Behavioral changes and hyperglycemia in NODEF mice following bisphenol S exposure are affected by diets.

Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 µg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 µg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L-cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 µg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.

Hyperglycemia elicits anxiety-like behaviors in zebrafish: Protective role of dietary diphenyl diselenide.

Diabetes mellitus (DM) is a chronic metabolic disease that may comorbid with various psychiatric disorders, such as anxiety and depression. The search for effective therapeutics to alleviate hyperglycemia and complications resulting from DM is continuous. Here we investigate the effects of diphenyl diselenide (DD), an organoselenium compound with several pharmacological properties, in a zebrafish model of hyperglycemia. Fish were fed for 74 days with a diet containing 3 mg/Kg DD, a concentration chosen after experiments based in a dose-response curve (DD 1, 2 and 3 mg/Kg) that did not cause overt toxicity (mortality, weight loss and neurobehavioral deficits). In the last 14 days of the experimental period, fish were concomitantly exposed to a glucose solution (111 mM). Afterwards, blood glucose levels, brain selenium (Se) content, and behavioral analysis aiming to assess anxiety-like behaviors and locomotor/exploratory activities were performed. In the novel tank diving test, glucose decreased vertical exploration and fish spent less time in the lit area when tested in the light-dark test, suggesting increased anxiety-like behavior. Moreover, DD decreased blood glucose levels in hyperglycemic fish as well as prevented the development of anxiety-related symptoms. DD diet alone did not change glycemia and behavioral parameters, but increased Se levels in the brain without affecting the cellular viability. Collectively, our findings highlight the growing utility of this zebrafish hyperglycemia model as a valuable strategy for further research in DM field and neuroprotective approaches.

Black pepper-based beverage induced appetite-suppressing effects without altering postprandial glycaemia, gut and thyroid hormones or gastrointestinal well-being: a randomized crossover study in healthy subjects.

Pleiotropic effects of spices on health, particularly on glucose metabolism and energy regulation, deserve further clinical investigation into their efficacy. The aim of the current study was to evaluate whether consumption of a black pepper-based beverage (BPB) preload containing 20 mg gallic acid equivalent (GAE) would exert any effect on postprandial glycaemia, appetite sensations, gut hormones, thyroid function, and gastrointestinal well-being after a white wheat bread (WWB) challenge meal containing 50 g available carbohydrates (CHO) compared to a control beverage. Sixteen healthy subjects (10 men; 6 women; 26 ± 0.9 years; BMI 22.93 ± 0.53 kg m-2) completed a randomized, crossover intervention study. The BPB's bioactive compounds were characterized using ultra high-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer with an electrospray ionization source (UHPLC-DAD-ESI-QTOF-MS). Nine compounds tentatively identified in BPB include: dihydroxybenzoic acid hexoside-pentoside, decaffeoyl-acteoside, cynaroside A, apigenin 6,8-di-C-hexoside, luteolin 6-C-hexoside-8-C-rhamnoside, apigenin 8-C-hexoside-C-deoxyhexoside, kaempferol 3-rhamnoside-4'-xyloside, apigenin 7-neohesperidoside, and apigenin-8-C-arabinopyranoside-2''-rhamnoside. Blood glucose and serum insulin responses, insulin sensitivity and ß-cell function were not affected during the acute intervention with BPB. Neither were effects on gastrointestinal well-being observed after BPB. However, BPB modulated overall acute appetite by lowering 'hunger', 'desire to eat', and 'prospective consumption', and increasing 'satiety' and 'fullness'. In contrast, there were no changes in gut (peptide tyrosine-tyrosine [PYY] and glucagon-like peptide-1 [GLP-1]) and thyroid (triiodothyronine [T3] and thyroxine [T4]) hormones after BPB compared to the control beverage. In conclusion, inclusion of BPB prior to the WWB challenge meal might be beneficial for appetite modulation, but we did not find supporting evidence in glycaemia, gut and thyroid hormones. Further studies are needed to elucidate the mechanisms of appetite-reducing pungent spices, such as black pepper.

Widespread blunting of hypothalamic and amygdala-septal activity and behavior in rats with long-term hyperglycemia.

Anxiety and depression in diabetic patients contributes to a poor prognosis, but possible causal relationships have been controversial. Anxiety, fear, and anhedonia are mediated by interactions between different deep structures of the temporal lobe (e.g., amygdala complex and hippocampus) and other forebrain-related structures (e.g., lateral septal nucleus). Connections between these structures and the hypothalamic orexinergic system are necessary for the maintenance of energy and wakefulness. However, few studies have explored the impact of long-term hyperglycemia in these structures on anxiety. We induced long-term hyperglycemia (glucose levels of ∼500mg/dl) in Wistar rats by injecting them with alloxan and simultaneously protecting them from hyperglycemia by injecting them daily with a low dose of insulin (i.e., just enough insulin to avoid death), thus maintaining hyperglycemia and ketonuria for as long as 6 weeks. Compared with controls, long-term hyperglycemic rats exhibited a significant reduction of Fos expression in the lateral septal nucleus and basolateral amygdala, but no differences were found in cerebellar regions. Orexin-A cells appeared to be inactive in the lateral hypothalamus. No differences were found in sucrose consumption or behavior in the elevated plus maze compared with the control group, but a decrease in general locomotion was observed. These data indicate a generalized blunting of the metabolic brain response, accompanied by a decrease in locomotion but no changes in hedonic- or anxiety-like behavior.

Involvement of orexin-A neurons but not melanin-concentrating hormone neurons in the short-term regulation of food intake in rats.

In order to elucidate the involvement of melanin-concentrating hormone (MCH) and orexin-A (ORX-A) neurons of the perifornical/lateral hypothalamic areas (PF/LH) in the regulation of food intake induced by acutely reduced glucose availability, we examined the food intake response and c-Fos expression in the MCH and ORX-A neurons in the PF/LH during 2-deoxy-D-glucose (2DG)-induced glucoprivation (400 mg/kg; i.v.) and systemic insulin-induced hypoglycemia (5 U/kg; s.c.) in male Wistar rats. The administration of both 2DG and insulin stimulated food intake and induced c-Fos expression in the ORX-A neurons corresponding to food intake, but not in the MCH neurons. These data indicate that ORX-A neurons, but not MCH neurons, play a role in the short-term regulation of food intake, and that the input signals for the neurons containing MCH and ORX-A are different, and these neurons play different roles in the regulation of feeding behavior.

Dietary iron supplements may affect stress adaptation and aggravate stress hyperglycemia in a rat model of psychological stress.

OBJECTIVE: Iron supplementation is believed to decrease the risk of iron-deficiency anemia or low birth weight. In modern society, a majority of people are in a continual state of stress. Stress-induced hyperglycemia, known as transient hyperglycemia, may be a risk factor causing diabetes. To understand the role of iron in people under stress, it is necessary to evaluate the effect of iron supplementation on glucose or stress hyperglycemia. METHODS: The effect of a diet containing non-heme iron (80 or 320 mg/kg) on Sprague-Dawley rats and those under psychological stress was evaluated. RESULTS: Compared with control rats, a high-iron diet (320 mg/kg) increased blood glucose transiently in normal rats but induced hyperglycemia persistently in stressed rats throughout the experiment. Iron supplements further aggravated iron deposition and oxidative stress injury to the liver induced by the stress exposure. Glucose-related stress hormones were also affected by iron supplementation in stressed rats. CONCLUSION: Oxidative stress may be one of the main reasons for insulin resistance. Moreover, changes in stress hormones indicate that high-iron supplements may affect stress adaptation. Both are primary reasons for the hyperglycemia induced by iron supplementation in stressed rats. Gaining an insight into the mechanisms and correlations of these changes may be beneficial to human health and is important for the prevention of pathologic glycemia-related diseases.

Swimming stress that causes hyperglycemia increases in vivo release of noradrenaline, but not acetylcholine, from the hypothalamus of conscious rats.

The effects of acute swimming stress (10 min) on noradrenaline release from the medial basal hypothalamus (MBH; consisting of the ventromedial and dorsomedial hypothalamus) and acetylcholine release from the lateral hypothalamic area (LHA) were investigated in freely moving rats by using in vivo microdialysis techniques. Serum glucose, noradrenaline and adrenaline concentrations were also determined. Acute swimming stress produced significant hyperglycemia, with increases in serum noradrenaline and adrenaline concentrations. The release of noradrenaline from the MBH was significantly stimulated during the swimming stress. On the other hand, the swimming stress has no significant effect on the release of acetylcholine from the LHA. These findings support the idea that hypothalamic noradrenergic neurons play an important role in the sympathoadrenal hyperglycemic response to stressful stimuli. Moreover, it is suggested that hypothalamic cholinergic neurons are not involved in the responses of serum glucose, noradrenaline and adrenaline concentrations to swimming stress.

Frontal cortex lesion prior to hyperglycemic ischemia: no decrease in ensuing substantia nigra pars reticulata damage or fatal post-ischemic seizures.

Preischemic hyperglycemia worsens brain damage after ischemia, and characteristically leads to post-ischemic seizures and a pan-necrotic lesion in substantia nigra pars reticulata (SNPR). The excitatory input to SNPR could contribute to the damage observed. By performing a unilateral frontal cortex lesion 6-19 days prior to the ischemia, we wanted to explore whether a decrease in excitatory input to the ipsilateral SNPR ameliorate the seizures or alter the light microscopical damage in SNPR. Our results demonstrate that unilateral frontal cortex lesion did not alter the development of fatal post-ischemic seizures after 10 min of ischemia in hyperglycemic subjects. Thus, 7/8 animals developed seizures and died within 20 h of recovery. This study also failed to show any difference between the left and right side in post-ischemic SNPR damage after 15 h of recovery in animals with preischemic unilateral frontal cortex lesion. Furthermore, no side difference was observed in any other brain region evaluated. The results thus suggest that the pan-necrotic lesion in SNPR after hyperglycemic ischemia is not caused by excessive excitatory input from frontal cortex. A decrease in the GABA-ergic inhibitory input from caudoputamen to SNPR may be a more important mechanism for the ensuing excitotoxic post-ischemic SNPR damage, and for seizure development.

Accuracy of subjective blood glucose estimation by patients with insulin-dependent diabetes.

A between-groups design using a baseline, treatment, follow-up procedure was used to investigate the accuracy of 20 patients with insulin-dependent diabetes when subjectively estimating their blood glucose levels. Patients were encouraged to attend to their mood for cues when making estimates of their blood glucose. Their capacity for reducing estimation errors when given immediate or delayed feedback of actual blood glucose was examined. The results showed that neither delayed nor immediate feedback produced a significant improvement in the mean estimation accuracy of these groups of patients or in their ability to predict whether their blood glucose was in the acceptable or unacceptable range. Patients were particularly inaccurate in detecting Low [less than 4.0 mmol/L (less than 72.0 mg/dl)] and Very High [greater than 16.0 mmol/L (greater than 288.0 mg/dl)] blood glucose levels. Examination of mood-blood glucose relationships revealed consistent patterns for individual subjects and considerable differences between subjects.

Biofeedback-assisted stress management for insulin-treated diabetes mellitus.

Six insulin-treated diabetic patients (four with type I and two with type II) who completed a biofeedback-assisted stress management program based on family systems theory improved their response to life stressors, and none had negative side effects. Four decreased their insulin requirement, including one who remained stable even during two pregnancies; the sixth became stable and discontinued drug abuse. All started biofeedback for reasons other than diabetes. Follow-ups of some individuals extend over 4 years.