Gianni Giustina

Cardiopulmonary performance during exercise in acromegaly, and the effects of acute suppression of growth hormone hypersecretion with octreotide.

We studied 10 adult patients with active acromegaly (4 men and 6 women, mean age 55 +/- 5 years and mean body mass index 27.9 +/- 1.1 kg/m2). Control values for the echocardiographic and exercise studies were obtained from 10 normal subjects matched for sex and age (5 men and 5 women, age 51.1 +/- 3.7 years and body mass index 25.3 +/- 1 kg/m2). Each patient underwent: (1) blood sampling for growth hormone (GH) assay every 3 hours; (2) a 2-dimensional, guided M-mode echocardiographic study; and (3) a cycloergometric exercise test at baseline and after treatment with a portable pump infusing octreotide, 500 micrograms/24 hours subcutaneously. All patients had left ventricular hypertrophy. Systolic function indexes did not significantly differ among normal subjects, whereas baseline Doppler studies showed abnormalities in left ventricular diastolic filling in acromegalic patients. At anaerobic threshold and at maximal exercise, acromegalic subjects sustained a significantly (p < 0.05) decreased workload (54 +/- 23 vs 94 +/- 11 and 87 +/- 37 vs 152 +/- 15 W) compared with control subjects. After octreotide, baseline heart rate (79 +/- 7 vs 87 +/- 8 beats/min, p < 0.05) and serum GH levels significantly decreased compared with levels before administration of octreotide. Systolic and diastolic functional indexes at rest significantly improved after octrotide in acromegalic patients. Both at anaerobic threshold and at maximal exercise, workload and oxygen consumption were significantly increased after octretide administration. Exercise capacity at anaerobic threshold was not significantly different in acromegalic subjects after octreotide when compared with normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-Term Administration of Captopril and Nifedipine and Exercise-Induced Albuminuria in Normotensive Diabetic Patients With Early-Stage Nephropathy

Recent studies have demonstrated that short-term angiotensin converting enzyme (ACE) inhibition with captopril can reduce urinary albumin excretion rate (UAER) after exercise in normotensive diabetic patients with early-stage nephropathy. The aim of this study was to investigate whether this effect of ACE inhibition was due to a systemic hypotensive action or a specific action at the intrarenal level. Thus, we compared the acute effects of captopril and the Ca2+-channel blocker nifedipine on exercise-induced UAER in normotensive (blood pressure <165/95 mmHg) diabetic patients who were normoalbuminuric or microalbuminuric at rest (stage 2 or 3 of diabetic nephropathy). Twenty-five stage 2 diabetic nephropathy patients, 39 stage 3 diabetic nephropathy patients, and 12 nondiabetic subjects performed five submaximal cycloergometric exercises (90% of theoretical heart rate) on nonconsecutive days. The first two exercises were performed in basal conditions; the next three exercises were performed 24 h after administration of captopril (25 mg twice daily) or nifedipine AR (20 mg twice daily) or placebo (1 tablet twice daily) according to a randomized double-blind crossover trial. After placebo, blood pressure and UAER did not change at rest or 1 h after exercise. After captopril, blood pressure at rest and during exercise was similar to that observed after placebo. UAER at rest was not modified, whereas 1 h after exercise, it was significantly decreased both in stage 2 and stage 3 diabetic nephropathy patients (P < 0.001). After nifedipine, blood pressure decreased significantly at rest and during exercise in respect to placebo and captopril. UAER at rest did not change significantly. UAER 1 h after exercise was significantly decreased both in stage 2 and stage 3 diabetic nephropathy patients (P < 0.01 vs. placebo), but it was significantly higher than that observed after captopril (P < 0.01). Captopril is more effective than nifedipine in reducing exercise-induced UAER in normotensive diabetic patients even though it does not influence blood pressure response to exercise. The effects of captopril on UAER induced by exercise may be due to a specific action at the intrarenal level.

Cortisol secretion in patients on simvastatin

We have investigated the effects of simvastatin on adrenal function in 7 men and 3 women (mean age 53 years) affected by, or at high risk of, ischaemic heart disease and with heterozygous familial hypercholesterolaemia (FH). After eight weeks on the American Heart Association phase-I diet and placebo treatment, our patients received simvastatin as a single daily bedtime dose of 10 mg for six weeks, 20 mg for a further six weeks, followed by 40 mg for twelve weeks. A rapid adrenocorticotropic hormone (ACTH) test (intravenous tetracosactrin, 0.25 mg), blood being obtained for cortisol assay before and 30 and 60 min after injection, was done at the start, at week twelve, and at the end of simvastatin treatment

Low-dose octreotide is able to cause a maximal inhibition of the glycemic responses to a mixed meal in obese type 2 diabetic patients treated with insulin

Short-term studies have shown that octreotide, a long-acting somatostatin analog, blunts postprandial glycemic responses and reduces insulin requirement in insulin treated diabetic patients. The aim of our study was to investigate the effects of three single, different doses of octreotide on the glycemic response to a mixed meal in eight insulin treated type 2 diabetic patients after secondary failure with hypoglycemic agents. Previous treatments were substituted by regular insulin, 0.5 U/kg/day divided into three sc injections, for at least seven days. All patients received: (a) regular insulin (0.1 U/kg, sc) at 7.30 am; (b) octreotide 25 micrograms sc or (c) 50 micrograms sc or (d) 100 micrograms sc simultaneously with insulin but injected at different sites. From 8.00 to 8.15 the patients consumed a preconstituted fluid mixed meal of 250 ml. Following insulin alone a significant increase in blood glucose levels was observed after the meal. Abolished and not significantly different blood glucose responses to the meal after each of the three doses of octreotide were observed. Our findings suggest that with a low dose of octreotide (25 micrograms) it is possible to abolish the postprandial glycemic peak in type 2 diabetic patients treated with insulin.

Effect of a new long-acting somatostatin analogue (SMS 201-995) on glycemic and hormonal profiles in insulin-treated type II diabetic patients.

Five type II diabetic patients were studied after secondary failure of oral agents, with and without the addition of the new long-acting somatostatin analogue SMS 201–995 to an intermediate-acting insulin regimen. SMS 201–995 was administered twice daily, before breakfast and dinner, as 100 µg sc injections, and resulted in a lowering of plasma glucose, as well as of plasma glucagon and serum C-peptide levels. SMS 201–995 abolished postprandial glycemic and xylosemic peaks related to meals and to oral d-xylose when they were taken shortly after the administration of the analogue, while it had no effect on glycemic and xylosemic increments that followed the midday meal. The new somatostatin analogue improves glucose tolerance in type II diabetic patients, both by inhibiting counterregulatory hormones and by delaying and reducing intestinal absorption of nutrients. Its administration could lead to a reduction of daily insulin requirements. Our findings indicate that SMS 201–995 may have a role as an adjunct to insulin in the management of type II diabetic patients after secondary failure of oral agents.

Hypothalamic control of growth hormone (GH) secretion in type i diabetic men: Effect of the combined administration of gh-releasing hormone and hexarelin, a novel GHRP-6 analog.

Insulin dependent (type I) diabetic patients show abnormal growth hormone (GH) secretion. Hexarelin is an analog of GHRP-6 which releases GH in part via somatostatin inhibition. The aim of our study was to evaluate the effects of hexarelin and GHRH, administered either alone or in combination, on GH secretion in 10 type I diabetic and 7 normal men. All the subjects were administered: 1) human GHRH (1-29) NH2 100 micrograms i.v. bolus at 0 min; 2) hexarelin 100 micrograms i.v. bolus at 0 min; 3) hexarelin 100 micrograms + hGHRH 100 micrograms i.v. bolus at 0 min. In type I diabetic patients significantly greater GH responses to GHRH and hexarelin have been observed with normal subjects. Hexarelin caused a significantly (p < 0.05) greater GH response as compared to GHRH in both diabetic and control subjects. After the administration of hexarelin+GHRH, a significant increase in both GH absolute and peak levels as compared to hexarelin or GHRH alone was found in all the subjects. However, the GH responses to the combined stimuli were not significantly different in diabetics as compared to normals; moreover, the interaction of GHRH and hexarelin was synergistic in controls and additive in diabetics. We hypothesize that a reduction in the hypothalamic somatostatin inhibitory tone combined with increased pituitary GH production may be responsible for the pattern of the GH responses to hexarelin and GHRH observed in our type I diabetic patients.

Effect of glucocorticoids on the paradoxical growth hormone response to thyrotropin-releasing hormone in patients with acromegaly

It has been hypothesized that in acromegalic patients, as well as in normal subjects, acute increases in serum cortisol levels may cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid-mediated growth hormone (GH) inhibition. The aim of this study was to investigate short-term effects of an intravenous (i.v.) infusion of hydrocortisone on the GH response to thyrotropin-releasing hormone (TRH) in acromegaly. We studied six adult patients with active acromegaly. The group was composed of four women and two men with a mean age of 55.8 +/- 6.4 years (range, 27 to 68) and a mean body mass index of 26.7 +/- 1 kg/m2 (range, 23.3 to 30). All patients underwent the following treatments: (1) hydrocortisone alone: a bolus i.v. injection of hydrocortisone succinate 100 mg in 2 mL saline at time -60 minutes, followed by a 120-minute i.v. infusion of hydrocortisone succinate 250 mg in 250 mL saline from -60 to 60 minutes; (2) TRH+hydrocortisone: a bolus i.v. injection of TRH 200 micrograms 60 minutes after initiation of a 2-hour hydrocortisone infusion; (3) TRH alone: a bolus i.v. injection of TRH at time 0, 60 minutes after initiation of a 2-hour saline infusion. In all six patients, TRH induced large GH increases (absolute peak GH level, 58.1 +/- 23.2 micrograms/L; maximum % GH change with respect to baseline, 1,397.8% +/- 807.8%; range, 205% +/- 5,219%).(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term effect of captopril and nifedipine on micro-albuminuria induced by exercise in hypertensive diabetic patients.

Physical exercise can induce micro-albuminuria, a urinary albumin excretion rate of 20-200 micrograms/min, in diabetics without micro-albuminuria at rest (stage II of diabetic nephropathy). The aim of the present study was to evaluate the acute effects of captopril, an angiotensin converting enzyme (ACE) inhibitor, and nifedipine, a calcium channel blocker, on exercise-induced micro-albuminuria in hypertensive diabetics with stage II nephropathy. Eleven hypertensive World Health Organisation (WHO) stages I-II non-obese diabetics (five insulin-dependent diabetics, six non-insulin dependent diabetics) underwent five submaximal cycloergometric tests, the first two in basal conditions, the other three after 24-h administration of captopril (25 mg twice a day), placebo (1 tablet twice a day) or nifedipine AR (20 mg twice a day) according to a randomized double-blind design. Our results demonstrate that despite a lower reduction in exercise blood pressure, captopril is more effective than nifedipine in blunting diabetic exercise-induced micro-albuminuria.

SMS 201-995 Improves Glucose Tolerance in Insulin-Treated Type II Diabetic Patients

cardiac routing of several drugs can be useful in cardiac arrest when peripheral or central drip are ineffective. In our patient, intracardiac insulin puncture, an undescribed type of treatment, was presumptively effective to locally decrease K levels so that myocardial membrane depolarizations reverted and sinusal rhythm could be restored. After this experience, we consider that intracardiac injection of regular insulin may be an additional treatment of cardiac arrest due to hyperkalemia, especially if it coexists with hyperglycemia.

Effect of galanin on the growth hormone response to growth hormone-releasing hormone in acromegaly.

Galanin enhances growth hormone (GH)-releasing hormone (GHRH)-stimulated GH secretion in normal man. In acromegaly, circulating GH levels are increased and the GH response to GHRH may be exaggerated. Galanin has been recently shown to decrease circulating GH levels in acromegaly. The aim of our study was to investigate the effects of galanin on the GH response to GHRH in acromegalic subjects. Five acromegalic patients (three men and two women) and seven healthy adult subjects (five men and two women) were studied. GHRH-induced GH secretion was evaluated during a 40-minute intravenous (IV) infusion of saline (100 mL) or porcine galanin (12.5 micrograms/min in 100 mL saline). In normal subjects, delta GH levels after GHRH+porcine galanin administration (47 +/- 7.5 micrograms/L) were significantly higher in comparison to levels obtained with GHRH+saline (21.7 +/- 3.5 micrograms/L, P < .05). In acromegalic patients, GH responses to GHRH (delta GH, 18.8 +/- 8.6 micrograms/L) were not altered by galanin infusion (delta GH, 17.6 +/- 5 micrograms/L). Our results give the first evidence that the same dose of galanin that induces a significant enhancement of the GH response to GHRH in normal subjects has no effect on the GH response to GHRH in acromegalic patients. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by somatotropes independent of GHRH. Failure of galanin to enhance GH response to GHRH in acromegalic patients could be due to a change in function of the galanin receptor on GH-secreting adenomatous cells.