Causes of obesity: looking beyond the hypothalamus.

The brain takes a primary position in the organism. We present the novel view that the brain gives priority to controlling its own adenosine triphosphate (ATP) concentration. It fulfils this tenet by orchestrating metabolism in the organism. The brain activates an energy-on-request system that directly couples cerebral supply with cerebral need. The request system is hierarchically organized among the cerebral hemispheres, the hypothalamus, and peripheral somatomotor, autonomic-visceromotor, and the neuroendocrine-secretomotor neurons. The system initiates allocative behavior (i.e. allocation of energy from body to brain), ingestive behavior (intake of energy from the immediate environment), or exploratory behavior (foraging in the distant environment). Cerebral projections coordinate all three behavioral strategies in such a way that the brain's energy supply is guaranteed continuously. In an ongoing learning process, the brain's request system adapts to various environmental conditions and stressful challenges. Disruption of a cerebral energy-request pathway is critical to the development of obesity: if the brain fails to receive sufficient energy from the peripheral body, it compensates for the undersupply by increasing energy intake from the immediate environment, leaving the body with a surplus. Obesity develops in the long term.

Positive rate-sensitive corticosteroid feedback mechanism of ACTH secretion in Cushing's disease.

To define the nature of the disturbance of the corticosteroid feedback mechanism in Cushing's disease, the dynamic aspects of the ACTH response to corticosteroid administration have been studied in patients with Cushing's disease after total adrenalectomy (C.d. post adx.). The results were compared with those obtained in patients with Addison's disease (control group). Different experimental designs for administration of cortisol were chosen to provide extreme variations in the input signal. The response of the system was evaluated by measuring plasma ACTH concentrations (radioimmunoassay) at short time intervals. Infusion of cortisol at constant rate (50 mg/h for 2 h) resulted in a transient, paradoxical rise in ACTH levels with a maximum at 15 min. (315+/-65%, mean+/-SEM). In contrast, in the control group there was an immediate and rapid decrease in ACTH levels with a significant inhibition after 15 min (80+/-6%, mean+/-SEM). Infusion of 50 mg cortisol for 5 and 15 min, respectively, produced an increase in ACTH levels, which was confined to the time when cortisol levels were rising (maximum: 137+/-30% and 139+/-10% at 5 and 15 min, respectively, mean+/-SEM). This increase corresponded in time to the first decrease in ACTH levels in the Addisonian patients. With bolus injections of 25 mg cortisol, ACTH levels remained unchanged during the first 15 min. The time-course in the patients with C.d. post adx. was essentially the same as in the Addisonian patients. From these results it is concluded that in the patients with C.d. post adx. the rapid, rate-sensitive feedback mechanism was converted into a positive one, whereas the delayed, dose-sensitive mechanism was completely undisturbed. The capacity of dexamethasone to activate rate-sensitive feedback elements was markedly diminished. Accordingly, there were only minor positive feedback effects upon ACTH secretion in the patients with C.d. post adx.

Differential and integral corticosteroid feedback effects on ACTH secretion in hypoadrenocorticism.

Recent work suggests the existence of a dual corticosteroid feedback mechanism of stress-induced ACTH secretion in the rat. This possibility led us to study the kinetics of suppression of ACTH levels by corticosteroid administration in patients with nonstress ACTH hypersecretion secondary to hypoadrenocorticism. Cortisol was administered according to different protocols, which were chosen to provide extreme variations of the input signal. By this means, two phases of suppression of ACTH levels could be differentiated. A first decrease occurred without latency whenever, and as long as, plasma cortisol levels were rising. There was a linear regression between the logarithm of the increments in cortisol concentrations and the decrease in ACTH levels per minute (r = 0.951) (differential or rate-sensitive feedback mechanism). Neither the absolute doses of cortisol, nor plasma cortisol concentrations were closely correlated with the degree of suppression of ACTH by this rapid mechanism. A second decrease in ACTH levels began congruent with30 min after corticosteroid administration. In this case there was a significant linear regression between the degree of inhibition of ACTH levels and the cortisol doses (r = 0.997) (integral or dose-sensitive feedback mechanism). The dose-sensitive feedback effects of dexamethasone were less than might have been predicted from its relative anti-inflammatory potency. No rate-sensitive effects were seen with dexamethasone doses of 1.0 or 1.25 mg.

PreproTRH(158-183) fails to affect pituitary-adrenal response to CRH/vasopressin in man: a pilot study.

Non-glucocorticoid inhibitors of the HPA-system are of utmost interest in the treatment of diseases with impaired regulation of this system, like the metabolic syndrome and depression. In rats, a fragment of the thyreotropin-releasing hormone (TRH) preprohormone, preproTRH((178-199)), has been demonstrated to inhibit basal and stimulated secretion of cortisol. Our pilot study aimed to explore the first time similar effects of the homologue peptide preproTRH((158-183)) in healthy humans. In a double-blind within-subject comparison, eight healthy young men were infused intravenously with placebo and preproTRH((158-183)) at varying doses of 5, 10, 25 and 50 mg/kg of body weight. After 15 min of infusion a corticotropin-releasing hormone (CRH)/vasopressin-test was performed. Plasma concentrations of pituitary hormones and free thyroxine, blood pressure, heart rate and feelings of activation and mood were assessed repeatedly at close intervals. Individual hormone profiles and collapsed data across all doses did not reveal any effects of preproTRH((158-183)) on HPA-activity, although it increased TSH and fT4, stimulated the release of GH and increased systolic blood pressure in the course of the experiment (p<0.05, for all effects). Self-reports indicated enhanced feelings of activation and general well-being following preproTRH (p<0.05). Our data exclude a substantial inhibitory effect of preproTRH((158-183)) on HPA secretory activity and, thus, contrast with findings in rats. In humans, the peptide appears to even exert an albeit weak stimulatory effect on autonomic stress systems as indicated by increased cardiovascular activity in combination with enhanced subjective arousal.

The selfish brain: competition for energy resources.

Although the brain constitutes only 2% of the body mass, its metabolism accounts for 50% of total body glucose utilization. This delicate situation is aggravated by the fact that the brain depends on glucose as energy substrate. Thus, the contour of a major problem becomes evident: how can the brain maintain constant fluxes of large amounts of glucose to itself in the presence of powerful competitors as fat and muscle tissue. Activity of cortical neurons generates an "energy on demand" signal which eventually mediates the uptake of glucose from brain capillaries. Because energy stores in the circulation (equivalent to ca. 5 g glucose) are also limited, a second signal is required termed "energy on request"; this signal is responsible for the activation of allocation processes. The term "allocation" refers to the activation of the "behavior control column" by an input from the hippocampus-amygdala system. As far as eating behavior is concerned the behavior control column consists of the ventral medial hypothalamus (VMH) and periventricular nucleus (PVN). The PVN represents the central nucleus of the brain's stress systems, the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Activation of the sympatico-adrenal system inhibits glucose uptake by peripheral tissues by inhibiting insulin release and inducing insulin resistance and increases hepatic glucose production. With an inadequate "energy on request" signal neuroglucopenia would be the consequence. A decrease in brain glucose can activate glucose-sensitive neurons in the lateral hypothalamus (LH) with the release of orexigenic peptides which stimulate food intake. If the energy supply of the brain depends on activation of the LH rather than on increased allocation to the brain, an increase in body weight is evitable. An increase in fat mass will generate feedback signals as leptin and insulin, which activate the arcuate nucleus. Activation of arcuate nucleus in turn will stimulate the activity of the PVN in a way similar to the activation by the hippocampus-amydala system. The activity of PVN is influenced by the hippocampal outflow which in turn is the consequence of a balance of low-affinity and high-affinity glucocorticoid receptors. This set-point can permanently be displaced by extreme stress situations, by starvation, exercise, hormones, drugs or by endocrine-disrupting chemicals. Disorders in the "energy on request" process will influence the allocation of energy and in so doing alter the body mass of the organism. In this "selfish brain theory" the neocortex and the limbic system play a central role in the pathogenesis of diseases, such as anorexia nervosa, obesity and diabetes mellitus type II. From these considerations it appears that the primary disturbance in obesity is a displacement of the hippocampal set-point of the system. The resulting permanent activation of the feedback system must result in a likewise permanent activation of the sympatico-adrenal system, which induces insulin resistance, hypertension and the other components of the metabolic syndrome. Available therapies for treatment of the metabolic syndrome (blockade of alpha- and beta-adrenergic receptors, insulin and insulin secretagogues) interfere with mechanisms, which must be considered compensatory. This explains why these therapies are disappointing in the long run. New therapeutic strategies based on the "selfish brain theory" will be discussed.

Acute effects of aldosterone on the autonomic nervous system and the baroreflex function in healthy humans.

Aldosterone has been reported to impair the baroreflex response in animal models. The present study aimed to investigate the acute effects of aldosterone on the autonomic nervous system and the baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate in healthy humans. Nine healthy subjects were examined in a double-blind, placebo-controlled, cross-over study design, receiving either i.v. aldosterone (100 microg) or placebo on the experimental day. Heart rate variability (HRV) was measured at rest, whereas blood pressure, heart rate and MSNA (assessed by microneurography from the peroneal nerve) were monitored both at rest and during baroreflex tests. Baroreceptor stimulation and deactivation was induced by i.v. infusion of incremental doses of phenylephrine and sodium nitroprusside. HRV indices at rest were specifically changed by aldosterone with a significant increase in standard deviation of RR intervals and total power, and a trend towards increased time domain parameters indicating parasympathetic predominance in heart rate regulation. Basal MSNA, blood pressure and heart rate remained unaffected by aldosterone administration. Sodium nitroprusside decreased diastolic blood pressure and increased MSNA as well as heart rate in both the aldosterone and placebo experiments. However, the tachycardic response to arterial baroreceptor deactivation was more pronounced in the aldosterone experiments. By contrast, baroreflex control of MSNA and heart rate during phenylephrine infusion was not affected by aldosterone. Thus, our study demonstrates that, in healthy humans, aldosterone tends to increase cardiac vagal activity and enhances the heart rate response to nitroprusside whereas MSNA remains unaffected.

Differential effects of human and pork insulin-induced hypoglycemia on neuronal functions in humans.

Insulin has been found to cross the blood-brain barrier, and insulin receptors have been detected in different structures of the brain. However, the biological significance of insulin acting in the brain remains unclear. Reports of differential awareness of hypoglycemic symptoms during human insulin (HI)- and pork insulin (PI)-induced hypoglycemia hint at a modulatory influence of insulin on sensory processing. In a double-blind study, we recorded auditory-evoked potentials (AEPs), indexing neuronal transmission along sensory pathways, in 30 healthy male subjects during a baseline condition and HI- and PI-induced mild hypoglycemia of 2.65 mM. Fifteen subjects were tested after 20 min and another 15 after 50 min of constant hypoglycemia. During hypoglycemia, subjects had to indicate the severity of hypoglycemic symptoms and their current mood. Hypoglycemia increased latencies of the P3 component and reduced amplitudes of the N1, P2, and P3 components. Despite identical blood glucose and serum insulin levels in both sessions, effects of PI-induced hypoglycemia on AEP components were significantly stronger than those of HI-induced hypoglycemia (P less than 0.05). Differences between the effects of the insulins were consistently apparent after 20 min of hypoglycemia, indicating a short-term action of these hormones on central nervous system functions. Also, after 20 min, but not after 50 min, of steady-state hypoglycemia, subjects felt more excited during PI than HI infusion (P less than 0.05). The results indicate different influences of HI and PI on sensory function during hypoglycemia. These differences, occurring during early hypoglycemia, could contribute to the differential awareness of hypoglycemic warning symptoms during HI- and PI-induced hypoglycemia in diabetic patients.

The subcutaneous lipolytic response to regional neural stimulation is reduced in obese women.

Disturbed fat tissue metabolism with a reduction of the lipolytic rate could be an important pathogenetic factor in obesity. Lipolysis of the subcutaneous tissue of the thigh is partly under neural control and can be increased by intraneural stimulation of the lateral cutaneous femoral nerve in lean women. In the present study, we tested whether the lipolytic response to intraneural stimulation is altered in vivo in obese subjects. Seven obese women were examined and the results were compared with those of seven age-matched lean women. After an overnight fast, the lateral cutaneous femoral nerve was intraneurally stimulated for 10 min, and the local subcutaneous lipolytic response to this procedure was evaluated with microdialytic measurements of interstitial glycerol concentrations in the receptive field of the stimulated nerve fascicle. To exclude unspecific effects of stimulation, lipolysis was also controlled in a corresponding area of the contralateral leg. Intraneural stimulation produced no significant change in subcutaneous lipolysis in obese women (25.7 +/- 9.7%, NS). This finding is in sharp contrast with the marked regional lipolytic response in lean women in which the same stimulation procedure enhanced the regional interstitial glycerol levels by 72 +/- 17% (P < 0.05) compared with the unstimulated corresponding area of the contralateral leg. These in vivo results suggest that human obesity is characterized by a profound unresponsiveness of the subcutaneous adipose tissue to neurally stimulated lipolysis. This could be an important factor in the development and treatment of obesity.

Central nervous system effects of intranasally administered insulin during euglycemia in men.

Insulin receptors have been detected in several structures of the brain, yet the biological significance of insulin acting on the brain remains rather unclear. In humans, direct central nervous effects of insulin are difficult to distinguish from alterations in neuronal functions because of insulin-induced decrease in blood glucose levels. Since several intranasally administered viruses, peptides, and hormones have been shown to penetrate directly from the nose to the brain, we tested whether insulin after intranasal administration likewise has access to the brain. After a 60-min baseline period, insulin (20 IU H-Insulin 100 Hoechst) or vehicle (2.7 mg/ml m-Cresol) was intranasally administered every 15 min to 18 healthy subjects according to a double-blind within-subject crossover design. Auditory-evoked potentials (AEP) indexing cortical sensory processing were recorded while the subjects performed a vigilance task (oddball paradigm) during the baseline phase and after 60 min of intranasal treatment with insulin or placebo. Blood glucose and serum insulin levels were not affected by intranasal insulin. Compared with placebo, intranasal administration of insulin reduced amplitudes of the N1 (P < 0.005) and P3 (P < 0.02) components of the AEP and increased P3 latency (P < 0.05). The reduction in P3 amplitude was most pronounced over the frontal recording site (2.42 +/- 1.00 vs. 4.92 +/- 0.79 microV, P < 0.0005). At this site, after insulin administration, a broad negative shift developed in the AEP between 280 and 500 ms poststimulus (area under the curve -166.0 +/- 183.8 vs. 270.8 +/- 138.7 microV x ms after placebo, P < 0.01). The results suggest that after intranasal administration, insulin directly enters the brain and exerts distinct influences on central nervous functions in humans.

Evidence for effects of insulin on sensory processing in humans.

Systemic insulin passes the blood-brain barrier and insulin receptors have been detected in various brain regions. Yet, the biological significance of insulin acting on the brain remains rather unclear. Reports of different awareness of hypoglycemic symptoms during hypoglycemia induced by human insulin (HI) and porcine insulin (PI) suggest a modulatory influence of insulin on sensory processing. In a double-blind, within-subject, crossover comparison, we recorded visual-evoked potentials (VEP) in 30 healthy men during euglycemia and after 20 or 50 min of constant hypoglycemia of 2.66 mM (47.9 mg/dl) induced by HI and PI. Blood glucose and serum insulin levels were identical in both sessions. Hypoglycemia reduced amplitudes of the VEP components P1 and N2 and increased latencies of N1, P1, and N2. However, hypoglycemia-induced changes in VEP amplitudes and latencies were significantly stronger during PI and HI infusion: P1-N2 difference amplitude decreased from (mean +/- SE) 11.9 +/- 0.9 to 10.7 +/- 0.8 muV during HI and from 12.4 +/- 0.9 to 8.7 +/- 0.7 muV during PI infusion (P < 0.002). P1 latency increased from 112.0 +/- 3.2 to 118.8 +/- 3.2 ms during HI and from 114.0 +/- 3.3 to 126.3 +/- 4.6 ms during PI infusion (P < 0.05). Differences between the effects of the insulins were consistently apparent after 20 min of hypoglycemia, which indicates a short-term action of the hormone. The results add to those of a foregoing study demonstrating differential effects of HI- and PI-induced hypoglycemia on auditory evoked potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential adaptation of neurocognitive brain functions to recurrent hypoglycemia in healthy men.

Antecedent hypoglycemia is known to attenuate hormonal and symptomatic responses to subsequent hypoglycemia. Whether this pertains also to hypoglycemia-induced cognitive dysfunction is controversially discussed. Neurocognitive adaptation might essentially depend on the type of function. Here, we compared the influence of recurrent hypoglycemia in 15 healthy men on counterregulatory hormones, subjective symptoms of hypoglycemia, short-term memory performance (word recall), and performance on an auditory attention task (oddball). The attention task was also used to record event-related brain potential (ERP) indicators of stimulus processing. In each subject, three consecutive hypoglycemic clamps were performed, two on day 1 and the third on day 2. Neurocognitive testing was performed during baseline and at two different hypoglycemic plateaus (2.8 and 2.5 mmol/l) during the first and last clamp. As expected, hormonal responses were significantly reduced to the last as compared to the first hypoglycemia indicating adaptation. Subjective symptoms also decreased in response to recurrent hypoglycemia. Short-term memory performance deteriorated distinctly on the first hypoglycemic clamp, but maintained the normal level on the last clamp (P=0.006). Likewise, the impairment in reaction time (P=0.022) and response accuracy (P=0.005) was distinctly smaller on the last than first hypoglycemia. In parallel, the hypoglycemia-induced decrease in P3 amplitude (P=0.019) and the increase in P3 latency (P=0.049) were diminished with recurrent hypoglycemia, indicating that late stages of controlled stimulus processing likewise adapted. In contrast, the distinct decrease in amplitudes of the N1 and P2 components of the ERP (preceding the P3) was closely comparable in response to the first and last hypoglycemia (P>0.3). Together results indicate an adaptation to recurrent hypoglycemia for signs of controlled stimulus processing presumably involving hippocampo-prefrontocortical circuitry, while earlier automatic stages of processing appear to be spared.

Melatonin does not inhibit hypothalamic-pituitary-adrenal activity in waking young men.

The pineal hormone melatonin is mainly secreted during night-time which, in humans, is the normal time of sleep. It has been proposed that, during this period, melatonin exerts an inhibitory influence on secretory activity of the hypothalamic-pituitary-adrenal (HPA) system, although there is little evidence for this view in humans. In blind humans, a single oral dose of melatonin at bed time suppressed nocturnal cortisol secretion. However, suppression could have been secondary to an improved sleep after melatonin in these experiments. In the present study, we examined whether melatonin exerts a similar inhibitory effect on HPA activity in waking subjects. Fourteen healthy young men were tested at bed time, but kept awake throughout the experimental epoch. Thirty minutes after oral ingestion of 5 mg melatonin, activity of the HPA-system was stimulated through a standard insulin-induced hypoglycaemia. Adrenocorticotrophin hormone and cortisol concentrations under basal conditions before insulin injection, as well as in response to insulin-induced hypoglycaemia, were almost identical for the melatonin and placebo control conditions (P > 0.5). However, melatonin increased plasma prolactin concentrations (P < 0.01) and reduced systolic blood pressure in the time interval following hypoglycaemia (P < 0.05). Based on a review of the literature and our results, we conclude that melatonin per se has no substantially suppressing effect on HPA secretory activity, although such an effect can be gated by sleep-related processes.

Sleep loss and the development of diabetes: a review of current evidence.

Emerging evidence suggests that short duration of sleep and sleep disturbances increase the risk of developing diabetes. The mechanism of this presumed adverse influence of sleep loss on glucose metabolism is not well understood yet. However, in diabetes research and diabetes care, the multitude of influences of sleep and sleep loss on glucose regulation has been largely neglected so far. Here, we provide a short overview of the current epidemiological and experimental evidence for a potential contribution of sleep loss to the development of diabetes.

Relationship between metabolic parameters, blood pressure, and sympathoendocrine function in healthy young adults with low birth weight.

The association between low birth weight (LBW) and elevated blood pressure has been attributed to disturbances in the endocrine and sympathetic nervous system. The present study focussed on parameters of cardiovascular and sympathetic function and on adrenocortical activity in 24 healthy subjects aged 20 - 30 years with a birth weight of less than 2500 g at term and a control group of 24 subjects with a normal birth weight (NBW; 3200 - 3700 g) who were thoroughly matched for gender, body mass index (BMI), and age. Blood pressure, heart rate, and insulin resistance (calculated according to the homeostasis model assessment) were determined. Additionally, free salivary cortisol was measured at 08 : 00 am and 11 : 00 pm. In 13 subjects of each group, muscle sympathetic nerve activity (MSNA) was measured microneurographically at rest and after baroreflex stimulation by nitroprusside (12 NBW and 9 LBW subjects). Metabolic parameters, blood pressure, and salivary cortisol did not differ between LBW and NBW subjects. MSNA was significantly lower in the LBW group. In both groups insulin resistance correlated positively with BMI and negatively with morning cortisol. In the LBW group, but not the NBW group, systolic and diastolic blood pressure correlated positively with BMI and insulin resistance, and negatively with morning salivary cortisol. A correlation between morning salivary cortisol and the MSNA was only found in NBW subjects. This positive correlation strengthened when MSNA was stimulated by nitroprusside administration. However, in the same maneuvre a negative correlation between morning salivary cortisol and MSNA was observed in the LBW group. The data indicate that insulin resistance depends on the same factors in LBW and NBW subjects. In LBW subjects the interplay between adrenocortical and sympathetic activity is altered. Furthermore, LBW subjects differ from the NBW group in their significant interrelationship between blood pressure and metabolic factors.

Differential regulation of human blood glucose level by interleukin-2 and -6.

While the acute phase reaction to infection is associated with hyperglycemia, during progressing infection hypoglycemia can develop. The cytokines regulating the dynamics of host defense may concurrently contribute to blood glucose regulation. To examine this hypothesis, changes in blood glucose concentrations in healthy men were compared following administration of interleukin-2 (IL-2) and IL-6 representing, respectively, major mediators of the adaptive and the early innate immune response to bacterial infection. Doses of 10 000 IU/kg IL-2 and 0.5 microg/kg IL-6 (vs. placebo) were administered subcutaneously in two groups of men (n = 18 and 16) at 1900 h before a period of nocturnal rest allowing an assessment of changes under basal conditions. Serum concentrations of glucose and of various hormones were assessed every 60 min. Despite generally lowered glucose concentration at night, IL-2 induced a transient but distinct decrease in blood glucose concentration most consistent 8 - 9 hours following injection (p < 0.01). The hypoglycemic response to IL-2 was not accompanied by changes in serum insulin, C-peptide or cortisol. In contrast to IL-2, IL-6 led to an increase in cortisol, followed by a pronounced increase in blood glucose again peaking about 8 hours after injection (p < 0.001). Results indicate a differential regulation of blood glucose concentration by cytokines. Contrasting with the hyperglycemic effects of the acute phase regulator IL-6, the T-cell cytokine IL-2 seems to support glucose uptake and utilization by immune cells.

Excess triiodothyronine as a risk factor of coronary events.

BACKGROUND: Abnormalities in cardiac function, eg, arrhythmias and congestive heart failure, often accompany thyrotoxicosis. A relationship between thyroid hormone excess and the cardiac complications of angina pectoris and myocardial infarction (MI) remains largely speculative. METHODS: The results of thyroid function studies on blood samples drawn from a total of 1049 patients (aged 40 years or older) immediately on emergency medical admission were related to frequencies of angina pectoris and myocardial infarction as determined according to current diagnostic algorithms. After 3 years, those patients who had initially presented with angina pectoris or acute MI were observed for subsequent coronary events; of these (n=185), 98% of the subjects (n=181) could be reevaluated. RESULTS: On hospital admission, the relative rate of angina pectoris and MI was markedly high (odds ratio, 2.6; 95% confidence interval, 1.3-5.2; P=.007) in patients with elevated serum free and total triiodothyronine (T(3)) levels. An initially elevated free T(3) level was a risk factor for subsequent coronary events during the 3-year follow-up (adjusted odds ratio, 4.8; 95% confidence interval, 1.3-17.4; P=.02). CONCLUSIONS: An elevation of serum free T(3) levels at hospital admission is associated with a 2.6-fold greater likelihood of the presence of a coronary event. Moreover, an initially elevated T(3) level is associated with a 3-fold higher risk of developing a subsequent coronary event during the next 3 years. Excess T(3) seemed to be a factor associated with the development and progression of acute myocardial ischemia.

Adaptation of cognitive function to hypoglycemia in healthy men.

OBJECTIVE: Antecedent hypoglycemia reduces hypoglycemic counterregulation and symptoms, thereby provoking the hypoglycemia unawareness syndrome. The effects of antecedent hypoglycemia on hypoglycemia-induced cognitive dysfunction are less well established. RESEARCH DESIGN AND METHODS: To determine whether antecedent hypoglycemia also reduces hypoglycemic cognitive dysfunction, we performed stepwise hypoglycemic clamp experiments (4.1, 3.6, 3.1, and 2.6 mmol/l) during a 6-h period in 30 young healthy men. A total of 15 subjects additionally received a 2.5-h antecedent hypoglycemic clamp (3.1 mmol/l) on the preceding day (prior-hypo group), whereas the other 15 subjects did not (control group). Cognitive function was assessed by auditory-evoked brain potentials (AEBPs) and reaction time during a vigilance task and short-term memory recall. Tests were performed during the stepwise hypoglycemic clamp at baseline and at each hypoglycemic plateau. RESULTS: In both groups, performance on all measures of cognitive function deteriorated during stepwise hypoglycemia (all P < 0.01). However, after antecedent hypoglycemia, the hypoglycemia-induced decrease in the amplitude of the P3 of the AEBP was distinctly reduced compared with the control condition (P < 0.05). Also, short-term memory performance was less impaired in the prior-hypo group than in the control group (P < 0.005), and a minor hypoglycemic impairment of reaction time (P < 0.05) was evident in the prior-hypo group. CONCLUSIONS: Data provide evidence that a single episode of mild antecedent hypoglycemia (3.1 mmol/l) attenuates several aspects of cognitive dysfunction during subsequent hypoglycemia 18-24 h later.

The selfish brain: competition for energy resources.

The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier, has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term 'allocation' refers to the allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitary-adrenal (LHPA) system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to the brain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a 'glutamate command' signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress, traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine system. Disorders in the 'energy on demand' process or the LHPA-system can influence the allocation of energy and in so doing alter the body mass of the organism. In summary, the presented model includes a newly discovered 'principle of balance' of how pairs of high and low-affinity receptors can originate setpoints in biological systems. In this 'Selfish Brain Theory', the neocortex and limbic system play a central role in the pathogenesis of diseases such as anorexia nervosa and obesity.

Impact of sleep on the circadian excursions in the pituitary gonadotropin responsiveness of early follicular phase women.

Whereas the nocturnal slowing of the LH pulse frequencies in the early follicular phase (EFP) of the menstrual cycle may be attributed to a sleep-associated increase in opioidergic activity, the concomitant augmentation of LH pulse amplitudes remains unexplained. We reasoned whether alterations in the pituitary gonadotropin responsiveness during the 24-hour rest-activity cycle may account for these enhanced LH pulse amplitudes during sleep. Accordingly, 12 EFP women (cycle days 3-5) were studied on 2 consecutive days during three occasions: a day time between 1000 and 1400 h (day studies), at night between 2200 and 0200 h, while the women were awake (night studies), and finally, during identical night hours, while the women were asleep (sleep studies). At all occasions, blood was collected at 10-min intervals for 4 h, while GnRH (25 micrograms) was administered twice within 2 h. During the day studies, prompt and sustained LH and FSH releases were noted in response to the first and second GnRH stimulations. However, the LH and FSH release after both the first and second GnRH challenges was markedly (P < 0.01) blunted during the night studies. By contrast, this decrease in LH, but not FSH response during the night was completely prevented, when GnRH was administered during sleep. Independent of the time at which GnRH had been administered, the second GnRH stimulations provoked much greater (P < 0.05 or less) LH and FSH releases than the first. Thus, a marked attenuation of the gonadotroph responsiveness is observed in EFP women during the night, and nocturnal sleep may eliminate this decline. Further, the priming actions on the gonadotrophs by repetitive GnRH stimulations are unaffected by the time of GnRH administrations. Collectively, these observations permit us to infer that the increased LH pulse amplitudes observed during sleep in EFP women may not be attributed to increased pituitary responsiveness.

Postmenopausal estrogen administration suppresses muscle sympathetic nerve activity.

The activity of the sympathetic nervous system shows gender-specific differences with lower sympathoneural activity to the muscle vascular bed in women compared with men, with this difference vanishing after menopause. The present study tested the hypothesis that estrogen exerts regulatory influence on the autonomic nervous system in postmenopausal women. Eleven healthy postmenopausal women (age, 58.5 +/- 1.0 yr; mean +/- SEM) were studied in a randomized double-blind crossover protocol with transdermal administration of 100 microgram/day estradiol (E(2)) or placebo (P) for 2 days. Muscle sympathetic activity (MSA), blood pressure, and heart rate were recorded at rest and during sympathoexcitatory maneuvers (apnea, cold pressor test). E(2) administration significantly increased serum E(2) to physiological levels (E(2), 469.5 +/- 51.5; P, 34.8 +/- 2.2 pmol/L; P < 0.05) and significantly lowered MSA (E(2), 30.1 +/- 3.0 vs. P 37.7 +/- 3.1 bursts/min; P < 0.05). At the same time, blood pressure and heart rate were not affected. MSA was significantly enhanced during apnea and the cold pressure test, and this physiological response to the maneuvers was not changed after estrogen supplementation. In conclusion, elevation of low postmenopausal estrogen levels to physiological premenopausal levels by transdermal E(2) administration supresses MSA. This effect is most likely the consequence of a direct E(2) effect on central nervous autonomic centers, which could explain the gender-specific differences in sympathetic outflow to the muscle vascular bed. The sympathoinhibitory estrogen effects could be important for beneficial cardiovascular effects of estrogen replacement therapy in postmenopausal women.