A. Dubini

Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man

The high concentrations of gamma aminobutyric acid (GABA) in the pancreatic islets and the neurotransmitter role played by this amino acid in the central nervous system, make it plausible that GABA also intervenes in the control of endocrine pancreatic function. In 12 normal subjects, a single oral dose of 5 or 10 g GABA, as compared to placebo, caused a significant (p less than 0.01) and dose-dependent (p less than 0.01) increase of plasma levels of immunoreactive insulin, C peptide and glucagon, without affecting plasma glucose concentration. By contrast, in 15 additional subjects, a single oral dose of 5 mg muscimol, a specific GABA receptor agonist, did not consistently influence the above parameters. Although the lack of effects of muscimol might indicate that the action of GABA is not mediated through specific receptors, the results with GABA suggest that this amino acid plays a specific role in the regulation of endocrine pancreatic function.

Impaired prolactin secretion in obese patients

To investigate a possible hypothalamic alteration in obesity, we have studied the pattern of PRL secretion in response to insulin hypoglycemia, arginine infusion and TRH injection in 12 grossly obese patients and in 12 normal-weight controls. In the obese patients, PRL secretion was significantly lower than in normal subjects in response to insulin hypoglycemia and arginine infusion, while it was not significantly different from that in controls in response to TRH. The mean ± SE values of the areas subtended by the PRL curves in the 3 above tests were 54.7 ± 155.81 vs 3677.3 ± 520.30 ng/2h,p<0,01, 210.3 ± 148.93 vs 1034.8 ± 203.15 ng/2h, p<0.05 and 1476.8 ±275.13 vs 2148.6 ± 682.06 ng/2h, NS, respectively, in the obese and in controls. These results are compatible with the concept of impaired hypothalamic control of PRL secretion in obesity, although it is still unclear what role this may play in the pathogenesis of this disorder.

Enhanced prolactin responsiveness to galanin in patients with Cushing's disease

OBJECTIVE Galanin is believed to play a role in the control of prolactin (PRL) secretion in the rat. Such a role is uncertain in humans where the neuropeptide is expressed by the corticotrophs. However, in clinical conditions of enhanced ACTH secretion, increased PRL levels are often observed. Therefore, we evaluated the effect of galanin infusion on serum PRL levels in patients with Cushings disease and in control subjects. For comparison, the PRL responses to TRH and metoclopramide were also investigated in the same patients.

Evaluation of hypothalamic-pituitary function in patients with thalassemia major

The increased survival of patients with thalassemia major, made possible by more adequate therapeutic regimens, has emphasized the importance of the endocrine abnormalities often associated with this disease. In twelve thalassemic patients, we evaluated the hypothalamic- pituitary function by measuring plasma levels of anterior pituitary hormones under basal conditions and in the course of provocative tests. An impairment of growth hormone (GH) secretion was demonstrated in a considerable proportion (7/12) of these patients. In some of them failure of GH response to insulin-hypoglycemia and normal hormone rise after growth hormone-releasing hormone indicate a hypothalamic defect. A defective prolactin secretion was observed in the female hypogonadic but not in the male thalassemic patients. This abnormality appears to be dependent on estrogen deficiency rather than on a hypothalamic-pituitary dysfunction. In our series a high prevalence (8/12) of hypogonadism was also noticed. In these cases, the low gonadotropin levels and their unresponsiveness to gonadotropin-releasing hormone are compatible with a hypothalamic and/or pituitary damage. Lastly, the enhanced ACTH responses to the stimuli associated to a reduced Cortisol release suggest the existence, in these patients, of a diminished adrenocortical reserve. On the whole, this study has shown several derangements of the hypothalamic-pituitary function in thalassemia. This emphasizes the need for careful endocrine surveillance in this disease.

The Serum Concentration of Tumor Necrosis Factor Alpha Is Not an Index of Growth-Hormone- or Obesity-Induced Insulin Resistance

Backgound: The tumor necrosis factor alpha (TNF-α) might play a central role in insulin resistance, a frequent correlate of obesity likely contributing to some obesity-associated complications. Adult growth hormone (GH) deficiency syndrome (GHDA) shares with obesity excessive fat mass, hyperlipidemia, increased cardiovascular risk, and insulin resistance. On the other hand, GH has been shown to induce transient deterioration of glucose metabolism and insulin resistance when administered in normal humans and in GHDA patients. No information is presently available on the relationship between serum TNF-α levels and insulin sensitivity in GHDA. Methods: We compared the serum TNF-α levels found in 10 GHDA patients before and after a 6-month recombinant human GH therapy (Genotropin), in an insulin resistance prone population of 16 obese (OB) patients and in 38 normal-weight healthy blood donors (controls). The insulin sensitivity was assessed by a euglycemic-hyperinsulinemic glucose clamp in all the GHDA patients and in 10 OB and in 6 control subjects. Results: The serum TNF-α levels were not significantly different in OB patients (42.2 ± 12.81 pg/ml), in GHDA patients at baseline (71.3 ± 23.97 pg/ml), and in controls (55.3 ± 14.28 pg/ml). A slight decrease of TNF-α values was noted in GHDA patients after 6 months of recombinant human GH treatment (44.5 ± 20.19 pg/ml; NS vs. baseline). The insulin sensitivity (M) was significantly reduced in OB patients (2.4 ± 0.30 mg/kg/min) as compared with control subjects (7.5 ± 0.39 mg/kg/min) and in GHDA patients both at baseline (6.6 ± 0.6 mg/kg/min) and after recombinant human GH therapy (5.6 ± 0.7 mg/kg/min). The insulin sensitivity in the GHDA patients, similar to that of controls at baseline, worsened after recombinant human GH treatment (p < 0.05 vs. baseline; p = 0.05 vs. controls). Linear regression analysis showed no correlation between TNF-α and M values (see text) in all patient groups. Conclusions: These data indicate that circulating concentrations of TNF-α do not reflect the degree of insulin resistance in obesity and GHDA. They, however, do not exclude that TNF-α may induce insulin resistance at tissue level.

Effect of small doses of dexamethasone on plasma leptin levels in normal and obese subjects: A dose-response study

To further elucidate the role of glucocorticoids in the regulation of leptin secretion, we studied the effects of overnight small doses of dexamethasone on plasma leptin levels in normal weight controls and in obese patients and correlated the results with indexes of insulin sensitivity and body fat distribution. In 114 subjects (81 obese patients, 49 women and 32 men, BMI 37.4±0.77 kg/m2 and 33 normal-weight subjects, 17 women and 16 men, BMI 22.1±0.41 kg/m2) plasma F and leptin levels were measured at 08:00 h basally and after the administration of different doses of dexamethasone (a fixed dose of 1-mg and 0.0035, 0.007, 0.015-mg/kg bw, given po at 23:00 h the night before). Tests were performed one week apart with bw remaining stable over the study period. Basal leptin levels were significantly higher in obese than in normal subjects (31.9±2.41 vs 7.7±0.93 ng/ml, p<0.0001). In obese patients, leptin levels increased significantly by 1-mg (from 31.9±2.41 to 35.0±2.59 ng/ml, p<0.005) and the 0.015-mg/kg bw dose (from 31.5±2.34 to 33.7±2.44 ng/ml, p<0.05), while they were unaffected by each dose of dexamethasone in normal subjects. However, after splitting subjects by gender, mean leptin levels rose from 39.3±2.97 to 43.3±3.12 ng/ml after the 1-mg dose, p<0.005, from 39.1±2.87 to 43.6±2.91 ng/ml after the 0.015-mg/kg bw dose, p<0.005, from 39.3±2.90 to 42.2±2.90 ng/ml after the 0.007-mg/kg bw dose, p<0.05 and from 38.8±2.66 to 41.1±2.87 ng/ml after the 0.0035-mg/kg bw dose, p=0.055, only in obese women. Conversely, no leptin changes were seen in the other groups and no differences were observed in the leptin response between groups. After the 1-mg dose, in the whole group, the absolute leptin variation was weakly but significantly related to BMI values (r=0.231, p<0.02) while in all sessions the percent leptin changes over baseline were not significantly correlated with age, BMI, waist, WHR, insulin, HOMA index, a marker of insulin sensitivity, plasma dexamethasone concentrations and to the percent cortisol variation following dexamethasone. In conclusion, in obese women but not in obese men and in normal weight subjects, small overnight increases in plasma glucocorticoid concentrations induced gender-related plasma leptin elevations that were unrelated to body fat distribution and insulin sensitivity. A greater sensitivity of female adipose tissue to glucocorticoids probably underlies this sexually dimorphic pattern of leptin response. These findings provide an additional piece of information on the regulation of leptin secretion exerted by glucocorticoids.

Four year treatment with a long acting somatostatin analogue in a patient with Verner-Morrison syndrome

The case is described of a woman with a Verner-Morrison syndrome of extreme severity, caused by an occult VIPoma. Administration of SMS 201–995 (Sandoz) (SMS) at the dose of 150 and subsequently of 250 µg daily, decreased plasma levels of vasoactive intestinal polypeptide (VIP) from about 500 to 100 pg/ml (highest normal limit 60 pg/ml). This was associated with complete regression of the diarrhea and normalization of serum potassium levels and hence with the return of the patient to a fully normal life. After 36 months of clinical remission, watery diarrhea recurred together with elevation of VIP plasma levels and appearance of liver metastases. Laparotomic exploration led to the removal of a pancreatic VIPoma and its liver secondarisms, which was followed by a second remission. Reappearance of the symptoms and development of new liver metastases 8 months later required reinstitution of SMS therapy, which allowed once again to control the clinical picture. Anterior pituitary function, assessed by dynamic testing, was unaffected by chronic SMS administration with the exception of the stimulated growth hormone secretion that was inhibited. Glucose tolerance and insulin secretion remained normal during treatment. Glucose intolerance ensued after pancreatectomy and was not worsened by reintroduction of SMS. Treatment with SMS may allow long-lasting remission of Verner-Morrison syndrome associated to VIPoma, though it does not arrest the progression of the tumor.

Effect of chronic treatment with biosynthetic growth hormone (GH) on the GH response to double GH-releasing hormone administration in children with short stature

Growth hormone (GH) exerts a negative feedback on its own secretion through direct and indirect mechanisms. Normal children, unlike adults, display consecutive GH responses after repeated GH-releasing hormone (GHRH) administration. In this study, we investigated the effects of long-term GH administration on this peculiar secretory pattern. Eight children with severe short stature and impaired GH responses to suprapituitary provocative stimuli associated with normal GH responsiveness to GHRH, underwent, while on chronic treatment with biosynthetic GH and on the 10th day following drug withdrawal, a double bolus GHRH test (two GHRH injections of 1 μg/kg b.w. given as i.v. boluses two hours apart). During GH therapy the GH response to the first GHRH bolus appeared to be reduced, though not significantly so, compared to that observed at diagnosis; after treatment withdrawal, this response returned quite similar to pretreatment. Both during and after treatment, the GH response to the second GHRH bolus was comparable for magnitude to that evoked by the first application. In conclusion, even prolonged treatments with rhGH do not induce persisting alterations of the physiological mechanisms subserving GH regulation.

Inhibition by phospholipid liposomes of the prolactin and cortisol response to insulin hypoglycemia in man

This study was designed to further investigate the purported dopaminergic activity of phospholipid liposomes (PL) prepared from bovine cerebral extracts, and to obtain further indications about their pituitary or suprapituitary site of action. In eight normal subjects, we have studied the effects of PL administration (250 mg as IV bolus plus additional 250 mg infused IV over a 60-min period), compared to placebo, on the prolactin (PRL), cortisol and growth hormone (GH) response to an insulin tolerance test (ITT). In eight additional subjects, the effects of PL on the PRL and TSH response to TRH were evaluated. PL medication blunted the PRL and cortisol response in the ITT: significant differences, with respect to placebo administration, were observed between mean peak PRL values (51.9±13.63 SEM vs 83.4±26.35 ng/ml, P<0.05) and mean cortisol values at 120 min time (20.9±0.67 vs 26.7±2.46 μg/dl, P<0.05). In contrast, PL administration did not modify the ITT-related GH rise or the PRL and TSH release in response to TRH. These findings favour the view that PL are endowed with intrinsic biological activity which is dopamine-mediated, and point to the hypothalamus as their primary site of action.