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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.

Hyperinsulinemia has been shown to induce activation of the sympathetic nervous system and vasodilatation. Whether these effects result in changes in blood pressure (BP) is discussed controversially. We measured BP and plasma catecholamine levels in 30 healthy men during a 60-minute baseline phase and 360-minute period of insulin infusion. In a double-blind, between-subject comparison, insulin was infused at a low rate (1.5 mU insulin/kg per minute) in one half of the subjects and at a high rate (15 mU/kg per minute) in the other half. Throughout the experiments, blood glucose levels were held constantly within the normal range by a simultaneous infusion of glucose. Serum insulin levels increased to a plateau of 543 +/- 34 pmol/L during low rate and to 24,029 +/- 1,595 pmol/L during high rate of insulin infusion. Compared with baseline, insulin infusion of either rate significantly increased systolic BP, BP amplitude, and heart rate (all P < .05). In comparison with the low rate of insulin infusion, the high rate provoked a more pronounced increase in heart rate (P < .02) and systolic BP (P < .05) but tended to decrease diastolic BP (P < .08) summing up to a distinctly more increased BP amplitude (P < .05). Plasma norepinephrine as well as epinephrine levels did not significantly change during the low-rate insulin infusion but significantly increased during high-rate insulin infusion (both P < .05). By showing a dose-dependent increasing influence of insulin on systolic BP and circulating catecholamine levels, the present study provides experimental evidence for the notion that hyperinsulinemia contributes to the development of hypertension.

Objective: Hypoglycaemia-induced decreases in male LH and testosterone concentrations are possibly mediated by activation of the hypothalamus-pituitary-adrenal (HPA) axis or by an increase in PRL. As counterregulatory stress hormone release is attenuated during recurrent hypoglycaemia, we questioned whether the gonadotrophic axis and PRL adapt similarly., Design: We performed two consecutive hypoglycaemic clamps on day 1 and one clamp on the following day in 15 healthy men. Blood concentrations of gonadotrophins, PRL, testosterone, ACTH and cortisol were measured during the first and the third clamp, taking place at the same time of day., Results: During hypoglycaemia, serum concentrations of LH and testosterone decreased (P < 0.003 for both), PRL, ACTH and cortisol increased (P < 0.001), and FSH remained unchanged (P = 0.90). The hypoglycaemia-induced decreases in LH and testosterone concentrations were similar during the first and the last clamp (P > 0.28 for both) whereas the increase in PRL, ACTH and cortisol was markedly attenuated during the third clamp (P < 0.001)., Conclusions: LH and testosterone responses do not adapt to recurrent hypoglycaemia, whereas the increase in PRL is attenuated, indicating adaptation. Considering the marked decrease in the responses of PRL and the HPA axis after antecedent hypoglycaemia, the data suggest that the hypoglycaemia-induced decreases in LH and testosterone concentrations, not adapting to recurrent hypoglycaemia, are mediated independently, probably by blood glucose itself.

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.

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.

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.

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.

Increased hypothalamo-pituitary-adrenal activity contributes to morbidity in widespread metabolic and psychiatric diseases. Inhibition of hypercortisolism represents a promising therapeutic strategy in these conditions, which currently cannot be used. Here, we tested the hypothesis that atrial natriuretic peptide (ANP) administered intranasally is a safe and feasible inhibitor of pituitary-adrenal activity at the central nervous level. Thirty minutes after intranasal administration of ANP (1 mg) and placebo, pituitary-adrenal activity was stimulated in 18 healthy men by two tests: 1) a standard insulin-hypoglycemia test and 2) CRH combined with vasopressin (VP), respectively. ACTH, cortisol, VP, blood pressure, heart rate, and measures of fluid balance were also recorded. Pretreatment with ANP suppressed cortisol (P < 0.01) and ACTH (P < 0.05) secretory responses to insulin-induced hypoglycemia to about half of that seen after placebo, but pituitary-adrenal activity was not suppressed by CRH/VP injection (P > 0.7). Indicators of fluid balance, cardiovascular parameters, and self-report measures were not influenced by the treatment. Results indicate a strong inhibition of stimulated pituitary-adrenal activity after intranasal administration of ANP. The absence of an effect on CRH/VP-induced pituitary-adrenal responses suggests a direct action of the peptide on the central nervous system inhibiting stimulated hypothalamo-pituitary-adrenal activity at the hypothalamic level.

Hypoxic respiratory diseases are frequently accompanied by glucose intolerance. We examined whether hypoxia is a cause of glucose intolerance in healthy subjects. In a double-blind within-subject crossover design, hypoxic versus normoxic conditions were induced in 14 healthy men for 30 minutes by decreasing oxygen saturation to 75% (versus 96% in control subjects) under the conditions of a euglycemic clamp. The rate of dextrose infusion needed to maintain stable blood glucose levels was monitored. Neurohormonal stress response was evaluated by measuring catecholamine and cortisol concentrations as well as cardiovascular parameters, and symptoms of anxiety. To differentiate between the effects of stress hormonal response, and hypoxia itself, on glucose intolerance, we performed hypoglycemic clamps as a nonspecific control. We found a significant decrease in dextrose infusion rate over a period of 150 minutes after the start of hypoxia (p < 0.01). Hypoxia also increased plasma epinephrine concentration (p < 0.01), heart rate (p < 0.01), and symptoms of anxiety (p < 0.05), whereas the other parameters remained unaffected. Glucose intolerance was closely comparable between hypoxic and hypoglycemic conditions (p < 0.9) despite clear differences in stress hormonal responses. Hypoxia acutely causes glucose intolerance. One of the factors mediating this effect could be an elevated release of epinephrine.

Aims: Hypoglycaemic symptoms and hormonal counter-regulation are of high importance to avoid the risk of severe hypoglycaemia in patients with diabetes mellitus. Various antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors, have been suspected for a long time to reduce this response to hypoglycaemia in diabetic subjects. Although ACE inhibitors are approved for controlling diabetic complications, previous investigations regarding this putative side-effect are controversial., Methods: We performed clamp experiments in 16 healthy men lasting for 6 h each. The subjects were pretreated for 7 days with captopril 3 x 25 mg day-1 vs placebo in a randomized, double-blind, crossover study. Plasma glucose was decreased in a stepwise manner during a hypoglycaemic clamp session and counter-regulatory hormones [epinephrine (adrenaline), norepinephrine (adrenaline), ACTH, cortisol, glucagon], symptoms, and haemodynamic parameters (blood pressure, heart rate] were measured., Results: Counter-regulatory hormone concentrations significantly increased in both sessions (ACE inhibitor vs placebo) during hypoglycaemia. The rise of counter-regulatory hormones as well as symptom scores were equal under both ACE inhibitor and placebo treatment. Systolic blood pressure and heart rate increased (from 110 +/- 3 vs 115 +/- 3 mmHg to 132 +/- 4 vs 133 +/- 4 mmHg) whereas diastolic blood pressure slightly decreased (from 63 +/- 2 vs 70 +/- 3 mmHg to 61 +/- 2 vs 64 +/- 2 mmHg) independent of pretreatment. Systolic and diastolic blood pressure were significantly lower in the captopril session vs placebo (P < 0.05)., Conclusions: Our results demonstrate that subchronic treatment with captopril does not attenuate symptomatic and hormonal response to hypoglycaemia. Thus, to patients at risk of hypoglycaemia who require antihypertensive or nephroprotective treatment, we would continue giving an ACE inhibitor.

The plasma glucose concentration is a major short-term regulator of hunger and food intake. In patients with diabetes, therapies lowering plasma glucose are frequently associated with body weight gain, suggesting that lowered plasma glucose leads to increased feelings of hunger and food intake. However, as many physiological and symptomatic responses to low plasma glucose are attenuated after repeated episodes of hypoglycemia, this may also pertain to feelings of hunger. Here we tested whether the stimulatory effect of low plasma glucose on feelings of hunger is likewise reduced by repeated episodes of hypoglycemia. As metformin has been shown to reduce plasma glucose levels without increasing body weight and also to decrease food intake, we tested for possible interacting effects of this substance with hypoglycemia-induced hunger. Feelings of hunger were assessed by rating scales during 3 consecutive hypoglycemic clamps performed on 2 consecutive d in 15 normal weight men. Subjects were tested once while being treated with 850 mg metformin twice daily and once while receiving placebo. Treatment was started 14 d before the clamp experiments and was performed in a random order and double-blind fashion. Hypoglycemia markedly enhanced feelings of hunger (P < 0.001). However, rated feelings of hunger on the first and last hypoglycemic clamps were comparable (P = 0.304). Compared with placebo, metformin decreased feelings of hunger during hypoglycemia (P = 0.015). This reduction was not associated with a decrease in posthypoglycemic food intake as measured by the number of cookies consumed after the last clamp (P = 0.676). Data indicate that the stimulatory effect of low plasma glucose on hunger is not attenuated after repeated episodes of hypoglycemia, which implies that, in contrast to other symptoms, hunger is not subject to adaptive attenuation upon repeated hypoglycemia. Metformin attenuates hypoglycemia-induced hunger, but does not appear to influence posthypoglycemic food intake.

Glucose, the most important fuel for the brain, is supplied by the actions of counterregulatory hormones and the sympathetic nervous system. Yet to obtain access to the brain, glucose must pass the blood-brain barrier. Here we show that vascular endothelial growth factor (VEGF), a potent regulator of blood vessel function, is a candidate hormone for facilitating glucose passage across the blood-brain barrier under critical conditions. In 16 healthy men, VEGF serum concentrations increased under 6 h of insulin-induced hypoglycemic conditions from 86.1 +/- 13.4 to 211.6 +/- 40.8 pg/ml (P = 0.002), whereas in the hyperinsulinemic euglycemic control condition, no change was observed. During hypoglycemia serum VEGF, but no other counterregulatory hormone, was associated with preserved neurocognitive function, as measured with a memory test (r = 0.539; P = 0.031) and the Stroop interference task (r = 0.569; P = 0.021). Findings show that acute hypoglycemia is accompanied by a brisk increase in circulating VEGF concentration and that VEGF could mediate rapid adaptation of the brain to neuroglycopenia.