Bernd Schultes

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 Alzheimers disease.

Short-term sleep loss decreases physical activity under free-living conditions but does not increase food intake under time-deprived laboratory conditions in healthy men

BACKGROUND Short sleep duration is correlated with an increased risk of developing obesity and cardiovascular disease, but the mechanisms behind this relation are largely unknown. OBJECTIVE We aimed to test the hypothesis that acute sleep loss decreases physical activity while increasing food intake, thereby shifting 2 crucial behavioral components of energy homeostasis toward weight gain. DESIGN In 15 healthy, normal-weight men, spontaneous physical activity was registered by accelerometry during the entire experiment, and food intake as well as relevant hormones were assessed during a 15-h daytime period after 2 nights of regular sleep (bed time: 2245-0700) and after 2 nights of restricted sleep (bed time: 0245-0700). Experiments were performed in a crossover design. RESULTS Sleep restriction significantly decreased physical activity during the daytime spent under free-living conditions after the first night of sleep manipulation (P = 0.008). Also, intensities of physical activity were shifted toward lower levels, with less time spent with intense activities (P = 0.046). Total energy intake, feelings of hunger, and appetite as well as ghrelin and leptin concentrations during day 2 remained unaffected by acute sleep restriction. CONCLUSIONS In contrast to our expectation, short-term sleep loss neither increased food intake nor affected concentrations of the hunger-regulating hormones leptin and ghrelin. However, the observed decrease in daytime physical activity may point to another potentially important behavioral mechanism for the health-impairing influence of sleep loss.

A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal‐weight healthy men

Sleep loss is currently proposed to disturb endocrine regulation of energy homeostasis leading to weight gain and obesity. Supporting this view, a reduction of sleep duration to 4 h for two consecutive nights has recently been shown to decrease circulating leptin levels and to increase ghrelin levels, as well as self‐reported hunger. We hypothesized that similar endocrine alterations occur even after a single night of sleep restriction. In a balanced order, nine healthy normal‐weight men spent three nights in our sleep laboratory separated by at least 2 weeks: one night with a total sleep time of 7 h, one night with a total sleep time of 4.5 h and one night with total sleep deprivation (SD). On a standard symptom‐rating scale, subjects rated markedly stronger feelings of hunger after total SD than after 7 h sleep (3.9 ± 0.7 versus 1.7 ± 0.3; P = 0.020) or 4.5 h sleep (2.2 ± 0.5; P = 0.041). Plasma ghrelin levels were 22 ± 10% higher after total SD than after 7 h sleep (0.85 ± 0.06 versus 0.72 ± 0.04 ng mL−1; P = 0.048) with intermediate levels of the hormone after 4.5 h sleep (0.77 ± 0.04 ng mL−1). Serum leptin levels did not differ between conditions. Feelings of hunger as well as plasma ghrelin levels are already elevated after one night of SD, whereas morning serum leptin concentrations remain unaffected. Thus, our results provide further evidence for a disturbing influence of sleep loss on endocrine regulation of energy homeostasis, which on the long run may result in weight gain and obesity.

Early Results of the Swiss Multicentre Bypass or Sleeve Study (SM-BOSS): A Prospective Randomized Trial Comparing Laparoscopic Sleeve Gastrectomy and Roux-en-Y Gastric Bypass

Objective:Laparoscopic sleeve gastrectomy (LSG) has been proposed as an effective alternative to the current standard procedure, laparoscopic Roux-en-Y gastric bypass (LRYGB). Prospective data comparing both procedures are rare. Therefore, we performed a randomized clinical trial assessing the effectiveness and safety of these 2 operative techniques. Methods:Two hundred seventeen patients were randomized at 4 bariatric centers in Switzerland. One hundred seven patients underwent LSG using a 35-F bougie with suturing of the stapler line, and 110 patients underwent LRYGB with a 150-cm antecolic alimentary and a 50-cm biliopancreatic limb. The mean body mass index of all patients was 44 ± 11.1 kg/m2, the mean age was 43 ± 5.3 years, and 72% were female. Results:The 2 groups were similar in terms of body mass index, age, sex, comorbidities, and eating behavior. The mean operative time was less for LSG than for LRYGB (87 ± 52.3 minutes vs 108 ± 42.3 minutes; P = 0.003). The conversion rate was 0.9% in both groups. Complications (<30 days) occurred more often in LRYGB than in LSG (17.2% vs 8.4%; P = 0.067). However, the difference in severe complications did not reach statistical significance (4.5% for LRYGB vs 1% for LSG; P = 0.21). Excessive body mass index loss 1 year after the operation was similar between the 2 groups (72.3% ± 22% for LSG and 76.6% ± 21% for LRYGB; P = 0.2). Except for gastroesophageal reflux disease, which showed a higher resolution rate after LRYGB, the comorbidities and quality of life were significantly improved after both procedures. Conclusions:LSG was associated with shorter operation time and a trend toward fewer complications than with LRYGB. Both procedures were almost equally efficient regarding weight loss, improvement of comorbidities, and quality of life 1 year after surgery. Long-term follow-up data are needed to confirm these facts.

Differential Sensitivity of Men and Women to Anorexigenic and Memory-Improving Effects of Intranasal Insulin

CONTEXT Brain insulin is critically involved in the regulation of body weight and memory processing. Long-term administration of intranasal insulin reduces body weight in men, but not in women, while improving hippocampus-dependent memory processing in both genders. OBJECTIVES Our objectives were to assess the effects of a single dose of intranasal insulin on food intake and memory function in men and women, and to determine any gender differences. METHODS A total of 32 healthy, normal-weight subjects (14 men, 18 women) were intranasally administered 160 IU regular human insulin or vehicle before performing a hippocampus-dependent two-dimensional-object location task, a working memory task (digit span), and a hippocampus-independent mirror tracing task. Subsequently, food intake from an ad libitum breakfast buffet was measured. RESULTS Insulin treatment decreased food intake in men but not in women (difference to placebo condition, men: -192.57 +/- 78.48 kcal, P < 0.03; women: 18.54 +/- 42.89 kcal, P > 0.67). In contrast, hippocampus-dependent memory and working memory were improved in women (P < 0.03, P < 0.05, respectively), whereas men did not benefit from acute insulin treatment (P > 0.17, P > 0.20). Performance on the hippocampus-independent mirror tracing task was not affected by insulin in women or men. CONCLUSIONS In accordance with animal data, results indicate that men are more sensitive than women to the acute anorexigenic effect of central nervous insulin signaling, whereas insulins beneficial effect on hippocampus-dependent memory functions is more pronounced in women. Our findings provide support for the notion of a fundamental gender difference in central nervous insulin signaling that pertains to the regulation of energy homeostasis and memory functions.

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 × 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 Alzheimers disease.

Hypoglycemia Unawareness in Older Compared With Middle-Aged Patients With Type 2 Diabetes

OBJECTIVE Older patients with type 2 diabetes are at a particularly high risk for severe hypoglycemic episodes, and experimental studies in healthy subjects hint at a reduced awareness of hypoglycemia in aged humans. However, subjective responses to hypoglycemia have rarely been assessed in older type 2 diabetic patients. RESEARCH DESIGN AND METHODS We tested hormonal, subjective, and cognitive responses (reaction time) to 30-min steady-state hypoglycemia at a level of 2.8 mmol/l in 13 older (≥65 years) and 13 middle-aged (39–64 years) type 2 diabetic patients. RESULTS Hormonal counterregulatory responses to hypoglycemia did not differ between older and middle-aged patients. In contrast, middle-aged patients showed a pronounced increase in autonomic and neuroglycopenic symptom scores at the end of the hypoglycemic plateau that was not observed in older patients (both P < 0.01). Also, seven middle-aged patients, but only one older participant, correctly estimated their blood glucose concentration to be <3.3 mmol/l during hypoglycemia (P = 0.011). A profound prolongation of reaction times induced by hypoglycemia in both groups persisted even after 30 min of subsequent euglycemia. CONCLUSIONS Our data indicate marked subjective unawareness of hypoglycemia in older type 2 diabetic patients that does not depend on altered neuroendocrine counterregulation and may contribute to the increased probability of severe hypoglycemia frequently reported in these patients. The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.

Acute sleep deprivation reduces energy expenditure in healthy men

BACKGROUND Epidemiologic evidence indicates that chronic sleep curtailment increases risk of developing obesity, but the mechanisms behind this relation are largely unknown. OBJECTIVE We examined the influence of a single night of total sleep deprivation on morning energy expenditures and food intakes in healthy humans. DESIGN According to a balanced crossover design, we examined 14 normal-weight male subjects on 2 occasions during a regular 24-h sleep-wake cycle (including 8 h of nocturnal sleep) and a 24-h period of continuous wakefulness. On the morning after regular sleep and total sleep deprivation, resting and postprandial energy expenditures were assessed by indirect calorimetry, and the free-choice food intake from an opulent buffet was tested in the late afternoon at the end of the experiment. Circulating concentrations of ghrelin, leptin, norepinephrine, cortisol, thyreotropin, glucose, and insulin were repeatedly measured over the entire 24-h session. RESULTS In comparison with normal sleep, resting and postprandial energy expenditures assessed on the subsequent morning were significantly reduced after sleep deprivation by ≈5% and 20%, respectively (P < 0.05 and P < 0.0001). Nocturnal wakefulness increased morning plasma ghrelin concentrations (P < 0.02) and nocturnal and daytime circulating concentrations of thyreotropin, cortisol, and norepinephrine (P < 0.05) as well as morning postprandial plasma glucose concentrations (P < 0.05). Changes in food intakes were variable, and no differences between wake and sleep conditions were detected. CONCLUSION Our findings show that one night of sleep deprivation acutely reduces energy expenditure in healthy men, which suggests that sleep contributes to the acute regulation of daytime energy expenditure in humans.

Acute Sleep Deprivation Enhances the Brain's Response to Hedonic Food Stimuli: An fMRI Study

CONTEXT There is growing recognition that a large number of individuals living in Western society are chronically sleep deprived. Sleep deprivation is associated with an increase in food consumption and appetite. However, the brain regions that are most susceptible to sleep deprivation-induced changes when processing food stimuli are unknown. OBJECTIVE Our objective was to examine brain activation after sleep and sleep deprivation in response to images of food. INTERVENTION Twelve normal-weight male subjects were examined on two sessions in a counterbalanced fashion: after one night of total sleep deprivation and one night of sleep. On the morning after either total sleep deprivation or sleep, neural activation was measured by functional magnetic resonance imaging in a block design alternating between high- and low-calorie food items. Hunger ratings and morning fasting plasma glucose concentrations were assessed before the scan, as were appetite ratings in response to food images after the scan. MAIN OUTCOME MEASURES Compared with sleep, total sleep deprivation was associated with an increased activation in the right anterior cingulate cortex in response to food images, independent of calorie content and prescan hunger ratings. Relative to the postsleep condition, in the total sleep deprivation condition, the activation in the anterior cingulate cortex evoked by foods correlated positively with postscan subjective appetite ratings. Self-reported hunger after the nocturnal vigil was enhanced, but importantly, no change in fasting plasma glucose concentration was found. CONCLUSIONS These results provide evidence that acute sleep loss enhances hedonic stimulus processing in the brain underlying the drive to consume food, independent of plasma glucose levels. These findings highlight a potentially important mechanism contributing to the growing levels of obesity in Western society.

The metabolic burden of sleep loss

In parallel with the increasing prevalence of obesity and type 2 diabetes, sleep loss has become common in modern societies. An increasing number of epidemiological studies show an association between short sleep duration, sleep disturbances, and circadian desynchronisation of sleep with adverse metabolic traits, in particular obesity and type 2 diabetes. Furthermore, experimental studies point to distinct mechanisms by which insufficient sleep adversely affects metabolic health. Changes in the activity of neuroendocrine systems seem to be major mediators of the detrimental metabolic effects of insufficient sleep, through favouring neurobehavioural outcomes such as increased appetite, enhanced sensitivity to food stimuli, and, ultimately, a surplus in energy intake. The effect of curtailed sleep on physical activity and energy expenditure is less clear, but changes are unlikely to outweigh increases in food intake. Although long-term interventional studies proving a cause and effect association are still scarce, sleep loss seems to be an appealing target for the prevention, and probably treatment, of metabolic disease.