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Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden P. Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective. Medicine 2002;81(2):87–100. 28 Diabetes Mellitus Type 2 and Stress: Pathophysiology and Treatment Bryan C. Batch and Richard S. Surwit CONTENTS Stress and Hyperglycemia: Animal Studies Highlighting Basic Physiology and Stress Responsivity Summary References Summary Psychological and physical stresses play a significant role in the development of hyperglycemia in the setting of type 2 diabetes. Although Thomas Willis demonstrated hyperglycemia in response to stress as early as the 17th century, results of subsequent animal and human studies are not consistent. This inconsistency exists despite clear physiologic evidence that stress hormones can cause hyperglycemia via modulation of the sympathetic nervous system. Studies, which use both behavioral and pharmacologic interventions to manage stress, offer mixed results regarding the ability of relaxation techniques to modify hyperglycemia. However, when the data are evaluated in the setting of a large meta-analysis, the evidence indicates that modification of stress leads to a modest reduction in hyperglycemia. Key Words: Stress; diabetes; hyperglycemia; sympathetic nervous system; epinephrine. STRESS AND HYPERGLYCEMIA: ANIMAL STUDIES HIGHLIGHTING BASIC PHYSIOLOGY AND STRESS RESPONSIVITY The hyperglycemic effects of stress were noted as early as the 17th century by Thomas Willis (1). The work of Willis was followed in 1849 by that of Claude Bernard (2,3), who demonstrated that lesioning an area of the hypothalamus in normal rabbits causes hyperglycemia, giving early credence to theories that the hypothalamic pituitary axis plays a distinct role in the development of hyperglycemia. In 1930, C.F. Cori (4) theorized a link between the physiologic stress response and development of hyperglycemia. In his early experiments with rabbits, Cori demonstrated that initiation of a continuous infusion of epinephrine precipitated hyperglycemia. This effect was reversed once the infusion was ceased. Unlike Cori, who chose a pharmacologic stress response mechanism, Cannon (5) examined the response to a physiological stress, induced by restraining cats in a holder for variable lengths of time. While the cat was in the holder, urine was collected and studied for evidence of glycosuria. Glycosuria was absent at baseline, but developed in animals that were observed to respond to restraint with emotions of fright or rage. Van Loon (6) extended these earlier studies by infusing beta endorphins intracisternally in conscious, unrestrained, adult male rats. He was able to not only demonstrate an increase in plasma glucose precipitated by the infusion, but was able to abolish the effect via adrenal denervation. Disabling neural control of the adrenal gland disrupted the production of cortisol, eliminating the stimulus for the development of hyperglycemia. Using the C57BL/6J ob/ob mouse model, Surwit et al (7) elicited a stress response in both lean C57BL/6J mice and their ob/ob littermates. Although C57BL/6J ob/ob mice were noted to be hyperinsulinemic at baseline, they From: Contemporary Endocrinology: Type 2 Diabetes Mellitus: An Evidence-Based Approach to Practical Management Edited by: M. N. Feinglos and M. A. Bethel © Humana Press, Totowa, NJ 433 434 Batch and Surwit were not noted to be significantly hyperglycemic in the nonstressed state. When stressed, the obese mice had an exaggerated hyperglycemic response compared to lean control animals, associated with a significant reduction in insulin levels. These findings suggested the presence of increased adrenergic sensitivity of the pancreatic islets, possibly explaining the expression of the diabetic phenotype in the obese animals. Further work by Kuhn et al (8) demonstrated a marked rise in glucose and suppression of insulin in the C57BL/6J ob/ob mouse as compared to its lean littermates in response to graded doses of subcutaneous epinephrine. A significant shift in the dose response curve to the left was found in the ob/ob mice, confirming increased adrenergic sensitivity of the cells in these animals. Such data highlighted the role that environmental stress factors may play in the expression of diabetes in the C57BL/6J ob/ob mouse. Additional studies by Surwit et al (9) demonstrated that hyperglycemia and hyperinsulinemia can be induced even in the lean C57BL/6J mouse model with exposure to stress or epinephrine. This response to stress and epinephrine was markedly exaggerated after obesity was induced by feeding the mice a high-fat simple carbohy- drate diet. This finding supports the hypothesis that an underlying genetic defect exists in the C57BL/6J mouse that result in a heightened pancreatic -cell response to adrenergic stimulation, leading to a diminished insulin secretory response and hyperglycemia. This hyper-responsiveness, and consequent hyperglycemia, is exaggerated by obesity. Additionally, when exposed to stress, the Otsuka Long-Evans Tokushima Fatty rat, another animal model of type 2 diabetes, develops hyperglycemia with increased levels of plasma catecholamines and corticosterone. (10) Stress and Hyperglycemia: Human Studies Highlighting Basic Physiology and Stress Responsivity Human studies have yielded contradictory results regarding stress stimuli and its effect on blood glucose. A small study by Naliboff et al (11) comparing type 2 diabetic subjects and controls showed no change in blood glucose when the intervention group was exposed to psychological stress. Vandenbergh et al (12,13) elicited stress responses through the use of hypnosis and electric shock and were able to demonstrate a statistically significant decrease in blood glucose. Alternatively, Goetsch et al (14) used mental arithmetic as an acute stressor and were able to demonstrate a hyperglycemic response to stress. Studies in the Pima Indians (15) showed that prediabetic human populations may also show exaggerated glycemic responses to stress. Euglycemic Pima Indians and age matched euglycemic Caucasian controls were given a glucose tolerance test followed by a standard mental arithmetic challenge known to reliably stimulate a sympatho-adrenal response. Although blood pressure and heart rate increased in all subjects during the mental arithmetic challenge, only the Pima subjects showed an elevation in glucose during and following the challenge. The authors postulated that this exaggerated glycemic stress-responsivity may be characteristic of individuals at risk for the development of diabetes. Because of impaired insulin sensitivity and/or disordered beta cell function, prediabetic individuals may be unable to compensate for the glucose mobilizing effects of sympatho-adrenal activation. Work by Hamburg et al (16) highlights the effect that even modest stress can have on glucose homeostasis during a glucose challenge. Small infusions of epinephrine (mimicking the level seen with an upper respiratory viral illness) administered to 7 normal subjects produced minimal changes in the fasting plasma glucose. However, the same infusion of epinephrine produced marked increases in insulin and glucose levels 2 hours after ingestion of 100 g of glucose. Bruce et al (17) compared the sensitivity of type 2 diabetic subjects’ response to a norepinephrine infusion with nondiabetic age and weight matched controls. Although norepinephrine caused a rise in plasma glucose in both groups, the plasma glucose response to norepinephrine in the diabetic group was significantly greater. Type 2 Diabetes and Stress Management Both behavioral and pharmacologic mechanisms have been used to reduce stress or modify an individual’s response to stress. As early as 1892 Osler identified a common treatment for what he termed “diabetes of obesity,” most likely type 2 diabetes, as opiates and rest (18). Animal studies by Borison and Feldberg (19,20) using intraventricular injection of morphine showed sustained elevation of blood glucose in cats and rats. This effect was thought to be mediated indirectly by the sympathetic nervous system, as section of the sympathetic ganglia or adrenal ablation caused a reduction in the hyperglycemic response (21). Chapter 28 / Diabetes Mellitus Type 2 and Stress 435 Giugliano et al (22) studied the effect of endogenous opiates on glucose in human subjects with type 2 diabetes. Acute exposure of subjects to 0.5 mg/h of intravenous (IV) beta endorphin led to increased concentrations of insulin and glucagon and decreased plasma glucose levels. Interestingly, Passariello et al (23) were able to demonstrate through work with heroin addicts that chronic exposure to opiates resulted in elevated insulin concentrations and reduced insulin secretory response to IV glucose. In retrospect, modulation of hyperglycemia via treatment with opiates by Osler may have modified insulin secretion as opposed to modifying stress response. Surwit and Feinglos (24) published one of the earliest reports of the effects of behavioral anxiolytic therapy on glycemic control in diabetes. They explored the effects of biofeedback-assisted relaxation on glucose tolerance in subjects with type 2 diabetes who were hospitalized on a clinical research ward. A 3-h glucose tolerance test and an intravenous insulin tolerance test were performed on each subject, after which half of the subjects underwent5dofamodified version of progressive relaxation training with EMG biofeedback. Exercises for progressive relaxation training were prerecorded on a cassette and practiced by the patient 2 times per day for 5 d. The EMG biofeedback sessions, given for 50 min on 5 separate occasions to subjects in the relaxation group, were designed to give information about muscle tone and assist in the process of relaxation. Thereafter, the treated patients were asked to continue practicing the relaxation techniques 2–3 times a day. After 1 wk, the oral and intravenous glucose tolerance tests were repeated while subjects in the relaxation group continued to practice the relaxation techniques. Relaxation therapy produced significant reduction in incremental glucose area in the intervention group compared to untreated controls. This finding was independent of any effect on insulin sensitivity or increase in insulin secretory activity. Lammers, Naliboff and Straatmeyer (25) investigated the impact of progressive muscle relaxation training on blood glucose and stress levels in 4 insulin-requiring type 2 diabetic patients. Participants were asked to measure levels of daily stress and anxiety using the State Trait Anxiety Inventory (STAI) (26) and a subjective scale of tension (27) as well as blood glucose levels. Progressive muscle relaxation significantly lowered blood glucose levels in 2 of the 4 subjects over 6 wks. Interestingly, the subjects with the largest response had higher baseline glucose values and worse baseline metabolic control. Lane et al (28) added EMG biofeedback-assisted relaxation training to conventional diabetes intervention, diet modification, and education to assess if there was any added benefit of relaxation training on percent hemoglobin A1c and glucose tolerance. The second objective of the study was to identify characteristics that would predict what subject would respond to relaxation therapy. Thirty-eight volunteers with poorly controlled type 2 diabetes (defined as 2-h post prandial glucose of >200mg/dL) were followed for 48 wk. In the initial phase of the study all subjects underwent measurement of HbA1c, urinary 24-h excretion of glucose, catecholamines, and cortisol, and completion of the Eysenck Personality Inventory (EdITS), the Nowicki Strickland Locus of Control Questionnaire and the STAI. The questionnaires were used to define psychological variables related to stress reactivity. The initial preliminary testing also included an oral glucose tolerance test (OGTT). In addition, participants underwent intravenous infusion challenge with epinephrine in solution (250 g EPI, 500mL normal saline, 500 mg ascorbic acid) to assess the effect of epinephrine on glucose and insulin responses to a mixed meal on day 4 before the intervention. On day 5 following the epinephrine infusion challenge, a repeat OGTT was performed after alprazolam pretreatment to evaluate the effect of an anxiolytic on glucose and insulin responses. This study revealed no significant clinical improvement in HbA1c or incremental glucose area when relaxation training was added to intensive conventional treatment. Although the results suggest that relaxation therapy does not confer added benefit, it is important to interpret these data with the understanding that relaxation therapy may only be beneficial in a subset of patients who are more stress responsive. This theory is supported by the results of the epinephrine and alprazolam responses to glucose in the pretreatment stage of the study. The results show that subjects who had a greater deterioration in glucose tolerance when given epinephrine, and whose glucose tolerance improved with alprazolam, showed greater improvements in glucose tolerance after relaxation training. Aikens, Kiolbasa, and Sobel (29) also applied the concepts of behavioral relaxation training, consisting of progressive muscle relaxation and imagery, in 6 non insulin dependent diabetics who were matched to 6 controls. There was no difference seen between the study or control group’s post intervention HbA1c and area under the 2 h oral glucose tolerance curve. Jablon et al (30) examined the effect of progressive relaxation training and EMG biofeedback on glucose tolerance (75 g 2-h OGTT), fasting blood glucose, 2-h post prandial blood glucose and fructosamine in an outpatient setting. Twenty subjects with type 2 diabetes were enrolled in a pretest-posttest 436 Batch and Surwit treatment versus control group (wait list) design. The participants were given a series of three 20-min audiotapes of relaxation procedures and were asked to practice the tape twice daily. Recordings of electromyographic (EMG) and electrodermal response (EDR) were made during the 2-h OGTT. The results of the study showed that significant improvements were made with regards to stress reduction as measured by the STAI as compared to controls. However, no changes were found in glucose tolerance, fasting blood glucose, 2-h postprandial blood glucose or fructosamine. Most studies of relaxation therapy have been small, of short duration, and used cumbersome techniques such as EMG-assisted relaxation training. In contrast, Surwit et al (31) demonstrated a reduction in HbA1c through the use of a group-administered stress management program. One hundred eight subjects with type 2 diabetes were randomized to participate in a diabetes education program with or without stress management training, consisting of progressive muscle relaxation, instruction in the use of cognitive and behavioral skills to reduce stress levels, and education regarding the health consequences of stress. Aftera1yrfollow up period, subjects who received stress management training had a small (0.5%) but significant reduction in HbA1c. Although more than one third of those receiving relaxation showed improvements of HbA1c of 1% or more, there was no significant difference in the effect of baseline trait anxiety scores or interactions with treatment. This latter finding suggests that baseline characteristics such as higher levels of anxiety and stress do not predict glycemic response to relaxation training. Group based approaches have not consistently been shown to improve diabetes control. A group based counseling program based on the cognitive behavioral therapy approach was described by Karlsen et al (32).In this study of 63 Norwegian adults with both type 1 and type 2 diabetes, cognitive behavioral therapy produced no reduction in the mean HbA1c. However, the overall level of diabetes control before the intervention for both the intervention and control groups left only modest room for improvement in HbA1c, as the mean HbA1c for the intervention group was 7.88% and 8.43% for the control group. Post intervention, the mean HbA1c in the treatment group was 7.99%. Okada et al (33) and Lustman et al (34) have explored the use of benzodiazepines to treat hyperglycemia. In an 8 wk randomized controlled trial, Lustman et al studied 58 patients with poorly controlled diabetes who had generalized anxiety disorder or were psychiatrically well (i.e., no extant axis I psychiatric disorder per DSM-IIIR), treating them with either alprazolam or placebo. The target dose of alprazolam was 2.0 mg/d but it is not clear how many patients reached this dose. A statistically significant difference in reduction in HbA1c was seen in the patients who received alprazolam as opposed to those receiving placebo (−1.1 versus −0.3%, p = 0.04). Surprisingly, the effect seen did not directly correlate with decreases in anxiety. A recent meta-analysis (35) evaluated the use of psychological interventions to enhance glycemic control. The interventions utilized across the 25 trials included individual or group cognitive behavioral therapy, relaxation training, stress management, or group or individual counseling. For the purposes of the meta-analysis, these interventions were classified based on 4 psychotherapeutic models: supportive counseling therapy, cognitive behavioral therapy, brief psychodynamic psychotherapy, and interpersonal psychotherapy. The main outcome measure recorded in the various studies included in the meta-analysis was long-term glycemic control based on glycated hemoglobin (including HbA1c and HbA1) and/or whole blood, plasma or serum glucose concentrations. According to the authors, standardization methods were used to allow for combination of different measures of the same outcome. They reported use of within- group SD of the differences (change scores) from baseline to follow-up for each outcome to calculate the SE of the effect size for each study. If the SD of the change score was missing, they used the square root of the average of the baseline and follow-up variance in each group. They further stated that their approach was based on the assumption that the correlation between the baseline and the follow-up outcomes values was 0.5. They then standardized the effect sizes by dividing them and their SE by the SD. Secondary outcome measures included body mass index (BMI) and psychological distress. Twelve of the 25 studies included glycated hemoglobin data that could be pooled. After pooling data from twelve of the trials, the mean percentage glycated hemoglobin (including HbA1c and HbA1) was lower in the people assigned to any psychological intervention than in the control group (standardized pooled mean difference of −0.32% [95% CI −0.57 to −0.07]). Improvements in blood glucose, however, were not significant. It is important to note that when 2 studies, in which the control was a less intensive psychological therapy (standard practice or conventional therapy), were excluded the pooled effect size was larger, showing a clinically significant difference in HbA1c of −1.00%. Chapter 28 / Diabetes Mellitus Type 2 and Stress 437 SUMMARY Research in animal and human models has established the effect of the sympathetic nervous system and the hypothalamic pituitary adrenal axis on glucose homeostasis. However, trials employing interventions aimed at stress reduction in human subjects have yielded mixed results with respect to their effect on glucose control. The most comprehensive evaluation of psychological intervention and glycemic control includes a meta-analysis of twelve of the best quality studies utilizing psychological therapies. The results of the meta-analysis suggest that statistically significant improvements in long term glycemic control can be achieved. However, even the best studies included in the meta-analysis were not without flaws in that the studies were often small and the measures used for long term glycemic control were not always equivalent (e.g., HbA1c versus HbA1). The subset(s) of patients more likely to have improvements in glycemic control when exposed to psychological intervention have thus not yet been defined. Unfortunately, the current literature cannot offer consistent guidelines. A decrease in baseline anxiety and stress over time does not always correlate with changes in glycemic control. This lack of transparency regarding the appropriate patient population to treat makes it difficult to recommend the broad application of psychological interventions in heterogeneous populations of patients with type 2 diabetes. Clearly, more work in this area is necessary. 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Nephrol 2006;17:S25–29 30 Influencing Self -Management: From Compliance to Collaboration Martha M Funnell and Robert M Anderson CONTENTS Introduction Diabetes Self -Management Influencing Self -Management: Diabetes Education Influencing Diabetes Self -management through Patient Empowerment Influencing Diabetes Self -management Through On-Going Support Influencing Self -Management: Collaborative Care Conclusion... References Summary Greater understanding of diabetes and its treatment, new technology and improved therapies have dramatically changed the clinical care of diabetes Unfortunately, implementing newer evidence-based findings for understanding and impacting self -management and diabetes self -management education has not kept pace Much of what we do is based on traditional beliefs and methods that are simply... roles, responsibilities and expectations of patients and health care providers in diabetes care as they are defined in the treatment of acute illness (9) The DAWN study (10) reported that only 46% (2–63% range) of patients with type1 diabetes and 39% of patients with type 2 diabetes reported achieving success in two-thirds of their self -management domains Patient reports of self -management success for... redesign of practices and health systems to incorporate collaborative models of care and more effectively use all of the members of the health care team to facilitate self -management ACKNOWLEDGEMENTS Work on this chapter was supported in part by grant number NIH5P60 DK20572 and 1R18 0K062323 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health... (Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial) was a 16-wk, multicenter, double-blind, placebo-controlled, randomized trial, which assigned 148 patients to 1 of 3 groups: placebo, extended-release (ER) niacin 1,000 mg daily, or ER niacin 1,500 mg daily (111) (Forty-seven percent of the patients were also on statin therapy.) Dose-dependent increases in HDL-cholesterol... with self-efficacy and self-reported self -management behaviors (46) INFLUENCING DIABETES SELF -MANAGEMENT THROUGH PATIENT EMPOWERMENT Self -management requires considerable effort that must be sustained over a lifetime of diabetes Patients are frequently asked to make multiple changes in their lives and lifestyle, learn new skills and make multiple decisions that can have both short and long-term consequences... self-directed behavioral changes, and ultimately to modify systems of care to influence patient self -management From: Contemporary Endocrinology: Type 2 Diabetes Mellitus: An Evidence-Based Approach to Practical Management Edited by: M N Feinglos and M A Bethel © Humana Press, Totowa, NJ 455 456 Funnell and Anderson DIABETES SELF -MANAGEMENT Diabetes self -management refers to all of the activities in which... of the effects of patient education in the treatment of insulin-dependent diabetes Diabetes Care 1983;6:256–261 22 Padgett D, Mumford E, Hynes M, Carter R Meta-analysis of the effects of educational and psychosocial interventions on management of diabetes mellitus J Clin Epidemiol 1988;41 :100 7 103 0 23 Brown, SA Studies of educational interventions and outcomes in diabetic adults: A meta-analysis revisited... 32% of heart transplant recipients because of a combination of risk factors, which include both pretransplant diabetes and the development of newonset diabetes owing to the effect of immunosuppressive agents (94–96) Recognition of this problem led to the creation of an International Expert Panel that developed guidelines for the diagnosis, treatment and management of PTDM (97,98) However, much of the... DIABETES SELF -MANAGEMENT THROUGH ON-GOING SUPPORT Because diabetes is a chronic illness, it is unrealistic to expect that a one-time educational intervention is adequate Patients need on-going education and self -management support Although the initial, comprehensive education may best be done outside the practice setting, the office setting is ideal for on-going education and self-directed goal-setting . of HbA1c, urinary 24-h excretion of glucose, catecholamines, and cortisol, and completion of the Eysenck Personality Inventory (EdITS), the Nowicki Strickland Locus of Control Questionnaire and. Results of double-blind, placebo- controlled trial. Diabetes Care 1995;18:1133–1139. 35. Ismail K, Winkley K, Rabe-Hesketh S. Systematic Review and meta-analysis of randomized controlled trials of. least 100 reported cases, have documented a significant incidence of both new-onset diabetes mellitus as well as exacer- bation of pre-existing diabetes. Of particular concern is the occurrence of