Kerstin M. Oltmanns

Intranasal Insulin Suppresses Food Intake via Enhancement of Brain Energy Levels in Humans

Cerebral insulin exerts anorexic effects in humans and animals. The underlying mechanisms, however, are not clear. Because insulin physiologically facilitates glucose uptake by most tissues of the body and thereby fosters intracellular energy supply, we hypothesized that intranasal insulin reduces food consumption via enhancement of the neuroenergetic level. In a double-blind, placebo–controlled, within-subject comparison, 15 healthy men (BMI 22.2 ± 0.37 kg/m2) aged 22–28 years were intranasally administered insulin (40 IU) or placebo after an overnight fast. Cerebral energy metabolism was assessed by 31P magnetic resonance spectroscopy. At 100 min after spray administration, participants consumed ad libitum from a test buffet. Our data show that intranasal insulin increases brain energy (i.e., adenosine triphosphate and phosphocreatine levels). Cerebral energy content correlates inversely with subsequent calorie intake in the control condition. Moreover, the neuroenergetic rise upon insulin administration correlates with the consecutive reduction in free-choice calorie consumption. Brain energy levels may therefore constitute a predictive value for food intake. Given that the brain synchronizes food intake behavior in dependence of its current energetic status, a future challenge in obesity treatment may be to therapeutically influence cerebral energy homeostasis. Intranasal insulin, after optimizing its application schema, seems a promising option in this regard.

Defective Awakening Response to Nocturnal Hypoglycemia in Patients with Type 1 Diabetes Mellitus

Background Nocturnal hypoglycemia frequently occurs in patients with type 1 diabetes mellitus (T1DM). It can be fatal and is believed to promote the development of the hypoglycemia-unawareness syndrome. Whether hypoglycemia normally provokes awakening from sleep in individuals who do not have diabetes, and whether this awakening response is impaired in T1DM patients, is unknown. Methods and Findings We tested two groups of 16 T1DM patients and 16 healthy control participants, respectively, with comparable distributions of gender, age, and body mass index. In one night, a linear fall in plasma glucose to nadir levels of 2.2 mmol/l was induced by infusing insulin over a 1-h period starting as soon as polysomnographic recordings indicated that stage 2 sleep had been reached. In another night (control), euglycemia was maintained. Only one of the 16 T1DM patients, as compared to ten healthy control participants, awakened upon hypoglycemia (p = 0.001). In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with increased hormonal counterregulation. In all the study participants (from both groups) who woke up, and in five of the study participants who did not awaken (three T1DM patients and two healthy control participants), plasma epinephrine concentration increased with hypoglycemia by at least 100% (p < 0.001). A temporal pattern was revealed such that increases in epinephrine in all participants who awakened started always before polysomnographic signs of wakefulness (mean ± standard error of the mean: 7.5 ± 1.6 min). Conclusions A fall in plasma glucose to 2.2 mmol/l provokes an awakening response in most healthy control participants, but this response is impaired in T1DM patients. The counterregulatory increase in plasma epinephrine that we observed to precede awakening suggests that awakening forms part of a central nervous system response launched in parallel with hormonal counterregulation. Failure to awaken increases the risk for T1DM patients to suffer prolonged and potentially fatal hypoglycemia.

Chronic fentanyl application induces adrenocortical insufficiency

We report a case of a 64‐year‐old man with secondary adrenocortical insufficiency who has been on a chronic transdermal fentanyl treatment because of sciatic pain syndrome. Shortly before admission to our hospital, the patient had discontinued his hydrocortisone medication. Adrenal crisis was assumed and during therapy with hydrocortisone infusion, the patient recovered. We suspected an opiate‐induced suppression of the hypothalamus‐pituitary‐adrenal (HPA) axis. Therefore, we gradually reduced the opiate dosage. After 1 week, HPA axis function was markedly improved. We conclude that opiate medication may inhibit – in a life‐threatening way – the organisms ability to respond to physical, emotional or metabolic stressors.

Obesity – A neuropsychological disease? Systematic review and neuropsychological model

Obesity is a global epidemic associated with a series of secondary complications and comorbid diseases such as diabetes mellitus, cardiovascular disease, sleep-breathing disorders, and certain forms of cancer. On the surface, it seems that obesity is simply the phenotypic manifestation of deliberately flawed food intake behavior with the consequence of dysbalanced energy uptake and expenditure and can easily be reversed by caloric restriction and exercise. Notwithstanding this assumption, the disappointing outcomes of long-term clinical studies based on this assumption show that the problem is much more complex. Obviously, recent studies render that specific neurocircuits involved in appetite regulation are etiologically integrated in the pathomechanism, suggesting obesity should be regarded as a neurobiological disease rather than the consequence of detrimental food intake habits. Moreover, apart from the physical manifestation of overeating, a growing body of evidence suggests a close relationship with psychological components comprising mood disturbances, altered reward perception and motivation, or addictive behavior. Given that current dietary and pharmacological strategies to overcome the burgeoning threat of the obesity problem are of limited efficacy, bear the risk of adverse side-effects, and in most cases are not curative, new concepts integratively focusing on the fundamental neurobiological and psychological mechanisms underlying overeating are urgently required. This new approach to develop preventive and therapeutic strategies would justify assigning obesity to the spectrum of neuropsychological diseases. Our objective is to give an overview on the current literature that argues for this view and, on the basis of this knowledge, to deduce an integrative model for the development of obesity originating from disturbed neuropsychological functioning.

Evidence for a relationship between VEGF and BMI independent of insulin sensitivity by glucose clamp procedure in a homogenous group healthy young men.

Background This is the first study to experimentally explore the direct relationship between circulating VEGF levels and body mass index (BMI) as well as to unravel the role of insulin sensitivity in this context under standardized glucose clamp conditions as the methodical gold-standard. In order to control for known influencing factors such as gender, medication, and arterial hypertension, we examined a highly homogeneous group of young male subjects. Moreover, to encompass also subjects beyond the normal BMI range, low weight and obese participants were additionally included and stress hormones as a main regulator of VEGF were assessed. Methodology/Principal Findings Under euglycemic clamp conditions, VEGF was measured in 15 normal weight (BMI 20–25 kg/m2), 15 low weight (BMI<20 kg/m2), and 15 obese (BMI>30 kg/m2) male subjects aged 18–30 years and the insulin sensitivity index (ISI) was calculated. Since stress axis activation promotes VEGF secretion, concentrations of ACTH, cortisol, and catecholamines were monitored. Despite of comparable ACTH (P = 0.145), cortisol (P = 0.840), and norepinephrine (P = 0.065) levels, VEGF concentrations differed significantly between BMI-groups (P = 0.008) with higher concentrations in obese subjects as compared to normal weight (P = 0.061) and low weight subjects (P = 0.002). Pearsons correlation analysis revealed a positive relationship between BMI and VEGF levels (r = 0.407; P = 0.010) but no correlation of VEGF with ISI (r = 0.224; P = 0.175). Conclusions/Significance Our data demonstrate a positive correlation between concentrations of circulating VEGF levels and BMI in healthy male subjects under highly controlled conditions. This relationship which is apparently disconnected from insulin sensitivity may be part of some pathogenetic mechanisms underlying obesity and type 2 diabetes.

Selective slow wave sleep but not rapid eye movement sleep suppression impairs morning glucose tolerance in healthy men

Shortened nocturnal sleep impairs morning glucose tolerance. The underlying mechanism of this effect is supposed to involve a reduced fraction of slow wave sleep (SWS). However, it remains unanswered if impaired glucose tolerance occurs due to specific SWS reduction or a general disturbance of sleep. Sixteen healthy men participated in three experimental conditions in a crossover design: SWS suppression, rapid eye movement (REM)-sleep disturbance, and regular sleep. Selective sleep stage disturbance was performed by means of an acoustic tone (532Hz) with gradually rising sound intensity. Blood concentrations of glucoregulatory parameters were measured upon an oral glucose tolerance test the next morning. Our data show that morning plasma glucose and serum insulin responses were significantly increased after selective SWS suppression. Moreover, SWS suppression reduced postprandial insulin sensitivity up to 20%, as determined by Matsuda Index. Contrastingly, disturbed REM-sleep did not affect glucose homeostasis. We conclude that specifically SWS reduction is critically involved in the impairment of glucose tolerance associated with disturbed sleep. Therefore, glucose metabolism in subjects predisposed to reduced SWS (e.g. depression, aging, obstructive sleep apnea, pharmacological treatment) should be thoroughly monitored.

Brain energy consumption induced by electrical stimulation promotes systemic glucose uptake.

BACKGROUND Controlled transcranial stimulation of the brain is part of clinical treatment strategies in neuropsychiatric diseases such as depression, stroke, or Parkinsons disease. Manipulating brain activity by transcranial stimulation, however, inevitably influences other control centers of various neuronal and neurohormonal feedback loops and therefore may concomitantly affect systemic metabolic regulation. Because hypothalamic adenosine triphosphate-sensitive potassium channels, which function as local energy sensors, are centrally involved in the regulation of glucose homeostasis, we tested whether transcranial direct current stimulation (tDCS) causes an excitation-induced transient neuronal energy depletion and thus influences systemic glucose homeostasis and related neuroendocrine mediators. METHODS In a crossover design testing 15 healthy male volunteers, we increased neuronal excitation by anodal tDCS versus sham and examined cerebral energy consumption with ³¹phosphorus magnetic resonance spectroscopy. Systemic glucose uptake was determined by euglycemic-hyperinsulinemic glucose clamp, and neurohormonal measurements comprised the parameters of the stress systems. RESULTS We found that anodic tDCS-induced neuronal excitation causes an energetic depletion, as quantified by ³¹phosphorus magnetic resonance spectroscopy. Moreover, tDCS-induced cerebral energy consumption promotes systemic glucose tolerance in a standardized euglycemic-hyperinsulinemic glucose clamp procedure and reduces neurohormonal stress axes activity. CONCLUSIONS Our data demonstrate that transcranial brain stimulation not only evokes alterations in local neuronal processes but also clearly influences downstream metabolic systems regulated by the brain. The beneficial effects of tDCS on metabolic features may thus qualify brain stimulation as a promising nonpharmacologic therapy option for drug-induced or comorbid metabolic disturbances in various neuropsychiatric diseases.

Repetitive electric brain stimulation reduces food intake in humans

BACKGROUND The dorsolateral prefrontal cortex (DLPFC) plays an important role in appetite and food intake regulation. OBJECTIVE Because previous data revealed that transcranial direct current stimulation (tDCS) of the DLPFC reduces food cravings, we hypothesized that repetitive electric stimulation of the right DLPFC would lower food intake behavior in humans. DESIGN In a single-blind, code-based, placebo-controlled, counterbalanced, randomized crossover experiment, 14 healthy young men with body mass index (in kg/m(2)) from 20 to 25 were examined during 8 d of daily tDCS or a sham stimulation. After tDCS or sham stimulation on the first and the last day of both experimental conditions, participants consumed food ad libitum from a standardized test buffet. RESULTS One week of daily anodal tDCS reduced overall caloric intake by 14% in comparison with sham stimulation. Moreover, repetitive tDCS diminished self-reported appetite scores. CONCLUSION Our study implies that the application of anodal direct currents to the right DLPFC represents a promising option for reducing both caloric intake and appetite in humans. This trial was registered at the German Clinical Trials Register (www.germanctr.de) as DRKS00005811.

Disturbed glucose disposal in patients with major depression; application of the glucose clamp technique.

Objective: To assess the whole-body glucose disposal in patients with both typical and atypical depression and to characterize the neuroendocrine responses during a hyper-, eu-, hypoglycemic stepwise clamp experiment in patients with both subtypes of major depression. Depressive disorders and alterations in glucose metabolism are closely associated. The glucose clamp technique is considered to be the “gold standard” for the assessment of whole-body glucose disposal. Methods: We studied 19 patients with typical major depressive disorder (MDD), 7 patients with atypical major depression, and 30 men and women of a healthy comparator group using a stepwise glucose clamp procedure. Glucose disposal rates were assessed and concentrations of hormones involved in glucose allocation were measured. Results: Glucose disposal rates were lower by 19% in patients with typical MDD and 30% in patients with atypical MDD than in the group of healthy controls (3.2 ± 0.8 and 2.8 ± 0.7 versus 4.0 ± 1.0 mmol h−1 kg−1). C-peptide concentrations were 26% higher in patients with atypical MDD and similar in patients with typical MDD and healthy controls. Vascular endothelial growth factor concentrations were 30% higher in typical MDD and similar in atypical MDD and the control group. Conclusions: Whole-body glucose disposal is reduced in patients with typical and atypical depression. The observed neuroendocrine responses suggest a hyperactive allocation system in typical depression and a hypoactive allocation system in atypical depression. ACTH = adrenocorticotropic hormone; ANOVA = analysis of variance; BMI = body mass index; CV = coefficient of variation; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, version IV; GH = growth hormone; GLUT1 = glucose transporter Type 1; GLUT4 = glucose transporter Type 4; HDL = high-density lipoproteins; HPA = hypothalamic-pituitary-adrenal; MDD = major depressive disorder; SCID = Structured Clinical Interview for DSM-IV; VEGF = vascular endothelial growth factor.

Continuous positive airway pressure therapy decreases evening cortisol concentrations in patients with severe obstructive sleep apnea

Patients with obstructive sleep apnea syndrome (OSAS) show recurrent episodes of nightly hypoxic stress. The purpose of this study is the detection of alterations of the hypothalamic-pituitary-adrenal stress axis in OSAS patients before and after continuous positive airway pressure (CPAP) therapy. An activation of the hypothalamic-pituitary-adrenal axis was proposed because of the nightly hypoxic stress in these patients, but previous studies were not conclusive. Here we hypothesize that CPAP therapy decreases salivary cortisol concentrations in patients with severe OSAS. We performed a clinical within-subject study including 50 patients with newly diagnosed OSAS and an apnea-hypopnea index greater than or equal to 40 h(-1). Diurnal profiles of salivary cortisol concentrations were compiled before and after 3 months of treatment with CPAP. Therefore, 6 cortisol samples were collected: before and after lunch, in the evening, the next morning after awakening, and before and after breakfast. Thirty-eight patients returned after 3 months of CPAP therapy for follow-up. According to the reference range for healthy subjects, cortisol values were not pathologically increased. Analysis of variance revealed a significant effect of CPAP therapy on diurnal cortisol profiles (P = .048). Subjects with severe OSAS showed a decrease (3.04 +/- 0.55 nmol L(-1) pre-CPAP vs 2.48 +/- 0.78 nmol L(-1) post-CPAP, P = .038) of evening cortisol levels after CPAP treatment, whereas prelunch levels were increased after CPAP therapy (7.18 +/- 0.83 nmol L(-1) pre-CPAP vs 10.22 +/- 1.10 nmol L(-1) post-CPAP, P = .044). Our results show that CPAP therapy decreases evening cortisol concentrations in patients with severe OSAS. These data suggest that OSAS may increase the cortisol nadir that is reversed after CPAP therapy.