Reproductive versatility in legumes: the case of amphicarpy in Trifolium polymorphum.

Amphicarpy is a fascinating reproductive strategy, defined as fruit produced both below the soil surface and as aerial fruit on the same plant. Trifolium polymorphum is a grassland species subject to herbivory that combines amphicarpy with vegetative reproduction through stolons. Underground flowers have been described as obligate autogamous and aerial ones as self-compatible allogamous, with aerial floral traits favouring cross-pollination. In the present work we performed different pollination treatments on aerial flowers to analyse rates of pollen tube development and offspring fitness, measured as fruit set, seed production and germination percentage. This last variable was compared to that of seeds produced underground. No significant differences were found between fruit set in self- and cross-pollinations. Seed production was higher in self-pollinations, which is consistent with the higher rate of pollen tube development observed in self-crosses. Spontaneous self-pollination is limited in aerial flowers; thus pollen transfer by means of a vector is required even within the same flower. Germination tests showed that aerial seeds produced after self- and cross-pollination did not differ in fitness, but underground seeds had higher germination percentage than aerial ones. Thus, we conclude that T. polymorphum has a mixed mating system. In grasslands with heavy grazing pressure, clonal propagation and underground seed production ensure persistence in the field. An intermediate level of selfing in aerial flowers ensures offspring, but morphological (herkogamy) and functional (dicogamy) floral traits maintain a window to incorporate genetic variability, allowing the species to tolerate temporal and spatial pressures.

Effect of dexamethasone on TSH secretion induced by TRH in human obesity.

BACKGROUND: The presence of an abnormally high thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) makes it difficult to distinguish some euthyroid obese subjects from subelinically hypothyroid obese patients. Here, we examine whether such distinction may be achieved after treatment with glucocorticoids, which inhibit TSH secretion at the hypothalamic-pituitary level. METHODS: TRH tests (200 microg as an intravenous bolus injection) were performed in 30 age- and weight-matched, obese, but otherwise healthy, men. All subjects were tested again with TRH after treatment with dexamethasone (dex) (2 mg/d in four divided doses orally for 3 days). RESULTS: In all subjects, total thyroxine and triiodothyronine concentrations were in the normal range. According to basal and TRH-stimulated serum thyrotropin (TSH) levels, subjects were divided into the following three groups: group I (n=10), euthyroid subjects; group II (n=10), euthyroid subjects with normal basal but abnormally elevated TSH responses to TRH; group III (n=10), subjects with elevated basal and TRH-induced TSH levels (subclinical hypothyroidism). Basal TSH levels were 1.8+/-0.4 mU/L in group I, 1.7+/-0.3 in group II, and 6.0+/-0.7 in group III. In both groups II and III, TRH-induced TSH increments were above the normal range (maximal increment> 15 mU/L) and were significantly higher than in group I. After the second treatment with TRH, pretreatment with dex significantly decreased both basal TSH levels and peak TSH responses to TRH in all groups. However, a striking percentage decrease (>50%) in TRH-induced peak TSH responses was observed in euthyroid obese subjects of groups I and II, whereas hypothyroid subjects of group III showed only a slight decrement (<25%). CONCLUSIONS: The sensitivity of the TSH secretory system to glucocorticoid inhibitory action is preserved in obese subjects with abnormally elevated TSH response to TRH, but not in subclinically hypothyroid obese patients. The TRH plus dex test might be useful in future studies to understand the mechanisms underlying alterations in TSH secretion in obesity.

Effect of systemic oxytocin administration on dexamethasone-induced leptin secretion in normal and obese men.

To establish whether the regulatory mechanism of leptin secretion is sensitive to oxytocin (OT), seven healthy nonobese men were tested with dexamethasone (dex; 4 mg, iv, at 0730 h) in feeding (2000 Cal given at 3 meals over 7 h) conditions either in the absence (iv normal saline infusion) or in the presence of a constant iv infusion of OT (1, 2, or 4 mIU/min from 0730 h for 10 h). In six additional subjects under similar experimental conditions, normal saline or OT (1, 2, or 4 mIU/min from 0730 h for 10 h) were infused iv without the previous treatment with dexamethasone. Serum leptin concentrations were measured in samples taken at 60-min intervals during infusion. Leptin levels remained constant during the infusion of normal saline or OT (1, 2, or 4 mIU/min) alone. In contrast, serum leptin concentrations rose significantly from the baseline after dex administration. The leptin response to dex was not modified by the concomitant infusion of 1 mIU/min OT, whereas it was completely abolished by the administration of 2 or 4 mIU/min OT. These findings led us to evaluate the secretory pattern of leptin in 12 obese patients in similar experimental conditions. In all patients basal leptin levels were significantly higher than those in normal weight subjects. In 6 obese subjects, the infusion of OT alone (1, 2, or 4 mIU/min) was unable to change serum leptin levels. In the remaining 6 obese subjects, dex administration significantly increased serum leptin levels; however, the leptin response to dex was not modified by the concomitant infusion of 1, 2, or 4 mIU/min OT. These data show inhibition by elevated circulating OT levels of glucocorticoid-induced, but not basal, leptin secretion in normal weight subjects, suggesting a possible role for OT in the regulatory control of leptin. Furthermore, the results obtained in obese subjects indicate that this regulation is disrupted in obesity.

Enhancement of the GH responsiveness to GH releasing stimuli by lysine vasopressin in type 1 diabetic subjects.

OBJECTIVE: We tested the possibility that lysine vasopressin (LVP) changes the GH responsiveness to exogenously administered GH-RH (at its minimal and maximal doses), clonidine (which is thought to stimulate endogenous GH-RH release) and arginine (which is thought to inhibit somatostatin) in patients with type 1 diabetes mellitus and normal subjects. DESIGN AND PATIENTS: Normal male subjects (NC) and age- and weight-matched insulin-dependent diabetic men (DM) with good metabolic control were studied. An iv bolus of LVP at a dose (15 microg/kg body weight (BW)) lower than the minimal GH releasing effective dose was injected just before the I.V. injection of the minimal effective dose of GH-RH (0.035 microg/kg BW) in 10 NC and 10 DM, the I.V. injection of the maximal effective dose of GH-RH (100 microg) in 7 NC and 7 DM, the I.V. infusion of arginine (30 g over 30 min) in 7 NC and 8 DM or the oral administration of clonidine (150 microg) in 7 NC and 8 DM. On different occasions, GH stimuli, LVP or normal saline were given alone to the same normal and diabetic subjects. MEASUREMENTS: GH responses in the presence and absence of LVP were measured and compared within each group and between normal and diabetic groups. RESULTS: LVP or normal saline administration did not modify the basal concentrations of GH in any subject. The administration of GH-RH (at the minimal dose), arginine or clonidine alone induced significantly higher GH responses in the diabetic subjects than in the normal controls. At the maximal dose GH-RH induced similar GH responses in normal and diabetic subjects. The simultaneous administration of LVP did not change the GH response to any challenging stimulation in the normal controls; in contrast, GH-RH- (at both minimal and maximal dose), arginine- and clonidine-induced GH increments were significantly enhanced by LVP in the diabetic subjects. CONCLUSIONS: These data show that in diabetic, but not in normal subjects LVP enhances the GH responsiveness to secretagogues, such as GH-RH, clonidine and arginine, which act through three different mechanisms. These findings suggest that in diabetes mellitus, vasopressin functions as a primer for various GH responses.

Influence of residual insulin secretion and duration of diabetes mellitus on the control of luteinizing hormone secretion in women.

BACKGROUND: The aim of the present study was to establish whether the persistence of residual beta-cell activity after long-term diabetes mellitus (DM) exerts a protective role on luteinizing hormone (LH) secretion. METHODS: The LH responses to stimulation with gonadotropin-releasing hormone (Gn-RH) (100 microg in an i.v. bolus) or naloxone (4 mg injected in an i.v. bolus, followed by the constant infusion of 8 mg in 2 h) were measured in C-peptide-positive (CpP) and C-peptide-negative (CpN) normally menstruating women with short-term (group 1 < 3 years, CpP n = 11, CpN n = 11) or long-term (group 2 > 10 years, CpP n = 11, CpN n = 11) DM and in age-matched normal control subjects (n = 11). RESULTS: Gn-RH induced significant increments in LH secretion in all groups. Significant LH responses to naloxone were observed in all groups, except in group 2 CpN patients. However, the LH response to either Gn-RH or naloxone was significantly lower in group 1 CpN, group 2 CpP and group 2 CpN patients than in the normal control subjects. Furthermore, the LH response was significantly lower in group 2 CpP than in group 1 CpP patients and in group 2 CpN than in group 1 CpN subjects. CONCLUSIONS: These results indicate a role for both deficiency in residual endogenous insulin secretion and duration of diabetes in the derangement of LH secretory control. The data suggest that the protective role exerted by residual beta-cell activity on LH secretion during the early years of DM diminishes with time elapsed after the onset of diabetes mellitus.

Cytotoxic effects of gold(III) complexes on established human tumor cell lines sensitive and resistant to cisplatin.

Gold(III) complexes, isostructural and isoelectronic with platinum(II) complexes, are potentially attractive as anticancer agents. We have synthesized a group of square planar gold(III) complexes, all containing at least two gold-chloride bonds in cis-position, and tested their in vitro cytotoxicity on a panel of established human tumor cell lines. Remarkably, all these compounds showed significant cytotoxic effects. In particular, the complexes containing the salycilaldiminate ligand induced tumor cell growth inhibitory effects comparable to or even greater than cisplatin. All gold(III) complexes substantially retained their antitumor potency against two cisplatin-resistant tumor cell lines (CCRF-CEM/R leukemia and A2780/R ovarian carcinoma); only minimal cross-resistance with cisplatin was observed. When considering the mechanism of action, it is reasonable to assume that the cytotoxicity of these gold(III) complexes derives from DNA binding. Preliminary spectroscopic results are consistent with this hypothesis; indeed, circular dichroism experiments show that both the salycilaldiminate- and the pyridine-containing gold(III) complexes bind calf thymus DNA in vitro and alter reversibly its B-type solution conformation. These results, however, must be treated with caution; solution studies indicate that gold(III) compounds are poorly stable under physiological conditions, possibly implying that, when injected, only a small amount will reach, unchanged, the DNA target. The results of our investigations are discussed in the perspective of future work on the cytotoxic and antitumor properties of gold(III) compounds.

Influence of residual C-peptide secretion on nocturnal serum TSH peak in well-controlled diabetic patients.

OBJECTIVE: Several alterations in hypothalamo-pituitary-thyroid (HPT) function have been described in diabetes mellitus and have been attributed to metabolic decompensation. The present study was performed in order to establish whether residual endogenous insulin secretion in patients with insulin-dependent diabetes mellitus (IDDM) may play a role in the control of HPT function. DESIGN: The nocturnal (2230 h-0200 h) serum TSH surge, the TSH response to TRH (200 microgram as an i.v. bolus) and serum free thyroid hormone levels were evaluated in C-peptide positive (CpP) (subjects with residual detectable endogenous pancreatic beta-cell activity) and C-peptide negative (CpN) patients both before and after optimization of metabolic status by 3 days of treatment with continuous subcutaneous insulin infusion, and in normal controls. TSH response to TRH and serum free thyroid hormone levels were assessed in the morning. SUBJECTS: Twenty male diabetic patients hospitalized to achieve a better control of hyperglycaemia were subdivided into 10 CpP (age: 33 +/- 1.5 years (mean +/- SE); body mass index (BMI): 22.6 +/- 0.3) and 10 CpN (age: 32 +/- 1.7 years; BMI: 22.5 +/- 0.4) patients. Nine normal men (age: 34.0 +/- 1.2 years; BMI: 23.1 +/- 0.4) served as controls. MEASUREMENTS: The nocturnal serum TSH peak was measured by dividing the highest night-time TSH value by the next morning TSH value and then multiplying by 100. Serum TSH levels were measured in samples taken just before (time 0) and 30 minutes, after TRH administration. Serum free thyroid hormone levels were measured in samples taken at time 0 of the TRH test. RESULTS: Before improvement of hyperglycaemia, CpP and CPN patients showed similar alterations in HPT function; i.e. serum free T3 levels and TSH responses to TRH were lower than normal; the nocturnal TSH surge was absent. Correction of hyperglycaemia normalized all examined HPT parameters in CpP diabetics, whereas normalization in serum free T3 levels and pituitary TSH responsiveness to TRH in CpN patients was not accompanied by restoration of the nocturnal TSH peak. CONCLUSIONS: These data indicate that the absence of residual pancreatic beta-cell function in patients with insulin-dependent diabetes mellitus is associated with neuroendocrine dysfunction in the regulation of circadian TSH secretion, which is not reversible after restoration of good glycaemic control.

Biological properties of two gold(III) complexes: AuCl3(Hpm) and AuCl2(pm).

The reactivity in solution of two recently characterized gold(III) complexes, AuCl3(Hpm) and AuCl2(pm), has been investigated in view of their potential use as anti-cancer agents. In water, both compounds undergo relatively fast hydrolysis of the bound chlorides without loss of the heterocycle ligand; the process is much faster within a physiological buffer. When the two gold(III) complexes react with proteins like albumin or transferrin, reduction of gold(III) to gold(I) and/or hydrolysis is observed. On the other hand, both complexes bind rapidly and tightly to either polynucleotides or calf thymus DNA, with gold remaining in the +3 oxidation state. Circular dichroism investigations reveal a large perturbation of DNA conformation upon gold(III) binding; preferential binding to GC sequences is shown. Cytotoxicity studies on a number of tumor cell lines demonstrate a good activity of these gold(III) complexes compared to cisplatin. However, quick hydrolysis and/or reduction of these compounds under physiological conditions may represent a severe limitation to their use.

Abnormal effect of cigarette smoking on pituitary hormone secretions in insulin-dependent diabetes mellitus.

OBJECTIVE: We observed the effect of smoking two cigarettes on GH, AVP and cortisol secretion in patients with diabetes and normal subjects. DESIGN AND PATIENTS: We tested 10 male smokers with insulin-dependent diabetes mellitus (IDDM) and 10 normal smokers. On a different occasion, normal and diabetic smokers were tested with an insulin (0.15 U/kg body weight) tolerance test (ITT). MEASUREMENTS: Hypoglycaemia-induced hormonal responses in smokers were compared with those observed in 10 diabetic and 10 normal non smokers. RESULTS: All subjects showed similar basal GH, cortisol and AVP levels. In the normal subjects, cigarette smoking induced a significant increase in circulating GH, AVP and cortisol levels, with mean peaks 3.3, 3 and 1.58 times higher than baseline, respectively. Smoking-induced hormonal responses were significantly higher in diabetics (mean peak was 5.2 times higher than baseline for GH, 4.0 for AVP and 1.83 for cortisol). Insulin induced a similar hypoglycaemic nadir in all subjects at 30 minutes, even though the diabetic subjects had a delayed recovery in blood glucose levels. GH and AVP responses to hypoglycaemia were significantly higher in diabetic (mean peaks 11.5 and 3.2 times higher than baseline, respectively) than in normal (mean peaks 7.3 and 1.9) non-smokers, whereas these groups showed similar cortisol responses (mean peak 2.3 times higher than baseline). Smoking did not change any hypoglycaemia-induced hormonal rise in the normal controls, whereas it significantly enhanced GH, AVP and cortisol levels (mean peaks 14.5, 4 and 3.8 times higher than baseline, respectively) in diabetics. CONCLUSIONS: In patients with IDDM, cigarette smoking not only elicits higher GH, AVP and cortisol responses than in normal subjects, but also enhances the counter-regulatory hormone responses to insulin-induced hypoglycaemia. These findings suggest interactions between nicotine inhaled with cigarette smoking and diabetes-induced neuroendocrine alterations.

Involvement of nitric oxide in arginine, but not glucose, induced insulin secretion in normal men.

OBJECTIVE: At present, there are no reports in the literature of studies in humans concerning a possible role of nitric oxide (NO) in the regulation of pancreatic endocrine secretions, whereas studies in the rat provided discrepant results. The aim of this study was to clarify whether NO is involved in the control of insulin and/or glucagon secretion in basal conditions and/or in response to arginine or glucose administration in normal male subjects. DESIGN: We investigated whether an intravenous infusion of the NO synthase (NOS) inhibitor L-NAME, at a dose previously demonstrated not to produce blood pressure alterations or untoward side-effects, modifies insulin and/or glucagon secretory patterns. SUBJECTS: Fourteen healthy male volunteers aged 24-35 years, within 10-13% of their ideal body weight and without family history of diabetes mellitus or other endocrine diseases. METHODS: Seven normal men were treated intravenously with L-arginine (30 g in 50 ml of normal saline over 30 minutes) or glucose (0.33 g/kg body weight in a bolus) with or without the concomitant infusion of L-NAME (90 micrograms/kg in 50 ml of normal saline). L-NAME was infused for 30 minutes before and during arginine infusion and over 30 minutes before and 30 minutes after glucose injection. Another group of 7 men was infused over 60 minutes with L-NAME (90 micrograms/kg in 50 ml of normal saline) alone or saline alone. RESULTS: Basal and L-arginine or glucose induced glucagon secretions and basal and glucose stimulated insulin secretions were not altered by L-NAME administration. In contrast, the drug produced a partial but significant decrease in the insulin response to L-arginine. In fact, the mean peak insulin response to L-arginine was 5.3 times (53 +/- 5 mU/l (mean +/- SE)) higher than basal value (10 +/- 2) in the absence of L-NAME, but only 3.33 times (40 +/- 4) higher than baseline (12 +/- 3) during the infusion of the NOS-inhibitor. CONCLUSION: These data suggest that NO at least partially mediates the stimulatory action of L-arginine on insulin secretion in normal human subjects.

Influence of residual C-peptide secretion on the arginine vasopressin response to hypoglycaemia and metoclopramide in insulin-dependent diabetes.

Arginine vasopressin (AVP) hypersecretion in response to metoclopramide or to insulin-induced hypoglycaemia has been described in type I diabetes mellitus. In the present study, we examined whether residual endogenous insulin secretion may play a role in the control of this abnormal AVP secretory pattern. For this purpose, 21 insulin-dependent diabetic men and 10 age- and weight-matched normal men were tested with MCP (20 mg in an i.v. bolus). On a different occasion, subjects were tested with insulin (0.15 IU kg-1). The diabetic patients were subdivided into C-peptide negative patients (CpN, 11 patients without detectable endogenous pancreatic beta cell activity) (group I) and C-peptide positive patients (CpP, 10 patients with residual endogenous insulin secretion) (group II). Experiments started after optimization of the metabolic status of the diabetic men by 3 days of treatment with continuous subcutaneous insulin infusion. The basal concentrations of AVP were similar in all groups. The administration of MCP induced a striking elevation in plasma AVP levels in the normal controls and in the diabetic subjects of groups I and II. However, the AVP rise was significantly higher in group I and group II than in normal controls. Furthermore, group I diabetics showed higher AVP increments than group II. Insulin induced a similar hypoglycaemic nadir in all subjects at 30 min, even though the diabetic subjects of groups I and II had a delayed recovery in blood glucose levels. The hypoglycaemic pattern was similar in group I and II. Hypoglycaemia induced a striking AVP increase in the normal controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with or without neuropathy.

The function of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated in insulin-dependent diabetics without (group I, n = 10) or with (group II, n = 10) established symptomatic neuropathy and in age- and weight-matched normal controls (n = 11). Since the corticotropin (ACTH)/cortisol response to the minimal-effective dose of corticotropin-releasing hormone ([CRH] 0.03 microgram/kg body weight) represents a useful tool for HPA axis examination, all subjects were tested with the low-dose ovine CRH stimulation test. Experiments started at 8:30 AM, when CRH was injected after two basal blood samples were withdrawn, and lasted 2 hours. Basal serum levels of ACTH were similar in the three groups. Administration of CRH induced a small but significant increase in ACTH levels in all subjects; however, the CRH-induced ACTH increase was significantly higher in normal controls than in diabetic groups I and II. Furthermore, a significantly lower ACTH response was observed in group II than in group I. In contrast, basal and CRH-induced cortisol levels were significantly higher in diabetics than in normal controls. Comparisons between diabetic groups showed that both basal and stimulated cortisol secretion was significantly higher in group II than in group I. When peak ACTH responses to CRH and basal cortisol levels were combined, a significant negative correlation was found (r = .545, P < .02). These data show that even uncomplicated diabetes mellitus is associated with adrenal hyperfunction. Such an alteration is more pronounced in the presence of neuropathy.

Influence of thyroid status on the paradoxical growth hormone response to thyrotropin-releasing hormone in human obesity.

Thyrotropin-releasing hormone (TRH) tests were performed in 38 age- and weight-matched obese but otherwise healthy men. In all subjects, total thyroxine (T4) and triiodothyronine (T3) concentrations were in the normal range. According to basal and TRH-stimulated serum thyrotropin (TSH) levels, subjects were divided into the following three groups: group I (n = 14), euthyroid subjects; group II (n = 11), euthyroid subjects with normal basal but abnormally elevated TSH responses to TRH; group III (n = 13), subjects with elevated basal and TRH-induced TSH levels (subclinical hypothyroidism). Basal TSH levels were 1.8 +/- 0.4 mU/L in group I, 1.7 +/- 0.3 in group II, and 6.0 +/- 0.7 in group III. In both groups II and III, TRH-induced TSH increments were above the normal range (maximal increment > 14 mU/L) and were significantly higher than in group I. The definition of euthyroidism for groups I and II and of subclinical hypothyroidism for group III according to the basal levels of TSH was confirmed by clinical (Billewicz index), hormonal (serum free-T4 levels), and metabolic (serum apoprotein [apo] AI levels) parameters. Basal concentrations of growth hormone (GH) were similar in all groups. When GH levels after TRH stimulation were measured, significant increments (peak minus baseline > 5 micrograms/L) were observed in nine of 13 hypothyroid obese men. The overall mean peak GH increase in group III was 4.5 times higher than baseline and was observed at 45 minutes. None of the euthyroid obese subjects of groups I and II showed any significant change in GH levels in response to TRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in the arginine vasopressin responses to metoclopramide and insulin-induced hypoglycemia in normal weight bulimic women.

A low plasma arginine vasopressin (AVP) responsiveness to hypertonic saline infusion has been described in bulimic women. At present, it is unknown whether this phenomenon is peculiar for the osmotic regulation of AVP secretion or whether it represents an aspect of a more general disorder of AVP secretion in bulimia nervosa. In order to answer these questions, in the present study the AVP responses to metoclopramide (MCP) (20 mg in an i.v. bolus) and insulin (0.15 IU/kg)-induced hypoglycemia were tested in normal weight bulimic women and in weight- and age-matched normal women. Basal AVP concentrations were similar in normal and bulimic women. In the normal controls, plasma AVP levels rose 2.6 times after MCP and 2.2 times in response to hypoglycemia. Both AVP increments were significantly lower in bulimic patients. In this group, plasma AVP levels rose 2 times after MCP and 1.8 times in response to hypoglycemia. When data of the MCP and insulin tolerance test were combined, regression analyses showed a significant positive correlation between AVP peak responses to MCP and hypoglycemia in the bulimic group. These data show an impaired AVP response to different releasing stimuli in bulimia, suggesting that a more general disorder than a simple change in the sensitivity to osmotic stimulation affects the AVP secretory system in bulimic patients. It is likely that bulimic subjects are affected by a neuroendocrine alteration in the control of AVP secretion, whose mechanisms are still unknown.

Abnormal growth hormone and cortisol, but not thyroid-stimulating hormone, responses to an intravenous glucose tolerance test in normal-weight, bulimic women.

Abnormal growth hormone (GH) and adrenocorticotropic hormone (ACTH)/cortisol secretory patterns in response to a glucose load have been observed in underweight anorectic women. The present study was performed in an attempt to establish whether changes in the hypothalamic/pituitary sensitivity to hyperglycemia occur in bulimia in the absence of weight disturbance. Therefore, serum GH, plasma cortisol, and plasma insulin concentrations were measured in eight women with normal weight bulimia and in eight normal women during an intravenous glucose (0.33 g/kg as an IV bolus) tolerance test (IGTT). In addition, since abnormal pituitary hormone responses to a glucose load might reflect alterations in somatostatin (SRIH) release, TSH secretion also was measured, in view of its sensitivity to SRIH inhibition. Both GH and cortisol levels progressively and significantly declined during IGTT in the normal subjects. In the bulimic women, cortisol levels remained unchanged, whereas GH concentrations rose significantly after glucose injection. Plasma cortisol and serum GH levels were significantly higher in the bulimic than in the control subjects. No significant differences between groups were observed in hyperglycemia-induced insulin increments or in TSH decrements. These data indicate that an altered sensitivity to hyperglycemia affects the hypothalamic/pituitary centers controlling the secretion of the counterregulatory hormones GH and ACTH/cortisol in bulimia nervosa. The lack of a simultaneous change in the TSH secretory pattern argues against a possible involvement of SRIH in the pathophysiology of this disorder.

Intravenously infused substance P enhances basal and growth hormone (GH) releasing hormone-stimulated GH secretion in normal men.

The effect of synthetic substance P (SP), infused intravenously (IV) in doses of 0.5, 1, or 1.5 pmol/kg-1/min-1 over 60 min, on GH secretion was evaluated in seven healthy men. Substance P tests and a control test with normal saline were randomly performed at weekly intervals. No untoward side effects or changes in blood pressure were observed during SP infusions. Serum GH concentrations did not change when normal saline, the lowest dose, or the middle dose of SP were infused. In contrast, GH levels rose significantly when the highest dose of SP was given, with a mean peak two times higher than baseline. Further studies were performed to test the possible influence of SP on the GH response to GH-RH. For this purpose, seven other healthy men were tested with GH-RH (1 micrograms/kg body weight in an IV bolus) during saline or SP (1.5 pmol/Kg-1/min-1 x 60 min) infusion. The GH-RH induced a significant GH rise, with a mean peak seven times higher than baseline. When subjects were infused with SP, the GH response to GH-RH was greatly enhanced, with a mean peak 12 times higher than baseline. These results demonstrate for the first time in humans that the systemic infusion of SP stimulates GH secretion, and suggest that SP might interact with GH-RH in the stimulation of GH secretion.

Hypoglycemia-induced arginine vasopressin and oxytocin release is mediated by glucoreceptors located inside the blood-brain barrier.

Arginine vasopressin (AVP) and oxytocin (OT) responses during an insulin (0.15 IU/kg body weight) tolerance test (ITT) were evaluated in normal men while they were infused with normal saline, glucose or fructose. Insulin-induced hypoglycemia produced significant plasma AVP and OT increments in the control test. The infusion of fructose was unable to change the posterior pituitary hormonal responses to hypoglycemia. In contrast, AVP and OT responses during ITT were completely abolished when the concomitant infusion of glucose prevented insulin-induced hypoglycemia. These data exclude a direct role of hyperinsulinemia in the mechanism underlying the AVP and OT responses during ITT. Furthermore, since glucose, but not fructose, crosses the blood-brain barrier (BBB), the posterior pituitary hormone responses to hypoglycemia appear to be generated by stimulations of glucosensitive areas located inside the BBB.

Luteinizing hormone responses to gonadotropin-releasing hormone and naloxone in menstruating women with type I diabetes of different duration.

Luteinizing hormone (LH) responses to gonadotropin-releasing hormone (GnRH) (100 micrograms injected intravenously (IV)) or naloxone (4 mg injected plus 8 mg infused in 2 hours IV) were evaluated in 29 women with insulin-dependent diabetes mellitus (IDDM) (duration, group I (n = 15): less than 10 years, range 3 to 9 years; group II (n = 14): greater than 10 years, range 11 to 20 years) and in 15 normal controls, on the 22nd days of normal menstrual cycles. Both GnRH- and naloxone-induced LH responses were similar in group I diabetics and normal controls, whereas they were significantly lower in group II than in group I diabetics or normal controls. Positive correlations were found between LH responses to GnRH and naloxone, whereas negative correlations were observed between maximal LH peaks in response to GnRH or naloxone and duration of diabetes. These data indicate that a hypothalamic pituitary disorder affects LH secretion with time after the onset of IDDM.

Increase by naloxone of arginine vasopressin and oxytocin responses to insulin-induced hypoglycemia in obese men.

The present study was carried out to establish whether the low arginine vasopressin (AVP) and oxytocin (OT) responses to insulin-induced hypoglycemia observed in obese men was due to alteration of the opioid control of posterior pituitary function. For this purpose, the AVP and OT releasing effect of insulin (0.15 IU/kg bw)--induced hypoglycemia was tested in eight normal weight men and in 10 age-matched obese subjects, without and with the previous treatment with the specific opioid receptor antagonist naloxone (3 mg in an iv bolus). In a control study, naloxone was given alone to the same subjects. Obese men showed similar basal glucose, AVP and OT levels, which remained unmodified after treatment with naloxone alone. Insulin induced a similar decrement of blood glucose levels in all subjects, with a nadir at 30 min. Plasma levels of AVP and OT rose strikingly in normal and obese subjects with mean peak responses at 30 min for AVP and at 45 min for OT. However, both AVP and OT responses were significantly lower in obese than in control subjects. Pretreatment with naloxone did not modify the AVP and OT responses to hypoglycemia in normal weight subjects, whereas it significantly enhanced both hormonal responses in obese subjects. In the presence of naloxone normal controls and obese subjects showed similar responses of both AVP and OT to hypoglycemia. These data indicate that an abnormal activity of endogenous opioids might account for the hypothalamic posterior pituitary dysfunction, which is responsible for the low AVP and OT responses to insulin-induced hypoglycemia in obesity.

Reduced sensitivity to pirenzepine-induced blockade of growth hormone responses to arginine, exercise, and growth hormone-releasing hormone in type I diabetic subjects.

The present study was performed to establish whether the mechanism by which the cholinergic system influences growth hormone (GH) release was altered in type I diabetic patients. Therefore, we investigated in a dose-response fashion the inhibitory effect of the muscarinic cholinergic receptor antagonist pirenzepine on the GH responses to arginine infusion (30 g infused intravenously (IV) in 30 minutes), exercise (bicycle ergometer test at an intensity of 75 W for 30 minutes), or 1-44 GH-releasing hormone (GHRH) (1 microgram/kg in an IV bolus). In a preliminary study, IV injection of 17.5 mg pirenzepine failed to produce modification in the GH response to arginine infusion in both diabetic (N = 4) and normal subjects (N = 4), and to exercise (diabetics, N = 4; normals, N = 4). Therefore, other subjects were tested without and with 20, 25, and 30 mg pirenzepine during arginine (diabetics, N = 7; normals, N = 7) or exercise (diabetics, N = 7; normals, N = 7) tests. Each subject was tested four times. Diabetic patients presented higher GH responses to stimulation with arginine or exercise than normal controls. In both groups, pirenzepine administered at doses ranging from 20 to 30 mg produced a dose-related inhibition of the GH response to arginine and exercise, which was almost complete when 30 mg pirenzepine was administered. However, the percent inhibition produced by 20 or 25 mg pirenzepine in the arginine test and by 20 mg in the exercise test was significantly lower in the diabetic patients than in the normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)