Acute effect of the somatostatin analogue SMS-201995 on plasma glucose and triglycerides in insulin-dependent diabetic patients.

1. The effect of the long-acting somatostatin analogue SMS-201995 on diabetes control was assessed in 6 insulin-dependent diabetic patients (3 men and 3 women aged 19-38 years). 2. Plasma glucose and triglyceride profiles were obtained on 4 consecutive days, from 8:00 a.m. to 2:00 p.m. On the first 2 days the patients received their usual dose of insulin and ate at 8:00 a.m. and at noon. On the third and fourth days they received 1/3 of their usual insulin dose together with 100 micrograms SMS-201995 injected subcutaneously. 3. Postprandial glucose and triglyceride increases were blunted during the 360 min of observation on both days after SMS-201995 administration. The areas under the glucose-time plots fell from 23.72 +/- 12.29 (mean +/- SD) to 7.98 +/- 14.26 (P < 0.05) and the areas under the triglyceride-time plots from 10.51 +/- 9.01 to -3.15 +/- 4.30 g.min.dl-1 (P < 0.01). 4. No adverse reactions were observed after SMS-201995 administration for 2 days. 5. We conclude that administration of the somatostatin analogue SMS-201995 may be beneficial for insulin-dependent diabetic patients.

Acute effect of the somatostatin analogue sms-201995 on plasma glucose and triglycerides in insulin-dependent diabetic patients

The effect of the long-acting somatostatin analogue SMS-201995 on diabetes control was assessed in 6 insulin-dependent diabetic patients (3 men and 3 women agged 19-38 years). Plasma glucose and triglyceride profiles were obtained ion 4 consecutive days, from 8:00 a.m. to 2:00 p. m. On the first 2 days the patients received their usual dose of insulin and ate at 8:00 a. m. and noon. On the third and fourth days they received 1/3 of their usual insulin dose together with 100 ug SMS-201995 injected subcutaneously. Postprandial glucose and triglyceride increases were blunted during the 360 min of observation on both day after SMS-201995 administration. The areas under the glucose-time plots fell from 23.72 ñ 12.29 (mean ñ SD) to 7.98 ñ 14.26 (P<0.05) and the areas under the triglyceride-time plots from 10.51 ñ 9.01 to -3.15 ñ 4.30 g. min.dl-1 (P<0.01). No adverse rfeactions were observed after SMS-201995 administration for 2 days. We conclude that administration of the somatostatin analogue SMS-201995 may be beneficial for insulin-dependent diabetic patients

Regulaçäo dos receptores de glicocorticóide em leucócitos mononucleares humanos / Glucocorticoid receptores of human mononuclear leukocytes

O presente estudo foi realizado com a finalidade de analisar receptores de glicocorticóide em leucócitos mononucleares (MNL) de sangue periférico de indivíduos normais, näo tratados e de indivíduos normal aos quais foram administrados exogenamente os corticóides: prednisona e deflazacort. MNL de mulheres e homens normais apresentaram uma concentraçäo de receptores de glicocorticóide de 7,52 ñ 2,5fMol/10**6 cel e uma constante de dissociaçäo (Kd) de 9,5 ñ 2,3nM. Näo houve diferença em relaçäo ao sexo e as fases do ciclo menstrual. Em indivíduos tratados com predinisona, näo houve mudança nos parâmetros de ligaçäo. A administraçäo deflazacort determinou uma sensível reduçäo dos sítios de ligaçäo. Concluímos que certos glicocorticóides podem exercer um efeito regulatório sobre seus receptores

Comparison of the subacute effects of a new glucocorticoid, deflazacort, and prednisone on the hypothalamic-pituitary-adrenal axis of normal subjects.

The effects of deflazacort (DFL), a new oxazoline derivative of prednisolone, were compared with those of prednisone (Pd) by measuring plasma cortisol (F) levels as an index of the function of the hypothalamic-pituitary-adrenal (HPA) axis. Twelve normal volunteers received each glucocorticoid for 16 to 24 days in a double-blind cross-over trial with random allocation of subjects to treatment with DFL (24 mg/day) and Pd (20 mg/day) in clinically equivalent doses, with a washout period from 20 to 45 days between administration of the glucocorticoids. The following tests were performed in a randomized sequence: cortisol (F) circadian rhythm, insulin tolerance test (ITT), lysine-vasopressin (LVP) and B1-24 ACTH stimulation. Despite basal F suppression by DFL, the relative maximum F response (maximum F increment above basal/basal x 100) was significantly greater than control for the ITT and ACTH tests and was similar to the control after intramuscular injection of LVP, suggesting that the responses were appropriate for the basal F levels, with the HPA being reset at a lower level. After Pd, despite higher basal F levels, the F diurnal rhythm disappeared and there was no significant response to ITT, LVP or ACTH, indicating that the limiting factor in the HPA response was the reduced adrenal F production independent of the effects on the steroid-sensitive tissues of the brain including the pituitary.

Regulation of the glucocorticoid receptor by glucocorticoids in human mononuclear leukocytes.

We analyzed glucocorticoid receptor binding in peripheral blood mononuclear leukocytes from normal adult males and from females at the follicular and luteal phases. Healthy controls were analyzed before and after 17 days of treatment with two synthetic glucocorticoids: prednisone and an oxazoline derivative of prednisolone (deflazacort). We also studied for comparison 4 patients with adrenocortical insufficiency, two of them on long-term corticoid replacement, and 7 patients with Cushing's syndrome. Using a whole-cell competitive binding assay and 3H-dexamethasone as tracer, normal human mononuclear leukocytes (19 males, 6 females) were found to have 4,529 +/- 1,532 (mean +/- SD) binding sites per cell and a dissociation constant (Kd) of 9.5 +/- 2.3 nM. In Cushing's syndrome the receptor parameters were within the normal range. Cells from patients with untreated Addison's disease had low levels of sites per cell. The number of binding sites increased to normal after long-term glucocorticoid replacement. All the adrenal insufficiency cases had a normal Kd. Finally, following treatment with the synthetic glucocorticoid, deflazacort, the sites per cell were reduced but the Kd remained unchanged. Prednisone had no effects.

Plasma glucagon suppressibility after oral glucose in obese subjects with normal and impaired glucose tolerance.

Blood glucose, plasma insulin, and glucagon responses after a 75 g oral glucose-tolerance test were assessed in 9 normal controls, 5 obese nondiabetics (ON), 5 obese nondiabetics with fasting hyperinsulinemia (obese "resistant" nondiabetics--OR), 9 obese with impaired glucose tolerance (O-IGT), and 9 nonobese insulin-dependent diabetics (IDD). Fasting plasma glucagon concentrations were significantly higher in all groups of patients in comparison to the normal controls. Insulin secretion, evaluated in all but the IDD, was similar to normal in the ON and increased in the OR and O-IGT. Normal glucagon suppression was observed in the lean controls and ON but not in OR, O-IGT, and IDD. We suggested that the resistance to glucagon suppression after glucose load in the OR and O-IGT in the presence of increased insulin response could be an indication that the A cell participates in the relative insulin insensitivity of these subjects.

Dissociated effects of somatostatin analogs on arginine-induced insulin, glucagon and growth hormone release in acromegalic patients.

Two analogs of somatostatin (Ala2,D-Trp8,D-Cys14-Somatostatin and L-5F-Trp8-Somatostatin) infused into acromegalics at the rate of 4.5 micrograms/min suppressed arginine-stimulated growth hormone release more strongly than 6 micrograms/min somatostatin (110 +/- 11% and 129 +/- 14%, respectively). Under the same conditions the two somatostatin analogs induced a much smaller inhibition of insulin (33 +/- 13% and 44 +/- 18%) and glucagon (28 +/- 10% and 45 +/- 17%, respectively) release than somatostatin did. Somatostatin analogs with dissociated actions could be promising for the treatment of diseases such as acromegaly, diabetes mellitus and some ectopic hormone syndromes.

Evaluation of resection of pituitary microadenoma for the treatment of Cushing's disease in patients with radiologically normal sella turcica.

Six patients with Cushing's disease and a radiologically normal sella turcica have been treated by transsphenoidal hypophysectomy. Microadenomas were found and removed in five. One patient was in complete remission by 2 months and three by 6 months post-operatively. Two of the remaining patients (one with and the other without a surgically demonstrable tumour) were not cured after 8 and 15 months follow-up, respectively. Our data suggest that pituitary tumours are present in the majority of patients with Cushing's disease. The possibilities of incomplete adenomectomy or of a tumour buried within the gland should be considered in patients in whom pituitary surgery does not induce remission. In one patient, subsequently proven to have a pituitary adenoma, the disease remitted pre-operatively with cyproheptadine, suggesting hypothalamic regulation of the tumour and/or direct drug action at the pituitary level.

Human growth hormone (hGH) stimulation tests: the sequential exercise and L-dopa procedure.

Forty-eight normal volunteers, thirteen subjects with short stature without apparent cause and thirty-one patients with delayed growth clinically highly suggestive of growth hormone deficiency (GHD), with chronological ages of 11.4 +/- 0.4 years (mean +/- SEM), 14.0 +/- 0.7 years and 12.8 +/- 0.8 years; height age of 11.0 +/- 0.4 years, 8.9 +/- 0.7 years and 6.3 +/- 0.4 years and bone age of 10.7 +/- 0.7 years, 9.9 +/- 0.8 years and 7.5 +/- 0.7 years respectively, were tested with provocative tests of human growth hormone (hGH) release-insulin-induced hypoglycaemia, arginine infusion, L-DOPA, exercise and sequential exercise and L-DOPA--in order to identify growth hormone deficiency. In the 'normal' subjects (control plus short stature) the sequential exercise and L-DOPA test induced the greatest peak and integrated secretion rates of plasma hGH (16.5 +- 1.2 ng/ml and 679 +/- 70 ng/ml/120 min respectively) when compared to other tests. This combined stumulus was the only one to which all 'normal' subjects responded: a similar degree of responsiveness has not been earlier described for other hGH-stimuli. The responses observed with all stimuli were significantly lower (P less than 0.001) in GHD group compared to the 'normal subjects'. Emphasis was given to the sequential exercise and L-DOPA test as an innocuous, sensitive and simplified procedure in the evaluation of children with growth retardation.

The effect of serum ionized calcium elevation on somatostatin inhibition of glucose-induced insulin release in humans.

The effect of somatostatin on the insulin response to an acute intravenous glucose load was studied in five normal subjects before and after induction hypercalcaemia. In the normocalcaemic state, the insulin response to glucose was depressed by somatostatin. In the hypercalcaemic state, insulin responses to glucose in the presence of somatostatin, were partially restored and appeared to be related to the level of increment of serum ionized calcium. It is concluded that, in the human being, hypercalcaemia and somatostatin have opposite actions on glucose-stimulated insulin secretion.

The adrenal response to exogenous adrenocorticotrophin in patients with infections due to Neisseria meningitidis.

The adrenal response to a soluble form of beta1-24-corticotropin (tetracosactrin [ACTH]: 250 microgram administered intramuscularly) was studied in 28 patients with meningitis due to Neisseria meningitidis (21 with petechiae and seven without) and in six patients with Salmonella typhi bacteremia. Six normal subjects also were tested for adrenal responsiveness at four different times of the day (8 A.M., 12 noon, 4 P.M., and 10 P.M.) and served as controls. The results showed that, whatever the time of testing, patients with meningococcal infections and typhoid fever had unstimulated (basal) levels of plasma cortisol above the 99% confidence limits for the mean unstimulated cortisol levels for the normal subjects. Furthermore, although patients with meningitis without petechiae and subjects with S. typhi bacteremia responded to ACTH stimulation in a manner similar to that of the normal subjects, most subjects with meningitis with petechiae did not have increased levels of plasma cortisol after treatment with ACTH. This lack of response could not be ascribed entirely to the higher basal levels of plasma cortisol in these patients. Patients with meningitis associated with petechiae may have a relatively decreased adrenal response to stimulation with exogenous ACTH.

Carbohydrate metabolism in thyrotoxicosis: studies on insulin secretion before and after remission from the hyperthyroid state.

The effects of thyrotoxicosis on insulin secretion were studied in 11 patients with Graves' disease and compared with the results obtained in 6 of the patients after they had attained clinical remission. Constant glucose infusion (CGI) and acute tolbutamide infusion (AIT) tests were chosen to investigate beta-cell function. For similar means of fasting plasma glucose, basal plasma insulin mean was significantly higher during thyrotoxicosis. During AIT, mean peak insulin was obtained earlier in the hyperthyroid state (2 min) than after remission (4 min), being its level higher in the hyperthyroid state. During CGI, early insulin responses to similar plasma glucose increments, were comparable for both hyper and euthyroid subjects. After 10 minutes of CGI, insulin concentrations in the hyperthyroid state did not increase as in the euthyroid state in spite of comparable increments of plasma glucose, being similar plateau insulin levels attained thereafter. These results suggest the presence of an insulin-resistant state in hyperthyroidism which may either disappear during a chronic glucose infusion and/or be accompanied by a deficient late glucose-induced insulin release.

Plasma insulin disappearance curve after intravenous insulin injection in human hyperthyroidism.

The disappearance curves of plasma insulin after intravenous injection of unlabelled pork insulin was studied in nine young female hyperthyroid subjects with Graves' disease and eleven young female normal subjects, who served as controls. Comparison of the curves by analysis of variance did not reveal statistical differences between them (F obtained = 2.8, F F 0.05 = 4.41), implying that there was no significant differences in the transference of injected insulin from plasma to the extra-vascular space between hyper- and euthyroid subjects. The results may suggest that the metabolism of insulin is not appreciably affected in hyperthyroidism.

Mechanism of action of phenethylbiguanide (phenformin) in man. III. interrelationship between ethanol and phenethylibiguanide (PBG) in normal and diabetic subjects.

A standard 4-hr ethanol infusion (236 mg/min) after a 3-day fast with and without phenformin (25 mg q.i.d.), with blood drawn every hour for 8 hr, was performed on five normal subjects, eight obese nondiabetics, seven obese chemical diabetics, and four nonobese diabetics. Control infusion induced in all subjects a decline in blood sugar levels during and/or after the alcohol challenge, with a parallel decrease in basal plasma insulin. Hypoglycemia and the decrease in insulin secretion were associated with increased plasma free fatty acid concentration. Addition of phenethylbiguanide (PBG) to the preparatory 3-day fast resulted in a greater drop in the blood glucose levels of the normal control subjects, obese and nonobese diabetics; in the obese nondiabetics, however, significantly lower degree of blood glucose decrease than control was elicited. Furthermore, obese nondiabetics altered their blood glucose-insulin interaction with apparent increased responsivess of the B cells of PBG. The results suggest that effects of phenformin on blood glucose levels are more dependent on the metabolic state of the patient than on a property of the drug itself.