acipimox and Hypopituitarism

Glucagon-like peptide-1 (GLP-1) is an incretin hormone used therapeutically in type 2 diabetes and obesity. The interplay between ambient free fatty acids (FFAs) and GLP-1 remains unclear. Acipimox suppresses adipose tissue lipolysis via activation of the PUMA-G (also known as HCA2 and GPR109a) receptor.. To investigate whether lowering of serum FFA level with acipimox affects GLP-1 secretion.. Two randomized crossover studies were performed in human subjects. Rat intestine was perfused intra-arterially and intraluminally, and l-cells were incubated with acipimox.. The participants were healthy overweight subjects and hypopituitary adult patients.. The overweight participants received acipimox 250 mg 60 minutes before an oral glucose test. The hypopituitary patients received acipimox 250 mg 12, 9, and 2 hours before and during the metabolic study day, when they were studied in the basal state and during a hyperinsulinemic euglycemic clamp.. Acipimox suppressed FFA but did not affect insulin in the clinical trials. In overweight subjects, the GLP-1 increase after the oral glucose tolerance test (area under the curve) was more than doubled [4119 ± 607 pmol/L × min (Acipimox) vs 1973 ± 375 pmol/L × min (control), P = 0.004]. In hypopituitary patients, acipimox improved insulin sensitivity (4.7 ± 0.8 mg glucose/kg/min (Acipimox) vs 3.1 ± 0.5 mg glucose/kg/min (control), P = 0.005], and GLP-1 concentrations increased ~40%. An inverse correlation between FFA and GLP-1 concentrations existed in both trials. In rat intestine, acipimox did not affect GLP-1 secretion, and l-cells did not consistently express the putative receptor for acipimox.. Acipimox treatment increases systemic GLP-1 levels in both obese subjects and hypopituitary patients. Our in vitro data indicate that the underlying mechanisms are indirect.

Topics: Adult; Animals; Blood Glucose; Cells, Cultured; Cross-Over Studies; Enteroendocrine Cells; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypolipidemic Agents; Hypopituitarism; Insulin Resistance; Intestinal Mucosa; Lipolysis; Male; Middle Aged; Overweight; Pilot Projects; Primary Cell Culture; Pyrazines; Rats

The nicotinic acid analogue acipimox is an antilipolytic agent, which acutely inhibits lipolysis and suppresses systemic levels of free fatty acids (FFA) and improves insulin sensitivity in obese patients. These effects of acipimox are transient due to a counter-regulatory increase in growth hormone levels that reverse the antilipolytic effect of acipimox. Hypopituitary patients constitute a viable model to study the growth hormone-independent effects of acipimox and the impact of isolated changes in FFA concentrations and insulin sensitivity on parasympathetic nervous activity. The aim of the present study was to investigate if pharmacological antilipolysis with acipimox acutely affects autonomic tone.. We studied heart rate variability as a measure of autonomic tone in eight hypopituitary men with and without acipimox treatment. The standard deviation of normal-to-normal intervals, root mean square of successive differences and high frequency were measured as heart rate variability parameters. The patients were studied in the basal and insulin-stimulated state with clamped plasma glucose on two occasions in a randomized, double-blind and placebo-controlled crossover study.. Plasma glucose (4.7 vs. 4.9 mmol l. Short-term inhibition of lipolysis by acipimox treatment lowered circulating FFA levels, improved insulin sensitivity, and was accompanied by reduced parasympathetic tone. The effect of acipimox on the parasympathetic modulation was reversed by hyperinsulinaemia.

Topics: Biomarkers; Blood Glucose; Blood Pressure; Cross-Over Studies; Denmark; Double-Blind Method; Fatty Acids, Nonesterified; Heart; Heart Rate; Humans; Hypolipidemic Agents; Hypopituitarism; Insulin; Lipolysis; Male; Parasympathetic Nervous System; Pyrazines; Time Factors; Treatment Outcome

It has been gradually realized that GH may have important physiological functions in adult humans. The biochemical diagnosis of adult GHD is established by provocative testing of GH secretion. The insulin-tolerance test (ITT) is the best validated. The ITT has been challenged because of its low degree of reproducibility and lack of normal range, and is contra-indicated in common clinical situations. Furthermore, in severely obese subjects the response to the ITT frequently overlaps with those found in non-obese adult patients with GHD.. The aim of the present study was to evaluate the diagnostic capability of four different stimuli of GH secretion: ITT, GHRH, GHRH plus acipimox (GHRH+Ac), and GHRH plus GHRP-6 (GHRH+GHRP-6), in two pathophysiological situations: hypopituitarism and obesity, and normal subjects.. Eight adults with hypopituitarism (four female, four male) aged 41-62 Years (48.8+/-1.4 Years), ten obese normal patients (five female, five male) aged 38-62 Years (48.1+/-2.5 Years), with a body mass index of 34.2+/-1.2 kg/m(2), and ten normal subjects (five female, five male) aged 33-62 Years (48.1+/-2.8 Years) were studied. Four tests were performed on each patient or normal subject: An ITT (0.1 U/kg, 0.15 U/kg for obese, i.v., 0 min), GHRH (100 microg, i.v., 0 min), GHRH (100 microg, i.v., 0 min) preceded by acipimox (250 mg, orally, at -270 min and -60 min) (GHRH+Ac); and GHRH (100 microg, i.v., 0 min) plus GHRP-6 (100 microg, i.v., 0 min) (GHRH+GHRP-6). Serum GH was measured by radioimmunoassay. Statistical analyses were performed by Wilcoxon rank sum and by Mann-Whitney tests.. After the ITT the mean peak GH secretion was 1.5+/-0.3 microg/l for hypopituitary, 10.1+/-1.7 microg/l (P<0.05 vs hypopituitary) for obese and 17.8+/-2.0 microg/l (P<0.05 vs hypopituitary) for normal. GHRH-induced GH secretion was 2+/-0.7 microg/l for hypopituitary, 3.9+/-1.2 microg/l (P=NS vs hypopituitary) for obese and 22.2+/-3.8 microg/l (P<0.05 vs hypopituitary) for normal. After GHRH+Ac, mean peak GH secretion was 3.3+/-1.4 microg/l for hypopituitary, 14.2+/-2.7 microg/l (P<0.05 vs hypopituitary) for obese and 35.1+/-5.2 microg/l (P<0.05 vs hypopituitary) for normal. GHRH+GHRP-6 induced mean peak GH secretion of 4.1+/-0.9 microg/l for hypopituitary, 38.5+/-6.5 microg/l (P<0.05 vs hypopituitary) for obese and 68.1+/-5.5 microg/l (P<0.05 vs hypopituitary) for normal subjects. Individually considered, after ITT, GHRH or GHRH+Ac, the maximal response in hypopituitary patients was lower than the minimal response in normal but higher than the minimal response in obese subjects. In contrast, after GHRH+GHRP-6 the maximal response in hypopituitary patients was lower than the minimal response in normal and obese subjects.. This study suggests that, in this group of patients, although both acipimox and GHRP-6 partially reverse the functional hyposomamotropism of obesity after GHRH, but are unable to reverse the organic hyposomatotropism of hypopituitarism, the combined test GHRH+GHRP-6 most accurately distinguishes both situations, without the side effects of ITT.

Topics: Adult; Body Mass Index; Evaluation Studies as Topic; Female; Glucose Tolerance Test; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypolipidemic Agents; Hypopituitarism; Insulin; Male; Middle Aged; Obesity; Oligopeptides; Pyrazines

In obesity, there is a markedly decreased GH secretion. The diagnosis of GH deficiency (GHD) in adults is based on peak GH responses to stimulation tests. In the severely obese, peak GH levels after pharmacological stimulation are often in the range that is observed in hypopituitary patients. To distinguish obese subjects from GHD patients, it will be necessary to demonstrate that reduced GH responsiveness to a given test is reversible in the former, but not in the latter, group. Recent studies have shown that reduction of plasma free fatty acids (FFA) with acipimox in obese patients restores their somatotrope responsiveness. There are no data evaluating GH responsiveness to acipimox plus GHRH in obese adults with hypopituitarism. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on GHRH-mediated GH secretion in obese normal subjects and obese adults with hypopituitarism. Eight obese patients with a body mass index of 34.2+/-1.2; eight obese adults with hypopituitarism, with a body mass index of 35.5+/-1.9; and six control subjects were studied. All the patients showed an impaired response to an insulin-tolerance test (0.15 U/kg, i.v.), with a peak GH secretion of less than 3 microg/L. Two tests were carried out. On one day, they were given GHRH (100 microg, i.v., 0 min), preceded by placebo; and blood samples were taken every 15 min for 60 min. On the second day, they were given GHRH (100 microg, i.v., 0 min), preceded by acipimox (250 mg, orally, at -270 min and -60 min); and blood samples were taken every 15 min for 60 min. The administration of acipimox induced a FFA reduction during the entire test. Normal control subjects had a mean peak (microg/L) of 23.8+/-4.8 after GHRH-induced GH secretion; previous acipimox administration increased GHRH-induced GH secretion, with a mean peak of 54.7+/-14.5. In obese patients, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 3.9+/-1; previous administration of acipimox markedly increased GHRH-mediated GH secretion, with a mean peak of 16.0+/-3.2 (P < 0.05). In obese adults with hypopituitarism, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 2+/-0.7; previous acipimox administration did not significantly modify GHRH-mediated GH secretion, with a mean peak of 3.3+/-1.1 (P < 0.05). The GH response of obese patients and obese adults with hypopituitarism was similar after GHRH alone. In contrast, the G

Topics: Adult; Fatty Acids, Nonesterified; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypolipidemic Agents; Hypopituitarism; Male; Middle Aged; Obesity; Pyrazines

Lipoprotein lipase (LPL) catalyzes the hydrolysis of circulating triglycerides into free fatty acids (FFA) and thereby promotes FFA uptake in peripheral tissues. LPL is negatively regulated by angiopoietin-like protein 4 (ANGPTL4) presumably by an FFA-dependent mechanism. Growth hormone (GH) suppresses LPL activity, but it is unknown whether this is mediated by FFA and ANGPTL4. Therefore, we investigated the concerted effect of GH on ANGPTL4 and LPL in the presence and absence of lipolysis in two in vivo studies in human subjects.. In a randomized, placebo-controlled, cross-over study, nine obese men were examined after injection of 1) a GH bolus, and 2) a GH-receptor antagonist followed by four adipose tissue biopsies obtained over a 5-h period. In a second study, nine hypopituitary men were examined in a 2 × 2 factorial design including GH and acipimox (an anti-lipolytic agent), with biopsies from adipose tissue and skeletal muscle obtained during a basal period and a subsequent hyperinsulinemic-euglycemic clamp. The mRNA expression of ANGPTL4 and LPL as well as LPL activity were analyzed in the biopsies.. In both studies, GH increased serum FFA levels, upregulated ANGPTL4 mRNA expression and suppressed LPL activity. In study 2, acipimox completely suppressed FFA levels and antagonized the effects of GH on ANGPTL4 and LPL.. These human in vivo studies demonstrate that GH upregulates ANGPTL4 mRNA and suppresses LPL activity via an FFA-dependent mechanism.

Topics: Adipose Tissue; Adult; Aged; Angiopoietin-Like Protein 4; Cross-Over Studies; Fatty Acids; Fatty Acids, Nonesterified; Human Growth Hormone; Humans; Hypolipidemic Agents; Hypopituitarism; Lipoprotein Lipase; Male; Middle Aged; Obesity; Pyrazines; RNA, Messenger; Single-Blind Method; Up-Regulation; Young Adult

The diagnosis of GH deficiency (GHD) in obese patients is complicated by the reduced GH secretion associated with overweight. A GH response to GHRH+arginine lower than 4.2 microg/l is currently considered indicative of GHD in obesity. The aim of the study was to investigate the effect of acute pharmacological blockade of lipolysis on the GH response to GHRH+arginine in obese patients.. Two groups of patients were studied: 12 obese patients with proven GHD and 14 patients with essential obesity. On separate occasions, two tests were carried out in each patient: GHRH+arginine and GHRH+arginine preceded by acipimox.. The mean GH peak after GHRH+arginine was significantly lower in hypopituitary patients than in subjects with essential obesity. Acipimox significantly increased the mean GH response in patients with essential obesity, but not in hypopituitary subjects. All hypopituitary patients and 7/14 patients with essential obesity displayed GH peaks lower than 4.2 microg/l after GHRH+arginine: the GH response to the test increased after acipimox pretreatment in five of these seven essentially obese subjects. After acipimox administration, free fatty acids (FFAs) significantly fell in both groups with comparable mean absolute decreases. All IGF1 values were normal in both groups of subjects.. Our study has demonstrated that the acipimox-induced acute reduction of circulating FFA levels increases mean somatotropin response to GHRH+arginine in patients with essential obesity, whereas it has no effect in hypopituitary subjects. The current criterion for the diagnosis of GHD in obese patients may be misleading. Indeed, subjects affected by third degree obesity, like most of our patients, may be erroneously classified as really GH-deficient and started on an expensive unjustified treatment. It appears therefore that the current criteria for the diagnosis of GHD in obesity should be reconsidered in the light of further studies also taking into account different body mass index groups.

Topics: Adult; Aged; Arginine; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypolipidemic Agents; Hypopituitarism; Insulin; Insulin-Like Growth Factor I; Linear Models; Lipolysis; Male; Middle Aged; Obesity; Pyrazines