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OBJECTIVE Restricting insulin to lose weight is a significant problem in the clinical management of type 1 diabetes (T1D). Little is known about this behavior or how to effectively intervene. Identifying when insulin restriction occurs could allow clinicians to target typical high-risk times or formulate hypotheses regarding factors that influence this behavior. The current study investigated the frequency of insulin restriction by time of day. METHODS Fifty-nine adults with T1D and eating disorder symptoms completed 72 hours of real-time reporting of eating and insulin dosing with continuous glucose monitoring. We used a generalized estimating equation model to test the global hypothesis that frequency of insulin restriction (defined as not taking enough insulin to cover food consumed) varied by time of day, and examined frequency of insulin restriction by hour. We also examined whether patterns of insulin restriction for 72 hours corresponded with patients' interview reports of insulin restriction for the past 28 days. RESULTS Frequency of insulin restriction varied as a function of time (p = .016). Insulin restriction was the least likely in the morning hours (6:00-8:59 AM), averaging 6% of the meals/snacks consumed. Insulin restriction was more common in the late afternoon (3:00-5:59 PM), peaking at 29%. Insulin was restricted for 32% of the meals/snacks eaten overnight (excluding for hypoglycemia); however, overnight eating was rare. Insulin restriction was associated with higher 120-minute postprandial blood glucose (difference = 44.4 mg/dL, 95% confidence interval = 22.7-68.5, p < .001) and overall poorer metabolic control (r = 0.43-0.62, p's < .01). Patients reported restricting insulin for a greater percentage of meals and snacks for the past 28 days than during the 72 hour real-time assessment; however, the reports were correlated (Spearman's ρ = 0.46, p < .001) and accounted for similar variance in HbA1c (34% versus 35%, respectively). CONCLUSIONS Findings suggest that insulin restriction may be less likely in the morning, and that late afternoon is a potentially important time for additional therapeutic support. Results also suggest that systematic clinical assessment and treatment of overnight eating might improve T1D management.

According to a review conducted by the Duke University Office of Research, Professor Edward C. Suarez was omitted as an author in the above-cited article. The university concluded that Dr. Suarez qualifies …

OBJECTIVE Individuals with type 1 diabetes who restrict insulin to control weight are at high risk for diabetes-related complications and premature death. However, little is known about this behavior or how to effectively intervene. The aim of the current study was to identify predictors of insulin restriction in the natural environment that might inform new treatment directions. RESEARCH DESIGN AND METHODS Eighty-three adults with type 1 diabetes and a range of eating disorder symptomatology completed 3 days of ecological momentary assessment. Participants reported emotions, eating, and insulin dosing throughout the day using their cellular telephone. Linear mixed models were used to estimate the effects of heightened negative affect (e.g., anxiety) before eating and characteristics of the eating episode (e.g., eating a large amount of food) on the risk of insulin restriction. RESULTS Individuals who reported greater-than-average negative affect (general negative affect and negative affect specifically about diabetes) during the study period were more likely to restrict insulin. Momentary increases in anxiety/nervousness and guilt/disgust with self before eating (relative to an individual’s typical level) further increased the odds of restricting insulin at the upcoming meal. Insulin restriction was more likely when individuals reported that they broke a dietary rule (e.g., “no desserts”). CONCLUSIONS Results suggest that insulin restriction might be decreased by helping patients with type 1 diabetes respond effectively to heightened negative affect (e.g., anxiety, guilt) and encouraging patients to take a less rigid, punitive approach to diabetes management.

Previous research has shown an association between hostility and fasting glucose in African American women. Central nervous system serotonin activity is implicated both in metabolic processes and in hostility related traits.The purpose of this study is to determine whether central nervous system serotonin influences the association between hostility and fasting glucose in African American women.The study consisted of 119 healthy volunteers (36 African American women, 27 White women, 21 White males, and 35 African American males, mean age 34 ± 8.5 years). Serotonin related compounds were measured in cerebrospinal fluid. Hostility was measured by the Cook-Medley Hostility Scale.Hostility was associated with fasting glucose and central nervous system serotonin related compounds in African American women only. Controlling for the serotonin related compounds significantly reduced the association of hostility to glucose.The positive correlation between hostility and fasting glucose in African American women can partly be explained by central nervous system serotonin function.

Objective This double-blind, placebo-controlled clinical study was designed to evaluate the effects of psyllium on fasting blood glucose (FBG) and HbA 1c in patients being treated for type-2 diabetes mellitus (T2DM). Research design and methods Patients were randomly assigned to 1 of the 3 treatment groups: placebo, psyllium 3.4 g BID or psyllium 6.8 g BID (just prior to breakfast and dinner). Patients had a total of 9 clinic visits during the 20-week study period (8 weeks baseline, 12 weeks treatment). A total of 37 patients [12 females, 34 Caucasians, mean age 62 years] were enrolled (8 in the placebo group, 15 in the psyllium 3.4 g BID group and 14 in the psyllium 6.8 g BID group) and were included in the Intent-to-Treat analysis. Results Both doses of psyllium significantly ( p 1c compared to placebo at Week 8 (−0.58±0.18, p =0.003), and both the 3.4 g dose and the 6.8 g dose of psyllium significantly ( p 1c compared to placebo at Week 12 (−0.53±0.20, p =0.013; −0.65±0.20, p =0.003, respectively). Conclusions The improvement in glycemic control observed with psyllium in T2DM patients was above that already conferred by a restricted diet (all patients) and a stable dose of a sulfonylurea (81.1% of patients). These data support that psyllium is an effective co-therapy for improving glycemic control in patients being treated for T2DM. NCT01582282.

Objective: To use measures of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) and genotype of a functional polymorphism of the monoamine oxidase A gene promoter (MAOA-uVNTR) to study the role of central nervous system (CNS) serotonin in clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes. Methods: In 86 healthy male volunteers, we evaluated CSF levels of the primary serotonin metabolite 5HIAA and MAOA-uVNTR genotype for association with a panel of 29 variables assessing hostility, other psychosocial, metabolic, and cardiovascular endophenotypes. Results: The correlations of 5HIAA with these endophenotypes in men with more active MAOA-uVNTR alleles were significantly different from those of men with less active alleles for 15 of the 29 endophenotypes. MAOA-uVNTR genotype and CSF 5HIAA interacted to explain 20% and 22% of the variance, respectively, in scores on one factor wherein high scores reflected a less healthy psychosocial profile and a second factor wherein high score reflected increased insulin resistance, body mass index, blood pressure and hostility. In men with less active alleles, higher 5HIAA was associated with more favorable profiles of hostility, other psychosocial, metabolic and cardiovascular endophenotypes; in men with more active alleles, higher 5HIAA was associated with less favorable profiles. Conclusions: These findings indicate that, in men, indices of CNS serotonin function influence the expression and clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes that have been shown to increase risk of developing cardiovascular disease. The findings are consistent with the hypothesis that increased CNS serotonin is associated with a more favorable psychosocial/metabolic/cardiovascular profile, whereas decreased CNS serotonin function is associated with a less favorable profile.

OBJECTIVE To examine whether the relationship of hostility (HOST) to fasting glucose indices is moderated by sex and race. HOST has been associated with abnormalities in glucose metabolism. Prior studies suggested that this association may be more prevalent in women and in African American (AA) individuals. METHODS A total of 565 healthy AA and white (W) men and women (mean age = 33 +/- 6 years) were assessed. HOST was measured by the 27-item version of the Cook Medley HOST Scale. The moderating effects of sex and race were evaluated for the associations of HOST to fasting glucose, insulin, and insulin sensitivity (HOMA-IR). RESULTS Analysis showed a moderating effect of sex and race on the association of HOST to fasting glucose (p = .03), but not for insulin (p = .12). Analysis of HOMA-IR revealed a trend (p = .06) for the interaction. Stratified analyses by race and sex revealed a positive association between HOST and fasting glucose only in AA women, which remained significant after controlling for age and body mass index. CONCLUSION A relationship between HOST and fasting glucose was evident in AA women only, a group that has twice the risk of developing Type 2 diabetes compared with W women. Further studies are needed to elucidate the mechanisms by which HOST may affect glucose metabolism in AA women.

SummaryMetabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

To test the hypothesis that low socioeconomic status (SES) and the 5HTTLPR L allele are associated with increased cardiovascular reactivity (CVR) to stress in a larger sample and that SES and 5HTTLPR genotypes interact to enhance CVR to stress. CVR to mental stress has been proposed as one mechanism linking stress to the pathogenesis of cardiovascular disease. The more transcriptionally efficient long (L) allele of a polymorphism of the serotonin transporter gene promoter (5HTTLPR) has been found associated with increased risk of myocardial infarction. We found the long allele associated with larger CVR to mental stress in a preliminary study of 54 normal volunteers.Subjects included 165 normal community volunteers stratified for race, gender, and SES, who underwent mental stress testing.Childhood SES as indexed by Father's Education Level was associated with larger systolic blood pressure (SBP) (p.05) and diastolic blood pressure (DBP) (p = .01) responses to mental stress. The L allele was associated with larger SBP (p = .04), DBP (p.0001), and heart rate (p = .04) responses to mental stress compared with the short (S) allele. Subjects with the SS genotype and high Father's Education exhibited smaller SBP (5.2 mm Hg) and DBP (2.9 mm Hg) responses than subjects with LL genotype and low Father's Education (SBP = 13.3 mm Hg, p = .002; DBP = 9.7 mm Hg, p.0001).Both the 5HTTLPR long allele and low SES, particularly during childhood, are associated with increased CVR to mental stress, which could account, at least in part, for the increased cardiovascular disease risk associated with these characteristics. If confirmed in further research, these characteristics could be used to identify persons who might benefit from preventive interventions.

OBJECTIVE—This study examined the associations of depressive symptoms with glucose concentrations and morning cortisol levels in 665 African-American and 4,216 Caucasian Vietnam-era veterans. RESEARCH DESIGN AND METHODS—Glucose level was measured as a three-level variable (diabetes, impaired glucose, and normal). Depressive symptoms were measured by the Obvious Depression Scale (OBD) from the Minnesota Multiphasic Personality Inventory. RESULTS—Regression models showed significant race × OBD interactions in relation to glucose concentration (P < 0.0001) and cortisol (P < 0.0001). The OBD was positively associated with glucose concentration and cortisol in both racial groups. However, the magnitude of those associations was larger for African Americans. Further analyses suggested that cortisol partially mediated the race difference in the relation of depressive symptoms to glucose concentrations. CONCLUSIONS—These results suggest that enhanced hypothalamic pituitary adrenal activity plays an important role in the relation of depressive symptoms to dysregulated glucose metabolism and may partially explain the differential effects of depressive symptoms on glucose levels in African-American and Caucasian male subjects.

Internet-based disease management programs have the potential to improve patient care. The objective of this study was to determine whether an interactive, internet-based system enabling supervised, patient self-management of oral anticoagulant therapy provided management comparable to an established anticoagulation clinic.Sixty patients receiving chronic oral anticoagulant therapy who had access to the internet and a printer, were enrolled into this prospective, single-group, before-after study from a single clinic and managed between March 2002 and January 2003. Patients learned how to use a home prothrombin time monitor and how to access the system through the internet. Patients used the system for six months, with daily review by the supervising physician. The primary outcome variable was the difference in time in therapeutic range prior to and following introduction of internet-supervised patient self-management.The mean time in therapeutic range increased from 63% in the anticoagulation clinic (control period) to 74.4% during internet-supervised patient self-management (study period). The mean difference score between control and study periods was 11.4% (P = 0.004, 95% confidence interval 5.5-17.3%). There were no hemorrhagic or thromboembolic complications.This novel approach of internet-supervised patient self-management improved time in therapeutic range compared to an anticoagulation clinic. This is the first demonstration of an internet-based expert system enabling remote and effective management of patients on oral anticoagulants. Expert systems may be applicable for management of other chronic diseases.

Objective To test whether caffeine administered in coffee increases postprandial hyperglycemia in patients with type 2 diabetes who are habitual coffee drinkers. Methods The study used a within-subject, double-blind, placebo-controlled experimental design. Twenty adult coffee drinkers (11 women and 9 men) with type 2 diabetes treated with diet, exercise, orally administered antidiabetic agents, or some combination of these factors completed two mixed-meal tolerance tests (MMTT) after an overnight fast. Before the MMTT, each study participant received 250 mg of caffeine in 16 oz (475 mL) of decaffeinated coffee or decaffeinated coffee alone, with the treatment order counterbalanced in the group. Fasting and 1-hour and 2-hour postprandial blood samples were collected for measurement of plasma glucose and insulin concentrations. Results Glucose and insulin responses to the MMTT were quantified by the incremental areas under the 2-hour concentration-time curves (AUC2h). Administration of caffeine in decaffeinated coffee increased postprandial glucose and insulin responses (both P = 0.02). The mean plasma glucose AUC2h was 28% larger and the mean plasma insulin AUC2h was 19% larger after administration of caffeine than after administration of placebo. Conclusion Other constituents in coffee did not prevent the exaggeration of postprandial hyperglycemia by caffeine in these patients with type 2 diabetes, who were habitual coffee drinkers. Repeated on a daily basis, such effects could impair long-term glucose control in those patients with type 2 diabetes who habitually drink coffee or other caffeinated beverages. (Endocr Pract. 2007;13: 239-243)

We have previously shown that the C57BL/6J (B6) mouse will develop obesity and diabetes if raised on a high-fat diet. Because high fat feeding is associated with hyperphagia, the present study was designed to separate the effects of fat from those of excess caloric consumption in this animal model. B6 mice were fed a low-fat diet (LF group) diet, high-fat diet (HF group) diet, or high-fat-restricted diet (HFR group), in which intake animals were pair-fed a high-fat diet to caloric level consumed by LF for 11 weeks. Within 3 weeks, HFR were significantly heavier than LF and, after 11 weeks, weight and glucose levels, but not insulin, were significantly increased in HFR when compared to LF. Body composition analysis showed the weight increase in HFR arose from an increase in percent fat consumed. We conclude that reducing the number of kilocalories consumed from a high-fat diet attenuates but does not prevent the development of type 2 diabetes and obesity in the B6 mouse.

The development of the metabolic syndrome in an increasing percentage of the populations of Western societies, particularly in the United States, requires valid models for establishing basic biochemical changes and performing preclinical studies on potential drug targets. The C57BL/6J mouse has become an important model for understanding the interplay between genetic background and environmental challenges such as high-fat/high-calorie diets that predispose to the development of the metabolic syndrome. This review highlights metabolic and signal transduction features that are altered during the course of disease progression, many of which mirror the human situation.

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.

Subjects with anorexia nervosa (AN) at low weight display metabolic, endocrine, and behavioral abnormalities. Whether these various differences are a consequence of the condition and persist after recovery is unclear. We tested the hypothesis that abnormalities in the insulin and leptin axes and in the desire to eat persisted in subjects who had recovered from AN in terms of body mass index (BMI) and menstrual function. Endocrine, metabolic, and psychological parameters were assessed by sampling under fasting conditions and serially in response to a standard meal. Subjects included 18 females recovered from AN and 18 female controls and measures included plasma insulin, leptin, glucose and beta-hydroxybutyrate (beta-HBA) concentrations together with desire to eat. Fasting glucose concentrations were normal in both groups, but fasting insulin concentrations were significantly lower and the fasting glucose/insulin ratio significantly higher in the recovered subjects. The glucose concentration was significantly higher at the end of the meal period in the recovered group. The peak increase of insulin during the meal was significantly less in the recovered group and in response to the meal, glucose/insulin ratios were significantly higher for the first 45 minutes indicating a delayed insulin response. Fasting beta-HBA concentrations were not significantly different between groups, but postmeal decreases were significant and larger in the recovered AN group. Fasting and meal-related leptin concentrations were not significantly different between the groups and in both groups were correlated with BMI. In controls, but not in recovered subjects, the reported desire to eat was correlated with plasma glucose and leptin concentrations. The insulin, glucose and beta-HBA data indicated the presence of insulin hypersensitivity in the recovered subjects. As the insulin response to the meal was blunted and apparently delayed, there may be a persistent alteration in pancreatic function as a long-term pathological consequence of the anorexia. Alternatively, these data indicate a possible trait marker for AN.

The current study utilized a within-subject, experience sampling methodology (ESM) to examine the relationship between neuroticism (N) and physical symptom reports. Individuals with type 2 diabetes monitored diabetes-related symptoms, rated negative and positive affect (NA and PA), estimated their blood glucose (BG) levels, and tested their actual BG levels with a glucometer four times per day for 7 days. Multilevel modeling analyses indicated that N, NA, and PA were related to reported symptom frequency. Neuroticism moderated the relation between PA and symptom reports: Lower PA was more strongly related to symptom reports among high-N individuals. In addition, there was evidence that symptoms mediated the relationship between N and state NA. Finally, N was related to overestimation of BG, beyond that accounted for by state NA. Results are discussed with respect to potential effects of N on the processing of negative self-relevant information and on self-regulatory behavior in health contexts.

Lifestyle factors related to obesity, eating behavior, and physical activity play a major role in the prevention and treatment of type 2 diabetes. In recent years, there has been progress in the development of behavioral strategies to modify these lifestyle behaviors. Further research, however, is clearly needed, because the rates of obesity in our country are escalating, and changing behavior for the long term has proven to be very difficult. This review article, which grew out of a National Institute of Diabetes and Digestive and Kidney Diseases conference on behavioral science research in diabetes, identifies four key topics related to obesity and physical activity that should be given high priority in future research efforts: 1) environmental factors related to obesity, eating, and physical activity; 2) adoption and maintenance of healthful eating, physical activity, and weight; 3) etiology of eating and physical activity; and 4) multiple behavior changes. This review article discusses the significance of each of these four topics, briefly reviews prior research in each area, identifies barriers to progress, and makes specific research recommendations.

We previously demonstrated that the expression and function of the adipocyte-specific beta3-adrenergic receptor (beta3AR) are significantly depressed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the anti-obesity effects of beta3AR agonists. Because all of these models are hyperinsulinemic, we hypothesized that hyperinsulinemia could be responsible for this abnormality in beta3AR function. The goal of this study was to determine whether lowering insulin with the K-ATP channel agonist, diazoxide (Dz) would reverse the depressed expression and function of the beta3AR found in a model of diet-induced diabetes and obesity in C57BL/6J (B6) mice. B6 male mice were placed on either high fat (HF) or low fat experimental diets. After 4 weeks, HF-fed mice were assigned to a group: HF or HF containing disodium (R,R)-5- [2-( [2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl-1,3-benzodioxole-2,2-di carboxylate (CL; 0.001%, wt/wt), Dz (0.32%, wt/wt), or their combination (CLDz). Dz animals exhibited significantly reduced plasma insulin levels as well as increased 3pAR expression and agonist-stimulated adenylyl cyclase activity in adipocytes. CLDz was more effective in reducing percent body fat, lowering nonesterified fatty acids, improving glucose tolerance, and reducing feed efficiency than either treatment alone.

Behavioral therapy has proved benefit for children with daytime wetting but most studies have used biofeedback techniques and provide no long-term assessment of results. We previously reported similar results using simple behavioral therapy without biofeedback. We report the long-term efficacy of behavioral therapy for daytime wetting.Our program of behavioral therapy included timed voiding, modification of fluid intake, positive reinforcement techniques and pelvic floor (Kegel) exercises to promote pelvic floor strengthening and relaxation. Questionnaires to assess therapeutic efficacy were mailed to patients who had completed therapy more than 1 year previously.A total of 48 patients responded. Mean ages at the time of the initial clinic visit and questionnaire were 8.2 and 12.9 years, respectively. Improvement in symptoms was noted in approximately 74% of the cases during the first year following therapy. At a mean of 4. 7 years after treatment 59.4% of the patients had improved daytime urinary control, 51.1% improved daytime urinary frequency and 45.6% improved daytime urinary urgency. The frequency of urinary tract infections decreased in 56.4% of the cases. Measures of psychological well-being were also noted to be improved in a majority of patients. A total of 77.3% of the patients stated that they would recommend the program to others.Simple behavioral therapy without biofeedback techniques is an effective and durable first line therapy for children with daytime wetting.

OBJECTIVE: To determine whether traits of normal personality are associated with variations in glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A longitudinal cohort study was conducted using data from 105 type 2 diabetic patients in a clinical trial of a stress management intervention. Before treatment assignment, patients completed the NEO Personality Inventory, Revised, which is a questionnaire inventory measuring 5 major domains of normal personality and 30 important traits that define these domains. Glycemic control was assessed by measures of HbA1c and average blood glucose levels based on 7 days of self-monitoring at baseline and at 6 and 12 months. Relationships between personality traits and measures of glycemic control were examined by correlation and linear regression models that were adjusted for age, sex, race, duration of diabetes, medication status, and experimental treatment. RESULTS: Lower average blood glucose values at baseline were associated with higher scores for the personality domain of neuroticism and several specific traits including anxiety, angry hostility depression, self-consciousness, and vulnerability but were associated with lower scores for the trait of altruism. Results were similar for HbA1c but were not as strong. Follow-up results were similar but were less consistent. CONCLUSIONS: Personality traits may offer new insights into variations in glycemic control in patients with type 2 diabetes undergoing standard management. The relative tendency to experience fewer negative emotions and to focus on the needs of others instead of oneself could prove to be a risk factor for poor glycemic control.

OBJECTIVE: To investigate the relationship of symptoms of depression to weight changes in healthy individuals of normal weight across a follow-up of over 20 y. PARTICIPANTS AND DESIGN: College students (3885 men and 841 women) were administered a self-report depression measure in the mid-1960s. Their baseline body mass index (BMI) was calculated from their college medical records. Participants were contacted by mail in the late 1980s and asked to report their current height and weight as well as their smoking and exercise habits. Another measure of depressive symptoms was obtained from 3560 individuals at follow-up. Multiple regression models were used to relate changes in weight to depression scores while controlling for background (gender, baseline BMI and the gender by BMI interaction) and behavioral (exercise and smoking) predictors. RESULTS: The relationship between depressive symptoms and body weight change took the form of an interaction with baseline BMI (P

In response to evidence linking obesity and high amounts of dietary fat, the food industry has developed numerous reduced-fat and nonfat food items. These items frequently derive a relatively large percentage of their energy from sugars and the effect of these sugars on weight regulation is not well known. We studied the comparative effects of high- and low-sucrose, low-fat, hypoenergetic diets on a variety of metabolic and behavioral indexes in a 6-wk weight-loss program. Both diets contained approximately 4606 kJ energy/d with 11% of energy as fat, 19% as protein, and 71% as carbohydrate. The high-sucrose diet contained 43% of the total daily energy intake as sucrose; the low-sucrose diet contained 4% of the total daily energy intake as sucrose. Twenty women aged 40.6 +/- 8.2 y (mean +/- SD) with a body mass index (in kg/m2) of 35.93 +/- 4.8 consumed the high-sucrose diet; 22 women aged 40.3 +/- 7.3 y with a body mass index of 34.93 +/- 4.4 consumed the low-sucrose diet. Mixed-design analysis of variance showed a main effect of time (P < 0.01), with both diet groups showing decreases in weight, blood pressure, resting energy expenditure, percentage body fat, free triiodothyronine (FT3), urinary norepinephrine, and plasma lipids. Small but significant interactions were found between group and time in total cholesterol (P = 0.009) and low-density lipoprotein (LDL) (P = 0.01). Both groups showed decreases in depression, hunger, and negative mood, and increases in vigilance and positive mood with time (P < 0.01). Results showed that a high sucrose content in a hypoenergetic, low-fat diet did not adversely affect weight loss, metabolism, plasma lipids, or emotional affect.

A mitochondrial protein called uncoupling protein (UCP1) plays an important role in generating heat and burning calories by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy-consuming process. This pathway has been implicated in the regulation of body temperature, body composition and glucose metabolism. However, UCP1-containing brown adipose tissue is unlikely to be involved in weight regulation in adult large-size animals and humans living in a thermoneutral environment (one where an animal does not have to increase oxygen consumption or energy expenditure to lose or gain heat to maintain body temperature), as there is little brown adipose tissue present. We now report the discovery of a gene that codes for a novel uncoupling protein, designated UCP2, which has 59% amino-acid identity to UCP1, and describe properties consistent with a role in diabetes and obesity. In comparison with UCP1, UCP2 has a greater effect on mitochondrial membrane potential when expressed in yeast. Compared to UCP1, the gene is widely expressed in adult human tissues, including tissues rich in macrophages, and it is upregulated in white fat in response to fat feeding. Finally, UCP2 maps to regions of human chromosome 11 and mouse chromosome 7 that have been linked to hyperinsulinaemia and obesity. Our findings suggest that UCP2 has a unique role in energy balance, body weight regulation and thermoregulation and their responses to inflammatory stimuli.

Fat intake has long been associated with the development of obesity. The studies described herein show that fat adversely affects adipocyte adrenergic receptor (AR) expression and function. As beta 3AR agonists have been shown to acutely reduce adipose tissue mass and improve thermogenesis in genetically obese rodents, we examined whether chronic supplementation of a high fat diet with a highly selective beta 3AR agonist, CL316,243 could prevent diet-induced obesity, and whether the effect could be sustained over prolonged treatment. C57BL/6J and A/J mice were weaned onto one of three diets: low fat (10.5% calories from fat), high fat (58% calories from fat), or high fat supplemented with 0.001% CL316,243. B/6J mice gained more weight on the high fat diet than A/J mice (at 16 weeks: B/6J, 36.6 +/- 1.4 g; A/J, 32.9 +/- 0.8 g; P 0.05; n = 10). CL316,243 prevented the development of diet-induced obesity in A/J animals, but not in B/6J animals. A/J mice weighed 26.0 +/- 0.5 g at 16 weeks, whereas B/6J animals on the same diet weighed 34.1 +/- 0.8 g (P < 0.00001; n = 10), but food intake was not different between the strains throughout the study. beta-Adrenergic stimulation of adenylyl cyclase in obese B/6J mice was decreased by more than 75% in white adipose tissue and by more than 90% in brown adipose tissue (BAT). In contrast, in fat-fed A/J mice, beta-agonist-stimulated adenylyl cyclase was decreased in white adipose tissue by about 10%, whereas the activity in interscapular BAT was decreased by 50%, indicating significant retention of beta AR-stimulated activity in A/J mice compared to B/6J mice. High fat feeding was associated with decreased expression of beta 3AR and beta 1AR in white adipose tissue of both strains. However, chronic CL316,243 treatment prevented both the obesity and the decline in beta 3AR and beta 1AR messenger RNA levels in all adipose depots from A/J mice, but not B/6J mice. As CL316,243-treated A/J mice, but not B/6J mice, also showed marked uncoupling protein expression in white adipose depots, the ability of chronic CL316,243 treatment to prevent diet-induced obesity is dependent upon the elaboration of functional BAT in these regions.

Objective: Withholding insulin for weight control is a dangerous practice among individuals with type 1 diabetes; yet little is known about the factors associated with this behavior. Studies of nondiabetic individuals with weight concerns suggest that eating in a disinhibited manner (e.g., binge eating) predicts the use of maladaptive compensatory strategies (e.g., self-induced vomiting). The purpose of this study was to test whether individuals with type 1 diabetes are less restrained in their eating when they think their blood glucose (BG) is low and whether this contributes to insulin omission for weight control purposes and subsequently higher hemoglobin A1c (HbA1c). Methods: Two-hundred and seventy-six individuals with type 1 diabetes completed an online survey of eating behaviors, insulin dosing and most recent HbA1c. We used structural equation modeling to test the hypothesis that disinhibited eating when blood sugar is thought to be low predicts weight-related insulin mismanagement, and this, in turn, predicts higher HbA1c. Results: The majority of participants endorsed some degree of disinhibition when they think their blood glucose is low (e.g., eating foods they do not typically allow) and corresponding negative affect (e.g., guilt/shame). The frequency of disinhibited eating was positively associated with weight-related insulin mismanagement. Controlling for age, sex, education, and insulin pump use, the model explained 31.3% of the variance in weight-related insulin mismanagement and 16.8% of the variance in HbA1c. Conclusion: Addressing antecedents to disinhibited eating that are unique to type 1 diabetes (e.g., perceived BG level) and associated guilt or shame may reduce weight-related insulin omission.

Previous research in our laboratory has demonstrated that the C57BL/6J (B/6J) mouse has a predisposition to develop severe obesity if placed on a high-fat diet. In the present study we assessed the role of physical activity in this phenomenon. Obesity-prone B/6J and obesity-resistant A/J mice were placed on one of four diets; high fat/high sucrose, high fat/low sucrose, low fat/high sucrose, and low fat/low sucrose. After 4 months, all animals on the high-fat diets had gained more weight than animals on the low-fat diets, and this phenomenon was greatly exaggerated in B/6J mice. Despite the fact that B/6J mice gained more weight than A/J mice on high-fat diets without consuming more calories, spontaneous motor activity was elevated in B/6J mice compared to A/J mice. There was no effect of the diets on activity either within or across strains. These data suggest that predisposition to diet-induced obesity is not explainable by reduced levels of physical activity.

Mutation of the obese (ob) gene results in severe hereditary obesity and diabetes in the C57BL/6J and related strains of mice. In this study we examined the expression of the ob gene in a dietary model in which moderate obesity develops in response to fat (58% of calories from fat) without mutation of the ob gene, and in four genetic models of obesity in mice: ob/ob, db/db, tubby, and fat. Several white and brown adipose depots were examined (epididymal, subcutaneous, perirenal, and interscapular). Northern blot analysis shows that levels of ob mRNA are increased in all adipose depots examined in every model of obesity. The average fold increases were 12.0 +/ 2.1 (ob/ob), 4.8 +/- 1.5 (db/db), 2.8 +/- 0.1 (tubby), 2.4 +/- 0.3 (fat), and 2.1 +/- 0.2 (high fat diet-induced A/J). Moreover, we found that the expression of the ob gene could be manipulated by pharmacologically blocking the development of diet-induced obesity. Supplementation of a high fat diet with a beta 3-adrenergic receptor agonist (CL316,243) prevented obesity, but not hyperphagia associated with high fat feeding (body weights of high fat-fed A/J mice = 34.0 +/- 1.0 g; high fat plus CL316,243-fed mice = 26.8 +/- 0.5 g; n = 10). CL316,243-treated, high fat-fed animals contained levels of ob mRNA in all adipose depots that were equal to or less than levels in low fat-fed mice (average levels in high fat plus CL316,243-fed mice relative to low fat-fed mice: 0.93 +/- 0.09). Inasmuch as fat cell size, but not number, was increased in a previous study in diet-induced obese A/J mice, these results indicate that expression of the ob gene serves as a sensor of fat cell hypertrophy, independent of any effects on food intake.

C57BL/6J (B/6J) mice are genetically predisposed to become overweight and develop hyperglycemia if raised on a high fat diet. The purpose of the present study was to explore the effect of dietary supplementation of L-glutamine (Gln), an inhibitor of fatty acid oxidation, on the development of hyperglycemia and excessive weight gain. Groups of 10 age- and weight-matched male B/6J mice were raised on one of four diets: 1) a low fat, low sucrose (LL), studied separately, 2) a high fat, low sucrose (HL) diet alone, 3) high fat, low sucrose supplemented with L-glutamine (HL+Gln) and 4) high fat, low sucrose supplemented with L-alanine (HL+Ala). Energy intake, body weight, plasma glucose and insulin concentrations were monitored over time. We found no difference in energy intake per unit body weight between any groups after the first 2 wk of feeding. However, the mean +/- SEM for body weight (27.1 +/- 0.6 g) of the LL group measured at 16 wk was lower (P < 0.05) than that of the HL group at 37.9 +/- 1.9 g. Also, after 5.5 mo, the mean +/- SEM for plasma glucose and insulin concentrations in the LL group of mice were 6.9 +/- 0.4 mmol/l and 146 +/- 30 pmol/l, which were lower (P < 0.05) than those in the HL group at 10.1 +/- 0.9 mmol/l and 438 +/- 84 pmol/l, respectively. Although both amino acids caused a 10% reduction (P < 0.05) in body weight compared with HL feeding at wk 16, only Gln supplementation resulted in persistent reductions in both plasma glucose and insulin concentrations over 5.5 mo. In another experiment, when Gln was added to the high fat (HL) diet of heavy hyperglycemic animals for 2 mo, body weight gain, hyperglycemia and hyperinsulinemia were attenuated. In conclusion, supplementing glutamine to a high fat diet reduces body weight and attenuated hyperglycemia and hyperinsulinemia in B/6J mice.

Objective To review the literature regarding the use of animal models in research addressing psychosomatic aspects of diabetes. Method We examine the key findings in animal model vs. human research in the area of stress and diabetes. Previous research has suggested that stress is a potential contributor to chronic hyperglycemia in diabetes. Stress affects metabolic activity via the stimulation of a variety of hormones that can result in elevated blood glucose levels. In patients with diabetes, due to a relative or absolute lack of insulin, stress-induced increases in glucose cannot be properly metabolized. Additionally, regulation of these stress hormones may be abnormal in diabetes. Results Human studies on the role of stress in the onset and course of type II diabetes are few and are limited by the constraints and logistics of examining life stress in humans. However, animal research allows for tight experimental control and the manipulation of factors that may contribute to the development and/or course of diabetes, such as stress, eating behavior, the nutrient content of food, and physical activity. Disease processes can be examined at a mechanistic level in animals which is typically limited in human research. Conclusions There is a large body of animal work to support the notion that stress reliably produces hyperglycemia in type II diabetes. Furthermore, there is evidence that the autonomic nervous system plays a role in the pathophysiology of this condition in both animals and humans. Examination of eating behavior and nutrient content of food in animal models of diabetes has shed light on the role of these factors in the development of diabetes, as well as obesity. Finally, genetic research using animal models of diabetes will provide new directions for research in humans to delineate the genetic contribution to the development of diabetes.

Various tissues were obtained from the well-characterized genetic model ( C57BL/6J- ob ob ) of non-insulin-dependent diabetes mellitus (NIDDM) and from a diet-induced model of NIDDM produced in the same genetic background (C57BL/6J). The objectives were to determine whether the previously observed changes in guanine nucleotide-binding regulatory protein (G protein) expression in adipose tissue from ob ob mice were mirrored by concomitant changes in other tissues, and whether NIDDM of a different etiology would share similar alterations in G protein expression. Plasma membranes from adipocytes, brain, heart, liver, and testes were probed with α-subunit-specific antisera, and the level of G protein expression in each model was compared with that in its lean littermate control. Adipose, heart, and liver cell membranes from ob ob mice contained significantly less α-subunit of stimulatory G protein (G s α) than those from their lean littermates. As compared with the lean littermates, heart α-subunit-2 of inhibitory G protein (G i α-2), liver G i α-3, and adipocyte G i α-1 and G i α-3 were also reduced in ob ob mice. In contrast, G i α-2 and G o α were increased over lean-control levels in brain tissue from ob ob mice, whereas G s α was unchanged. G protein expression in the testes did not differ between lean and ob ob mice. In the diet-induced model of NIDDM, G s α expression in the liver was twofold greater in obese/diabetic mice as compared with lean controls. However, G protein expression in all other tissues examined did not differ between obese/diabetic animals and lean littermates. Although the severity of overt symptoms of NIDDM is comparable between the two models, the diet-induced model does not suffer from the documented endocrine abnormalities of hypothyroidism and hyperadrenocorticism noted in the ob ob mouse. Thus, it seems likely that the G protein changes noted in the ob ob mouse are not the direct result of the obese or diabetic condition, but may be secondary to endocrine differences between the two models.

We have previously demonstrated that the C57BL/6J (B/6J) mouse will develop severe obesity, hyperglycemia, and hyperinsulinemia if weaned onto a high-fat, high-sucrose (HH) diet. In the present study, we compared the effects of fat and sucrose separately and in combination on diabetes- and obesity-prone B/6J and diabetes- and obesity-resistant A/J mice. After 4 months, the feed efficiency ([FE] weight gained divided by calories consumed) did not differ across diets in A/J mice, but B/6J mice showed a significantly increased FE for fat. That is, B/6J mice gained more weight on high-fat diets without consuming more calories than A/J mice. The increase in FE was related to adipocyte hyperplasia in B/6J mice on high-fat diets. Fat-induced obesity in B/6J mice was unrelated to adrenal cortical activity. In the absence of fat, sucrose produced a decreased in FE in both strains. Animals fed a low-fat, high-sucrose (LH) diet were actually leaner than animals fed a high-complex-carbohydrate diet. Fat was also found to be the critical stimulus for hyperglycemia and hyperinsulinemia in B/6J mice. In the absence of fat, sucrose had no effect on plasma glucose or insulin. These data clearly show that across these two strains of mice, genetic differences in the metabolic response to fat are more important in the development of obesity and diabetes than the increased caloric content of a high-fat diet.

BACKGROUND: A growing body of evidence suggests that caffeinated beverages may impair chronic glucose control in type 2 diabetes. This pilot study tested the chronic effects of caffeine abstinence on glucose control in type 2 diabetic patients who were daily coffee drinkers. METHODS: Twelve coffee drinkers (six males) with established type 2 diabetes participated. Seven (five males) completed 3 months of total caffeine abstinence. Measures of chronic glucose control, long-term (hemoglobin A1c [HbA1c]) and short-term (1,5-anhydroglucitol [1,5-AG]), were collected at baseline and during follow-up. Abstinence was established by diaries confirmed by saliva caffeine assays. RESULTS: Abstinence produced significant decreases in HbA1c and increases in 1,5-AG, both indicating improvements in chronic glucose control. Fasting glucose and insulin did not change, nor were changes in body weight observed. CONCLUSIONS: Although preliminary, these results suggest that caffeine abstinence may be beneficial for patients with type 2 diabetes. This hypothesis should be confirmed in larger controlled clinical trials.

Inbred mouse strains fed a diabetogenic diet have different propensities to develop features analogous to type 2 diabetes mellitus. To define chromosomal locations that control these characteristics, recombinant inbred strains from diabetes-prone C57BL/6J (B/6J) and diabetes-resistant A/J strains were studied. Insulin levels and hyperglycemia correlated with two different regions of mouse chromosome 7 (two point LOD scores > 3.0). For insulin levels, 15 of 16 recombinant inbred strains were concordant with a region that contains the tubby mutation that results in hyperinsulinemia. For hyperglycemia, 19 of 23 strains were concordant with the D7Mit25 marker and 20 of 23 strains with the Gpi-1 locus on proximal mouse chromosome 7. Using more stringent criteria for hyperglycemia, 10 of 11 strains characterized as A/J or B/6J like were concordant with D7Mit25. This putative susceptibility locus is consistent with that of the glycogen synthase gene (Gys) recently suggested as a candidate locus by analyses of type 2 diabetes patients. Fractional glycogen synthase activity in isolated muscle was significantly lower in normal B/6J diabetic-prone mice compared with normal diabetic-resistant A/J mice, a finding similar to that reported in relatives of human patients with type 2 diabetes. These data, taken together, raise the possibility that defects in the Gys gene may in part be responsible for the propensity to develop type 2 diabetes.

It has been suggested that the association between anthropometric measures of adiposity (e.g., waist circumference (WC) and body mass index (BMI)) and high blood pressure vary by race.1 These anthropometric measures, however, only broadly capture more complex underlying patterns of body composition and adiposity (e.g., visceral vs. subcutaneous adipose tissue, upper body vs. abdominal fat), which also vary by sex and race.2 Despite their relative lack of specificity with respect to adiposity, techniques for assessing anthropometric measures such as BMI and WC are comparatively inexpensive and widely accessible. Thus, further elucidation of how these relatively simple measures are associated with disease remains important. The present study describes the association between WC and systolic blood pressure (SBP), with a focus on how these relations may vary by race and sex, using a large nationally representative sample of young adults in the United States. We focus on SBP in the present study because, although associations have been shown to vary by age,3 many studies have shown SBP to be more important than diastolic blood pressure (DBP) with respect to health risk,4–9 and also possibly more responsive than DBP to changes in modifiable risk factors such as exercise, diet, and weight loss.10 WC has been shown to add to the prediction of visceral fat beyond measurements of BMI.11,12 Visceral adipose tissue is an independent predictor of the metabolic syndrome in both men and women,13 and has also been found to add to the prediction of hypertension.14,15 Following Tybor et al.,16 we use statistical partialling to remove the effect of BMI from the association between WC and SBP. WC partialled for BMI reflects WC independent of overall body size, and thus, by definition, must reflect body shape or body fat distribution. We also allow for the possibility that these associations may be nonlinear. Examination of these questions in this manner may provide more precise information about the pathophysiology underlying high blood pressure and also further guide risk stratification in clinical practice.

It has been suggested that a genetic predisposition and an increased total fat mass, particularly a specific increase in visceral fat, contribute to the metabolic aberrations associated with human non-insulin-dependent diabetes mellitus (NIDDM). In this study, we investigated the interactions between genetic and dietary components on fat distribution and metabolism in two mouse strains, one genetically predisposed to NIDDM ( BL 6 ) and one not ( A J ), fed either a chow diet or a high-fat, high-simple carbohydrate (HFHSC) diet for 5 months. As expected, both strains of mice fed a HFHSC diet were heavier, had more fat in both the subcutaneous (inguinal [ING]) and visceral (mesenteric [MES]) regions, and had larger fat cells and higher lipoprotein lipase (LPL) activities. The results of interactions between strain and diet showed important differences in fat distribution and metabolism between strains. In comparison with A J mice, BL 6 mice fed a HFHSC diet developed hyperglycemia, hyperinsulinemia, and hypercholesterolemia, were heavier, had more overall fat, and particularly increased their MES adipose tissue. This increase in visceral fat mass was due to an increase in fat cell number. In contrast, BL 6 mice fed a chow diet had less overall fat, a smaller MES fat pad with smaller adipocytes, and lower LPL activity than A J controls. Significant differences between BL 6 and A J mice fed either a HFHSC or a chow diet were not observed in ING adipose tissue. These data suggest that in BL 6 mice, changes in the metabolic characteristics of visceral fat seem to be a specific characteristic associated with the genetic predisposition for NIDDM. Since this mouse model appears to develop diet-induced NIDDM in association with an increase in visceral fat, it seems to be a good model for further studies relevant to the human disease.

OBJECTIVE To examine the benefits of relaxation training for patients with NIDDM and to investigate individual differences that could predict a positive response to relaxation training. RESEARCH DESIGN AND METHODS Thirty-eight subjects with NIDDM were treated with intensive conventional diabetes therapy after an initial metabolic evaluation and psychological and pharmacological testing. Half were assigned to also receive biofeedback-assisted relaxation training. Treatment effects on GHb levels and glucose tolerance were evaluated after 8 wk. RESULTS Subjects demonstrated significant improvements in GHb level, but not in glucose tolerance, after 8 wk of intensive conventional treatment. These improvements persisted throughout the follow-up period. However, the group provided with relaxation training did not experience greater improvements on either measure than the group given conventional diabetes treatment only. Within the group that received relaxation training, correlations occurred between the improvements in glucose tolerance after treatment and individual differences in trait anxiety and in the effect of alprazolam on glucose tolerance. Differences in the effects of EPI on glucose tolerance and personality measures of neuroticism and perceived locus of control also appeared to be related to improvements in glucose tolerance after training. CONCLUSIONS Relaxation training did not confer added benefit over and above that provided by conventional diabetes treatment for patients with NIDDM. Additional research is needed to determine whether the administration of relaxation training to selected patients, especially those who are most responsive to stress, would provide benefits for glucose control that are not achieved by conventional treatment.

Stress has long been suspected as having major effects on metabolic activity. The effects of stress on glucose metabolism are mediated by a variety of "counter-regulatory" hormones that are released in response to stress and that result in elevated blood glucose levels and decreased insulin action. This energy mobilizing effect is of adaptive importance in a healthy organism. However, in diabetes, because of a relative or absolute lack of insulin, stress-induced increases in blood glucose cannot be adequately metabolized. Thus, stress is a potential contributor to chronic hyperglycemia in diabetes, although its exact role is unclear. Although there is some suggestion from retrospective human studies that stress can precipitate type I diabetes, animal studies are contradictory with different stressors either having facilitatory or inhibitory effects upon the development of the disease. Human investigations in patients with established diabetes are equally confusing with some showing that stress can stimulate hyperglycemia, hypoglycemia or have no effect at all on glycemic status. There is more consistent evidence supporting the role of stress in animal models of type II diabetes. However, human studies on the role of stress on the course of established type II diabetes are few. Intervention studies suggest that behavioral or pharmacologic intervention to manage stress may contribute significantly to diabetes treatment, but more long-term research is needed. It is concluded that further research is needed to establish the importance of behavioral factors in the etiology and management of diabetes, and several areas of methodologic improvement are suggested.

The high prevalence of diabetes in African-American (AA) women has been widely assumed to be related to the greater prevalence of obesity in this group. Catecholamine release acting on central adipose tissue has been proposed to be a contributing factor. The aim of this article was to examine the interaction of plasma catecholamines and central adiposity on fasting and nonfasting glucose levels in two separate samples. In both studies, the women were healthy, nondiabetic of similar age. In addition, both studies assessed plasma epinephrine (EPI) and norepinephrine (NOREPI) levels collected at three time points. In study 1, catecholamines were measured during a standardized laboratory mental stress task and in study 2, they were measured during the initial phase (10 min) of an intravenous glucose tolerance test (IVGTT). Results from both studies revealed significant effects of EPI on fasting glucose in the obese women. In study 1, mean EPI levels were significantly related to fasting glucose in AA women with high trunk fat (β = 0.60, P < 0.001). Because high BMI was associated with high trunk fat in women, we used BMI >30 as a proxy for high trunk fat (>32%) in study 2. In study 2, EPI response to the glucose bolus was a strong predictor of fasting glucose in AA women with BMI >30 (β = 0.75, P < 0.003). We conclude that the effect of central adiposity on fasting glucose may be moderated by plasma EPI. This suggests that adrenal medullary activity could play a role in the pathophysiology of type 2 diabetes.

Stress is a potential contributor to chronic hyperglycemia in diabetes. Stress has long been shown to have major effects on metabolic activity. Energy mobilization is a primary result of the fight or flight response. Stress stimulates the release of various hormones, which can result in elevated blood glucose levels. Although this is of adaptive importance in a healthy organism, in diabetes, as a result of the relative or absolute lack of insulin, stress-induced increases in glucose cannot be metabolized properly. Furthermore, regulation of these stress hormones may be abnormal in diabetes. However, evidence characterizing the effects of stress in type I diabetes is contradictory. Although some retrospective human studies have suggested that stress can precipitate type I diabetes, animal studies have shown that stressors of various kinds can precipitate—or prevent—various experimental models of the disease. Human studies have shown that stress can stimulate hyperglycemia, hypoglycemia, or have no affect at all on glycemic status in established diabetes. Much of this confusion may be attributable to the presence of autonomic neuropathy, common in type I diabetes. In contrast, more consistent evidence supports the role of stress in type II diabetes. Although human studies on the role of stress in the onset and course of type II diabetes are few, a large body of animal study supports the notion that stress reliably produces hyperglycemia in this form of the disease. Furthermore, there is mounting evidence of autonomic contributions to the pathophysiology of this condition in both animals and humans.

To explore the underlying physiology of hostility (HOST) and to test the hypothesis that HOST has a greater impact on fasting glucose in African American (AA) women than it does on AA men or white men or women, using an intravenous glucose tolerance test (IVGTT) and the minimal model of glucose kinetics.A total of 115 healthy subjects selected for high or low scores on the 27 item Cook Medley HOST Scale underwent an IVGTT. Fasting nonesterified fatty acids (NEFA) levels were measured before the IVGTT. Catecholamine levels were measured 10 minutes into the IVGTT.Moderation by group (AA women versus others) of HOST was found for glucose effectiveness (Sg, p = .02), acute insulin response (AIRg, p = .02), and disposition index (DI, p = .02). AA women showed a negative association between HOST and both Sg (beta = -0.45, p = .04) and DI (beta = -0.49, p = .02), controlling for age and body mass index. HOST was also associated with changes in epinephrine (beta = 0.39, p = .05) and fasting NEFA (beta = 0.44, p = .02) in the AA women. Controlling for fasting NEFA reduced the effect of HOST on both Sg and DI.This study shows that HOST is related to decreased DI, a measure of pancreatic compensation for increased insulin resistance as well as decreased Sg, a measure of noninsulin-mediated glucose transport compared in AA women. These effects are partly mediated by the relationship of HOST to fasting NEFA.

Background: The isotope-labeled intravenous glucose tolerance test (IVGTT) combined with computer modeling is widely used to derive parameters related to glucose metabolism in vivo. Most of these methods involve use of either 2H2-labeled or 13C1-labeled d-glucose as a tracer with GC-MS to measure the isotope enrichment. These methods are challenging, both technologically and economically. We have developed a novel approach that is suitable for labeled-IVGTT studies involving a large cohort of individuals. Methods: The tracer, d-[13C6]glucose, is a low-cost alternative with the significant advantage that the sixth isotope of natural glucose has virtually zero natural abundance, which facilitates isotopomer analysis with Results: With labeled-IVGTT data from 10 healthy male individuals, the values for insulin sensitivity, glucose effectiveness, and the plasma clearance rate estimated with the 2-pool minimal model compared well with values obtained via traditional methods. Conclusions: The relative simplicity and robustness of the new method permit the preparation and analysis of up to 48 samples/day, a throughput equivalent to 2 complete IVGTT experiments, and this method is readily adaptable to existing 96 well–format purification and analytical systems.

Caregiving stress is associated with negative health outcomes. Neuroendocrine functioning may be a mediator of such outcomes. The MAOA gene regulates activity of neurotransmitters involved with neuroendocrine responses to stress. Differences in polymorphisms of this gene have been shown to influence susceptibility to stress. Therefore, we examined allelic variation in MAOA-uVNTR, a functional polymorphism of MAOA, as a moderator of chronic stress effects on urinary cortisol excretion in 74 males enrolled in a case/control study of caregivers for relatives with dementia. Mixed models analysis of variance were used to examine MAOA-uVNTR genotype (3 repeats vs. 3.5/4 repeats) as a moderator of the impact of stress (caregiver vs. non-caregiver) on the urinary excretion pattern (overnight, daytime, evening) of cortisol. Caregivers with MAOA-uVNTR alleles associated with less transcriptional activity (3-repeats) displayed a pattern of cortisol excretion -- a decrease from overnight to daytime -- that was suggestive of HPA axis blunting, as compared to non-caregivers and those caregivers with the more active alleles (3.5/4 repeats) (cortisol p.043). Individuals with less active MAOA-uVNTR alleles who are under chronic stress may be at increased risk for exhaustion of the HPA response to such stress.

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.

Diabetes patients have a twofold increased risk of suffering from depression as compared to individuals without diabetes. This commonly overlooked comorbidity affects about a quarter of the diabetic population. Because depression among diabetes patients has been associated with decreased metabolic control, poor adherence to medication and diet regimens, a reduction in quality of life, it is of importance for health care providers to recognize and properly treat depression among diabetes patients. When screening for depression, it is important to take into account that the physical symptoms of depression and diabetes overlap to some degree. Also, when deciding on a treatment plan for depression in diabetic patients, the health care provider must be aware of the unique side effects of antidepressants in this population. Psychotherapy and pharmacotherapy are effective in treating depression in the presence of diabetes; both cognitive behavior therapy and selective serotonin reuptake inhibitors have been associated with glycemic improvement in some studies.

This study examined the associations of depressive symptoms with glucose concentrations and morning cortisol levels in 665 African-American and 4,216 Caucasian Vietnam-era veterans.Glucose level was measured as a three-level variable (diabetes, impaired glucose, and normal). Depressive symptoms were measured by the Obvious Depression Scale (OBD) from the Minnesota Multiphasic Personality Inventory.Regression models showed significant race x OBD interactions in relation to glucose concentration (P0.0001) and cortisol (P0.0001). The OBD was positively associated with glucose concentration and cortisol in both racial groups. However, the magnitude of those associations was larger for African Americans. Further analyses suggested that cortisol partially mediated the race difference in the relation of depressive symptoms to glucose concentrations.These results suggest that enhanced hypothalamic pituitary adrenal activity plays an important role in the relation of depressive symptoms to dysregulated glucose metabolism and may partially explain the differential effects of depressive symptoms on glucose levels in African-American and Caucasian male subjects.