Biomedical subjects

Manfred Hallschmid

Publications and source records attributed to Manfred Hallschmid.

15 recordsLinked to original sources

PubMed2006

Intranasal insulin improves memory in humans: superiority of insulin aspart.

There is compelling evidence that intranasal administration of regular human insulin (RH-I) improves memory in humans. Owing to the reduced tendency of its molecules to form hexamers, the rapid-acting insulin analog insulin aspart (ASP-I) is more rapidly absorbed than RH-I after subcutaneous administration. Since after intranasal insulin administration, ASP-I may also be expected to access the brain, we examined whether intranasal ASP-I has stronger beneficial effects on declarative memory than RH-I in humans. Acute (40 IU) and long-term (4 x 40 IU/day over 8 weeks) effects of intranasally administered ASP-I, RH-I, and placebo on declarative memory (word lists) were assessed in 36 healthy men in a between-subject design. Plasma insulin and glucose levels were not affected. After 8 weeks of treatment, however, word list recall was improved compared to placebo in both the ASP-I (p<0.01) and the RH-I groups (p<0.05). ASP-I-treated subjects performed even better than those of the RH-I-treated group (p<0.05). Our results indicate that insulin-induced memory improvement can be enhanced by using ASP-I. This finding may be especially relevant for a potential clinical administration of intranasal insulin in the treatment of memory disorders like Alzheimer's disease.

Administration, Intranasal↗

PubMed2006

Brief sleep after learning keeps emotional memories alive for years.

BACKGROUND: Sleep after learning supports memory consolidation. However, long-lasting memory effects of sleep have not yet been investigated. Postlearning sleep may be particularly involved in the long-term retention of emotional memories and could thereby contribute to the development of posttraumatic stress disorder (PTSD), a disease thought to result from overconsolidation of traumatic memories. METHODS: Subjects (healthy men) who had learned neutral and emotional texts immediately before sleeping or remaining awake for the subsequent 3 hours were recontacted after 4 years for long-term memory assessment (forced-choice recognition test). RESULTS: Sleep following learning compared with wakefulness enhanced memory for emotional texts after 4 years (p = .001). No such enhancement was observed for neutral texts (p = .571). CONCLUSIONS: Brief periods of sleep immediately following learning cause preservation of emotional memories over several years. Sleep deprivation in the immediate aftermath of traumatic events could be a promising therapeutic measure to prevent PTSD.

Chi-Square Distribution↗

PubMed2006

Sleep-dependent surges in growth hormone do not contribute to sleep-dependent memory consolidation.

In the search for the mechanisms that mediate the effects of sleep on the consolidation of memories, growth hormone (GH) recently became of interest, because in humans it is released mainly during slow-wave sleep (SWS), a period of enhanced declarative memory consolidation. In addition, recent studies showed that GH is involved in proper memory function in GH deficient and elderly humans and this effect has been linked to regulatory influences of GH on hippocampal NMDA receptors. Here, we blocked GH secretion by intravenous infusion of somatostatin in healthy young subjects during the first 3 h of sleep, which contain mainly SWS. Declarative and procedural memory consolidation was tested across this period, using a word pair association task and a mirror tracing task, respectively. Although GH was effectively suppressed, memory performance as well as sleep were entirely unaffected by this suppression. Whereas GH may in the long run generally support brain systems required for maintaining proper memory function, our data exclude a necessary contribution of the nocturnal surge in pituitary GH secretion to the acute processing and formation of specific memories during sleep.

Adult↗

PubMed2005

Overweight humans are resistant to the weight-reducing effects of melanocortin4-10.

CONTEXT: By enhancing energy expenditure and suppressing appetite, melanocortin peptides derived from proopiomelanocortin play a primary role in the hypothalamic regulation of body weight. In a recent study in normal-weight adults, the 6-wk intranasal administration of the MSH/ACTH(4-10) core fragment of proopiomelanocortin resulted in a distinct reduction of body weight and body fat, accompanied by significant decreases in leptin and insulin plasma concentrations. OBJECTIVE: The present study aimed to generalize this finding to overweight patients. DESIGN, SUBJECTS, AND INTERVENTION: MSH/ACTH(4-10) (0.5 mg) and placebo were intranasally administered once in the morning and once in the evening over a period of 12 wk in 23 overweight men (body mass index, mean +/- sem: 29.72 +/- 0.43 kg/m(2)). RESULTS: MSH/ACTH(4-10) did not induce any significant reduction in body weight, body fat, and plasma levels of insulin and leptin as compared with the effects of placebo. Melanocortin treatment was accompanied by reduced cortisol concentrations. CONCLUSIONS: We conclude that contrasting with normal-weight humans, overweight subjects are not susceptible to the effects of melanocortin administration on hypothalamic weight regulatory systems. In overweight subjects, a decreased sensitivity to ACTH/MSH peptides may derive from alterations at the level of the melanocortin receptor or at subsequent steps in the processing of the body fat signal.

Administration, Intranasal↗

PubMed2005

Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings.

Intranasal administration of insulin has been shown to influence neuroendocrine functions via an effect on central nervous mechanisms. Because insulin, in particular when infused into cerebral arteries, induces blood pressure (BP) elevation by an unknown mechanism, we investigated whether insulin exerts similar effects on BP after intranasal administration. To evaluate the immediate effects of insulin on BP, 20 IU of human insulin was intranasally administered every 10 minutes over a 2-hour period. Blood pressure, heart rate, and muscular sympathetic nervous activity (MSNA) were continuously monitored. For evaluating the effects of subchronic administration of insulin, changes during and after 8 weeks of treatment with 160 IU insulin/d on BP were monitored. Compared with placebo, the immediate nasal administration of insulin raised diastolic BP (12.21% +/- 5.10%; P < .05), mean arterial BP (10.81% +/- 4.32%; P < .04), and systolic BP (9.53% +/- 4.66%; P < .08), whereas MSNA and heart rate were unaffected. In contrast, prolonged intranasal insulin administration did not affect BP (P > .62 for all comparisons). The immediate increase in BP in the face of an unsuppressed MSNA after insulin suggests that intranasal insulin transiently changes the baroreflex set point. Thus, data suggest that intranasal insulin administration affects BP regulatory centers in the brain. However, the effect is not observed with prolonged administration of the hormone, suggesting the emergence of counterregulatory processes.

Administration, Intranasal↗

PubMed2005

Modulation of food intake by glucose in patients with type 2 diabetes.

OBJECTIVE: A gain in body weight is a common adverse effect of glucose-lowering therapies in patients with type 2 diabetes, the mechanisms of which are not completely understood. Blood glucose is considered to play a crucial role in the regulation of food intake. On this background, we hypothesized that a short-term reduction of blood glucose concentration to normal values acutely increases food intake in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: To test this hypothesis, 12 patients with type 2 diabetes were examined twice, once during a euglycemic (5.0 mmol/l) clamp experiment and another time during a hyperglycemic (10.5 mmol/l) clamp. The experiments were performed in a single-blind fashion with the order of conditions balanced across patients. On both clamp conditions, insulin was infused at a constant rate of 2.5 mU/kg per min for 125 min. Simultaneously, a glucose solution was infused at a variable rate to achieve target glycemic levels. During the final 30 min of the clamps, the patients were allowed to eat as much as they liked from a standard breakfast buffet. RESULTS: Compared with the hyperglycemic condition, the patients ingested on average 25 +/- 10% more energy during euglycemia (645 +/- 75 vs. 483 +/- 37 kcal; P = 0.029). The increased energy intake during euglycemia was equally distributed across macronutrient components, i.e., during euglycemia the patients ate more carbohydrates (+27.1 +/- 11.4%; P = 0.037), fat (+22.5 +/- 10.0%; P = 0.046), and proteins (+25.2 +/- 11.2%; P = 0.046) than during hyperglycemia. Circulating levels of insulin, amylin, leptin, ghrelin, and glucagon-like peptide-1 did not differ between the euglycemic and hyperglycemia clamp, excluding a major contribution of these hormones to the difference in food intake. Summing up the glucose administered intravenously and the food ingested yielded a remarkably similar total energy influx in both conditions (794 +/- 64 vs. 790 +/- 53 kcal; P = 0.961). CONCLUSIONS: Together our data suggest that total energy supply to the organism is tightly regulated on a short-term basis independent of the route of influx. Alternatively, it can be hypothesized that euglycemia stimulated or that hyperglycemia suppressed food intake at the subsequent buffet meal in our type 2 diabetic patients. Regardless of these different interpretations, our data indicate an important regulatory role of glucose for food intake in type 2 diabetic patients that is of considerable clinical relevance.

Blood Glucose↗

PubMed2004

Gut protein uptake and mechanisms of meal-induced cortisol release.

The enhanced cortisol release after protein-rich meals might represent a neuroendocrine response to food allergens. We tested whether the antigenicity of proteins contributes to this effect. Twelve healthy men nasogastrically received casein, its less allergenic hydrolysate, and placebo. Contrary to expectations, secretion of cortisol (area under the curve, 742.70 +/- 73.48 vs. 542.95 +/- 70.31 micromol/liter.min, P < 0.03) and ACTH (2020.21 +/- 251.10 vs. 1649.82 +/- 241.23 micromol/liter.min, P < 0.05) was stronger on casein-hydrolysate than casein. Systemic immune activity remained unaffected as indicated by unchanged IL-6 plasma concentrations. This finding indicates that the grade of hydrolysis of a protein and the presence of particular amino acids, rather than its antigenicity, are crucial for the pituitary-adrenal response to nutrients. To further examine whether this response is triggered at the gastrointestinal mucosa or after the substance has reached the circulation, in a supplementary experiment, amino acids were given either nasogastrically or iv to healthy men (n = 4). Only the nasogastric infusion of amino acids induced a significant rise in cortisol concentrations. Serum concentrations of tryptophan, which is known to directly excite the hypothalamo-pituitary-adrenal axis, were comparable for both conditions. We conclude that the meal-related hypothalamo-pituitary-adrenal axis response to amino acids results from a signal that rather acts at the gastrointestinal mucosa than directly via the circulating blood.

Adrenocorticotropic Hormone↗

PubMed2004

Transcranial direct current stimulation during sleep improves declarative memory.

In humans, weak transcranial direct current stimulation (tDCS) modulates excitability in the motor, visual, and prefrontal cortex. Periods rich in slow-wave sleep (SWS) not only facilitate the consolidation of declarative memories, but in humans, SWS is also accompanied by a pronounced endogenous transcortical DC potential shift of negative polarity over frontocortical areas. To experimentally induce widespread extracellular negative DC potentials, we applied anodal tDCS (0.26 mA) [correction] repeatedly (over 30 min) bilaterally at frontocortical electrode sites during a retention period rich in SWS. Retention of declarative memories (word pairs) and also nondeclarative memories (mirror tracing skills) learned previously was tested after this period and compared with retention performance after placebo stimulation as well as after retention intervals of wakefulness. Compared with placebo stimulation, anodal tDCS during SWS-rich sleep distinctly increased the retention of word pairs (p < 0.005). When applied during the wake retention interval, tDCS did not affect declarative memory. Procedural memory was also not affected by tDCS. Mood was improved both after tDCS during sleep and during wake intervals. tDCS increased sleep depth toward the end of the stimulation period, whereas the average power in the faster frequency bands (,alpha, and beta) was reduced. Acutely, anodal tDCS increased slow oscillatory activity <3 Hz. We conclude that effects of tDCS involve enhanced generation of slow oscillatory EEG activity considered to facilitate processes of neuronal plasticity. Shifts in extracellular ionic concentration in frontocortical tissue (expressed as negative DC potentials during SWS) may facilitate sleep-dependent consolidation of declarative memories.

Adult↗

PubMed2004

Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man.

Maintaining a stable body weight set-point is assumed to rely on a homeostatic central nervous system (CNS) regulation of body fat with the particular involvement of hypothalamic pathways. The peripheral adiposity signals insulin and leptin convey information on the amount of energy stored as body fat to the arcuate nucleus of the hypothalamus, where anabolic/orexigenic and catabolic/anorexigenic pathways interact to regulate food intake and energy expenditure. One of the most prominent orexigenic messengers is neuropeptide Y (NPY), whereas melanocortins, including alpha-melanocyte-stimulating hormone (alpha-MSH), are essential for inducing anorexigenic effects. The melanocortin receptor 4 (MC4-R) plays the most important role in mediating catabolic effects of alpha-MSH. In this review, we present a series of own studies on NPY, insulin and MSH/ACTH4-10, an MC4-R agonist. The studies were all based on the intranasal route of administration which enables a direct access of the peptides to hypothalamic functions. NPY acutely attenuated electrocortical signs of meal-related satiety. Prolonged intranasal administration of insulin as well as of MSH induced weight loss in healthy human subjects. However, overweight subjects did not lose body fat after MSH administration. The results corroborate in humans the significance of all three messengers for the central nervous regulation of adiposity and might contribute to the future development of medical strategies against body-weight-related disorders.

Administration, Intranasal↗

PubMed2004

Preserved circadian rhythm of serum insulin concentration at low plasma glucose during fasting in lean and overweight humans.

Circadian rhythms in glucose metabolism are well documented. Most studies, however, evaluated such variations under conditions of continuous glucose supply, either via food intake or glucose infusion. Here we assessed in 30 subjects circadian variations in concentrations of plasma glucose, serum insulin, and C-peptide during a 72-hour fasting period to evaluate rhythms independent from glucose supply. Furthermore we assessed differences in these parameters between normal-weight (n = 20) and overweight (n = 10) subjects. Blood was sampled every 4 hours. During fasting, plasma glucose, serum insulin, and C-peptide levels gradually decreased (all P < .001). While there was no circadian variation in plasma glucose levels after the first day of fasting, serum levels of insulin were constantly higher in the morning (8.00 h) than at night (0.00 h) (P < .001), although the extent of this morning-associated rise in insulin levels decreased with the time spent fasting (P = .001). Also, morning C-peptide concentrations were higher compared to the preceding night (P < .001). The C-peptide/insulin ratio (CIR) decreased during prolonged fasting (P = .030), suggesting a decrease in hepatic insulin clearance. Moreover, CIR was significantly lower in the morning than at the night of day 1 and day 2 of fasting (P = .010 and P = .004, respectively). Compared to normal-weight subjects, overweight subjects had higher plasma glucose, as well as serum insulin and C-peptide levels (all P < .03). Data indicate preserved circadian rhythms in insulin concentrations in the presence of substantially decreased glucose levels in normal-weight and overweight subjects. This finding suggests a central nervous system contribution to the regulation of insulin secretion independent of plasma glucose levels.

Adult↗

PubMed2004

Intranasal insulin improves memory in humans.

Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92 +/- 1.00, Insulin 6.20 +/- 1.03, p < 0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger (p < 0.02) and enhanced self-confidence (p < 0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer's disease.

Administration, Intranasal↗

PubMed2004

Intranasal insulin reduces body fat in men but not in women.

Insulin acts in the central nervous system to reduce food intake and body weight and is considered a major adiposity signal. After intranasal administration, insulin enters the cerebrospinal fluid compartment and alters brain functions in the absence of substantial absorption into the blood stream. Here we report the effects of 8 weeks of intranasal administration of insulin (4 x 40 IU/day) or placebo to two groups of healthy human subjects (12 men and 8 women in each group). The insulin-treated men lost 1.28 kg body wt and 1.38 kg of body fat, and their waist circumference decreased by 1.63 cm. Plasma leptin levels dropped by an average of 27%. In contrast, the insulin-treated women did not lose body fat and gained 1.04 kg body wt due to a rise in extracellular water. Our results provide a strong, first confirmation in humans that insulin acts as a negative feedback signal in the regulation of adiposity and point to a differential sensitivity to the catabolic effects of insulin based on sex.

Adipose Tissue↗

PubMed2004

Transcortical direct current potential shift reflects immediate signaling of systemic insulin to the human brain.

Circulating insulin is thought to provide a major feedback signal for the hypothalamic regulation of energy homeostasis and food intake, although this signaling appears to be slowed by a time-consuming blood-to-brain transport. Here we show, by recording direct current potentials, a rapid onset of the effects of circulating insulin on human brain activity. Recordings were obtained from 27 men who were intravenously injected with insulin (0.1 mU/kg body wt as bolus) and placebo. In a euglycemic condition, hypoglycemia was prevented, while in the hypoglycemic condition, plasma glucose reached a postinjection nadir of 43 mg/dl. Insulin injection induced a marked negative direct current (DC) potential shift starting within 7 min in all subjects. With euglycemic conditions, the DC potential at 10-60 min postinsulin injection averaged -621.3 microV (compared with preinjection baseline). Hypoglycemia reduced this potential to an average of -331.2 microV. While insulin per se did not affect oscillatory electroencephalographic activity, hypoglycemia peaking 25 min after insulin injection was accompanied by an immediate increase in theta activity. The rapid emergence of the DC potential shift, reflecting gross ionic changes in brain tissues, indicates that systemic insulin can serve as an immediate feedback signal in the control of hypothalamic and higher brain functions.

Adult↗

PubMed2003

Signs of REM sleep dependent enhancement of implicit face memory: a repetition priming study.

Faces are processed and stored in distinct neuroanatomical systems. Based on evidence of a critical role of sleep in memory processes, we investigated the impact of nocturnal sleep on implicit memories for faces in healthy men. Face repetition effects in reaction times were compared across sleep periods early in the night, which are dominated by slow wave sleep (SWS), and late in the night, where rapid eye movement (REM) sleep prevails, as well as across corresponding nocturnal intervals of wakefulness. An inverse priming effect was found selectively across REM sleep rich late sleep, as indicated by distinctly prolonged response latencies to previously presented faces compared with novel faces after this period of sleep (P<0.05). We assumed this inverse priming to reflect a facilitated identification of previously presented faces after extended REM sleep periods, thereby producing interference with the response generation in our task which did not require face identification but rather required recognizing formal features of the faces. This interpretation was supported by a supplementary experiment where enhanced positive repetition priming was found across late, REM sleep dominated sleep in a task requiring face identification. Together, these findings indicate that implicit face memories particularly benefit from REM sleep associated brain mechanisms.

Circadian Rhythm↗

PubMed2002

Sleep forms memory for finger skills.

Practicing a motor skill triggers a process of memory consolidation that continues for hours after practice has ended, and becomes manifest in an improved skill at later testing. We used a sequential motor task (finger-to-thumb opposition task) to show that, in humans, the formation of motor skill memories essentially benefits from sleep. Independent of whether placed during daytime or nighttime, sleep after practice enhanced speed of sequence performance on average by 33.5% and reduced error rate by 30.1% as compared with corresponding intervals of wakefulness. The effect of sleep after learning proved to be stable when retesting was postponed for another night, to exclude effects of sleep loss and to assure that all subjects had sufficient sleep before retrieval testing. Also, the consolidating effect of sleep was specific for the motor sequence learned. It did not generalize to a similar sequence containing identical movement segments in a different order. Retention periods of wakefulness improved performance only moderately and only if placed during daytime. The observations demonstrate a critical role of sleep for storing and optimizing motor skills.

Adolescent↗