Effect of acute reduction of free fatty acids by acipimox on growth hormone-releasing hormone-induced GH secretion in type 1 diabetic patients.

BACKGROUND: In type 1 diabetes mellitus (DM1), high GH basal levels and exaggerated responses to several stimuli have been described. Acipimox is an antilipolytic drug that produces an acute reduction of free fatty acids (FFA). The aim of this study was to evaluate the effect of the reduction of plasma FFA with acipimox, alone or in combination with GHRH, on GH secretion in DM1. METHODS: Six type 1 diabetic patients were studied (three women, three men), mean age of 30 +/- 2.1 years, body mass index (BMI) 23.1 +/- 1.5 kg/m2. As a control group, six normal healthy subjects of similar age, sex and weight were studied. Each patient and control received GHRH [1 microg/kg intravenously (i.v.) at min 180], acipimox (250 mg orally at min 0 and 120) and GHRH plus acipimox on three separated days. Subjects served as their own control. Blood samples were taken at appropriate intervals for determination of GH, FFA and glucose. RESULT: In control subjects, the GH area under the curve (AUC; microg/l x 120 min) was for acipimox-treated 1339 +/- 292 and 1528 +/- 330 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 3031 +/- 669, significantly greater than the response after acipimox alone (P<0.05) or GHRH alone (P<0.05). In diabetic patients, the GH AUC was for acipimox-treated 2516 +/- 606 and 1821 +/- 311 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 7311 +/- 1154, significantly greater than the response after acipimox alone (P<0.05) or GHRH alone (P<0.05). The GH response after acipimox was increased in diabetic when compared with normal (P<0.05), with a GH AUC of 1339 +/- 292 and 2515 +/- 606 for normal subjects and diabetic patients, respectively. The GH response after acipimox plus GHRH was increased in diabetic when compared with normal (P<0.05), with a GH AUC of 3031 +/- 669 and 7311 +/- 1154 for normal subjects and diabetic patients, respectively. The administration of acipimox induced a FFA reduction during the entire test. CONCLUSIONS: Reduction of free fatty acids with acipimox is a stimulus for GH secretion in DM1. The combined administration of GHRH plus acipimox induces a markedly increased GH secretion in type 1 diabetic patients when compared with normal subjects. These data suggest that patients with DM1 exhibit a greater GH secretory capacity than control subjects, despite the fact that endogenous FFA levels seems to exert a greater inhibitory effect on GH secretion in these patients.

Effect of withdrawal of somatostatin plus growth hormone (GH)-releasing hormone as a stimulus of GH secretion in Cushing's syndrome.

OBJECTIVE: Somatostatin (SS) may not merely be inhibitory to GH secretion but, under appropriate temporal conditions, may act in a paradoxically positive manner to sensitize somatotroph responsiveness to GHRH. SS infusion withdrawal (SSIW) produces a rebound GH rise in humans and increases GHRH-induced GH release. Theoretically SSIW leaves the somatotroph cell in a situation of low endogenous SS. In Cushing's syndrome, GH secretion appears blunted to all stimuli. The mechanisms by which glucocorticoids impair GH secretion in Cushing's syndrome are unknown. There are no data evaluating GH responsiveness to SSIW plus GHRH in Cushing's syndrome patients. The aim of the present study was to evaluate the GH response to SSIW plus GHRH in a group of Cushing's syndrome patients, in order to further understand the deranged GH secretory mechanisms in Cushing's syndrome. PATIENTS AND MEASUREMENTS: Eight female patients with Cushing's syndrome were studied. As a control group, eight normal subjects of similar age and sex were studied. Three tests were done. On one day, SS intravenous (i.v.) infusion (500 micro g for 0-90 min) was performed followed by placebo i.v. bolus at min 90 after SS withdrawal (SSIW). On another day, SS i.v. infusion (500 micro g for 0-90 min) was performed followed by GHRH (100 micro g) i.v. bolus at min 90 after SS withdrawal. On a third day, slow infusion of 150 mmol/l NaCl administration was performed followed by GHRH (100 micro g) i.v. bolus at min 90 after the start of the infusion. Blood samples were taken at appropriate intervals for determination of GH. RESULTS: GHRH-induced GH secretion in normal subjects showed a mean peak of 15.4 +/- 2.1 micro g/l (conversion factor: 1 micro g/l = 1.2 mUI/l). Normal control subjects had a mean peak of 3.3 +/- 1.6 micro g/l after SSIW-induced GH secretion. When GHRH was administered after SSIW there was increased GH secretion with a mean peak of 23.7 +/- 4.2 micro g/l significantly greater than the response after SSIW alone (P < 0.05) and GHRH alone (P < 0.05). The patients with Cushing's syndrome had a blunted GH response after GHRH administration with a mean peak of 1.4 +/- 0.4. After SSIW, Cushing's syndrome patients had a mean peak of 1.0 +/- 0.5 micro g/l. When GHRH was administered after SSIW there was a similar GH response with a mean peak of 1.7 +/- 0.6 micro g/l, not statistically different than the response after SSIW alone (P = ns) and GHRH alone (P = ns). When we compare the response of normal subjects and Cushing's syndrome patients, after SSIW plus GHRH, it was decreased in Cushing's syndrome patients (P < 0.05), with a mean GH peak of 23.7 +/- 4.2 micro g/l and 1.7 +/- 0.6 micro g/l for normal subjects and Cushing's syndrome patients, respectively. CONCLUSIONS: This study has demonstrated a significantly blunted peak GH response to somatostatin infusion withdrawal plus GHRH in Cushing's syndrome patients. In this theoretical situation of decreased somatostatinergic tone there is persistence of GH hyposecretion in Cushing's syndrome, suggesting the existence of a pituitary defect responsible for the decreased GH secretion in Cushing's syndrome.

Effect of withdrawal of somatostatin plus GH-releasing hormone as a stimulus of GH secretion in obesity.

OBJECTIVES: Somatostatin (SS) may not merely be inhibitory to GH secretion but, under appropriate temporal conditions, may act in a paradoxically positive manner to sensitize somatotroph responsiveness to GH-releasing hormone (GHRH). SS infusion withdrawal (SSIW) produces a rebound GH rise in humans and increases GHRH-induced GH release. Theoretically, SSIW leaves the somatotroph cell in a situation of low endogenous SS. In obesity, there is markedly decreased GH secretion. In both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli. It has been postulated that increased hypothalamic somatostatin secretion is the main mechanism responsible for the blunted GH secretion of obesity. There are no data evaluating GH responsiveness to SSIW plus GHRH in obese adults. The aim of the present study was to evaluate the GH response to SSIW plus GHRH in a group of control subjects and a group of obese patients. PATIENTS AND MEASUREMENTS: Seven obese patients (six female, one male) with a BMI of 36.1 +/- 7.7 kg/m2 were studied. As a control group, seven normal subjects (six female, one male) with a BMI of 20.3 +/- 0.9 kg/m2 were also studied. Two tests were performed. On one day, somatostatin (SS) i.v. infusion (500 microg from 0-90 min) was performed followed by a placebo i.v. bolus 90 min after SS withdrawal (SSIW). On another day, SS i.v. infusion (500 microg from 0-90 min) was performed followed by a GHRH (100 microg) i.v. bolus 90 min after SS withdrawal. A second group of seven obese patients (six female, one male) with a BMI of 32.2 +/- 2.3 kg/m2 were studied. As a second control group, seven normal healthy subjects (six female, one male) with a BMI of 20.1 +/- 0.6 kg/m2 were also studied. On one day, saline infusion was performed followed by a placebo i.v. bolus at 90 min. On another day, saline infusion was performed followed by a GHRH (100 microg) i.v. bolus at 90 min. Blood samples were taken at appropriate intervals for determination of GH. Serum GH was measured by chemiluminescent immunometric assay. Statistical analysis was performed by Wilcoxon and Mann-Whitney tests. RESULTS: GHRH-induced GH secretion in normal subjects showed a mean peak of 15.8 +/- 2.1 microg/l. Normal control subjects had a mean peak of 3.1 +/- 1.5 microg/l after SSIW-induced GH secretion. When GHRH was administered after SSIW there was an increased GH secretion with a mean peak of 23.3 +/- 4.4 microg/l, significantly greater than the response after SSIW alone (P < 0.05) and GHRH alone (P < 0.05). GHRH-induced GH secretion in obese patients was decreased with a mean peak of 3.9 +/- 1.5 microg/l. In obese patients, GH secretion after SSIW was markedly decreased with a mean peak of 1.0 +/- 0.4 microg/l. When GHRH was administered after SSIW, an increase in GH secretion was observed with a mean peak of 4.3 +/- 0.9 microg/l, significantly greater than SSIW alone (P < 0.05) but not GHRH alone (P = NS), and significantly less than in normal subjects (P < 0.05). CONCLUSIONS: This study demonstrates a significantly blunted peak GH response to somatostatin infusion withdrawal plus GHRH in obese patients compared to normal subjects. In this theoretical situation of decreased somatostatinergic tone, there is persistence of GH hyposecretion in obesity, suggesting the existence of multiple defects responsible for decreased GH secretion in obesity. We also found that in obese patients, in contrast to normal subjects, SSIW did not increase GHRH-induced GH secretion.