronic stress. A good example of chronic activation of the HPA is Cushing syndrome.

Slide 26: Prevalence of diabetes mellitus and impaired glucose tolerance (IGT) in patients with overt and subclinical Cushing syndrome

Cushing syndrome is caused by chronic exposure to excess glucocorticoids, such as cortisol, either of endogenous or exogenous origin. Cushing syndrome is characterized by a constellation of symptoms, including central obesity, thinned skin, purple striae, proximal muscle weakness, fatigue, acne, hirsutism, menstrual irregularity, and neuropsychological disturbances such as depression, irritability, sleep disturbances, and cognitive deficits. Subclinical Cushing syndrome is defined as a status of altered HPA activity in the absence of classical symptoms of overt cortisol excess (16). Diabetes mellitus is a frequent complication of Cushing syndrome. Interestingly, both overt and subclinical Cushing syndromes have been associated with an increased prevalence of impaired glucose tolerance (17% and 23%, respectively) and type 2 diabetes (36% and 22%, respectively), highlighting the negative effect of chronic activation of the HPA axis on glucose metabolism (16).

Slide 27: Pathophysiological mechanisms of glucocorticoid (GC)–induced diabetes

In the context of glucocorticoid excess, diabetes occurs as a consequence of an insulin-resistant state combined with impaired insulin secretion. Glucocorticoids reduce insulin secretion by pancreatic β cells and induce a state of insulin resistance in various insulin-sensitive tissues, such as muscle, adipose tissue, and liver. This combination of decreased insulin sensitivity and secretion contributes to the pathogenesis of hyperglycemia (16).

Slide 28: Stress and obesity or metabolic syndrome

Obesity or metabolic syndrome associated with stress is another link between stress and diabetes.

Slide 29: Stress and metabolic syndrome or type 2 diabetes

There is evidence suggesting that chronic stress, which activates both the HPA axis and the sympathetic nervous system, and the associated changes in health behavior, can contribute to the development of visceral obesity and metabolic syndrome (1). The latter is a well-known constellation of metabolic alterations (hypertension, dyslipidemia, glucose intolerance, insulin resistance, and obesity) that significantly increases the risk of cardiovascular disease and type 2 diabetes (17).

Slide 30: Conclusions

Acute and chronic stress can affect glycemic control in patients with type 1 and type 2 diabetes. In addition, there is evidence suggesting that approaches to reduce stress are key components of diabetes management. In contrast, there is no clear evidence for an effect of stress on the onset of type 1 diabetes. However, stress can influence the onset of type 2 diabetes indirectly by promoting obesity and metabolic syndrome. Finally, stress hyperglycemia in sick patients is common and is associated with adverse outcomes.

Editor’s Note: This contribution is not intended to be equivalent to an original research paper. Note, in particular, that the text and associated slides have not been peer-reviewed.

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