acipimox and Obesity

Topics: Animals; Biological Transport; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipolysis; Models, Biological; Niacin; Obesity; Pyrazines

Increased circulating free fatty acids (FFAs) have been proposed to contribute to insulin resistance in obesity. Short-term studies have investigated the effects of acipimox, an inhibitor of hormone-sensitive lipase, on glucose homeostasis, but longer-term studies have not been performed.. To test the hypothesis that long-term treatment with acipimox would reduce FFA and improve insulin sensitivity among nondiabetic, insulin-resistant, obese subjects.. At an academic medical center, 39 obese men and women were randomized to acipimox 250 mg thrice-daily vs identical placebo for 6 months.. Plasma lipids, insulin sensitivity, adiponectin, and mitochondrial function via assessment of the rate of post-exercise phosphocreatine recovery on (31)P-magnetic resonance spectroscopy as well as muscle mitochondrial density and relevant muscle gene expression.. Fasting glucose decreased significantly in acipimox-treated individuals (effect size, -6 mg/dL; P = .02), in parallel with trends for reduced fasting insulin (effect size, -6.8 μU/mL; P = .07) and HOMA-IR (effect size, -1.96; P = .06), and significantly increased adiponectin (effect size, +668 ng/mL; P = .02). Acipimox did not affect insulin-stimulated glucose uptake, as assessed by euglycemic, hyperinsulinemic clamp. Effects on muscle mitochondrial function and density and on relevant gene expression were not seen.. These data shed light on the long-term effects of FFA reduction on insulin sensitivity, other metabolic parameters, and muscle mitochondrial function in obesity. Reduced FFA achieved by acipimox improved fasting measures of glucose homeostasis, lipids, and adiponectin but had no effect on mitochondrial function, mitochondrial density, or muscle insulin sensitivity.

Topics: Adult; Blood Glucose; Body Composition; Down-Regulation; Energy Metabolism; Fatty Acids, Nonesterified; Female; Humans; Hypolipidemic Agents; Lipid Metabolism; Male; Middle Aged; Obesity; Pyrazines; Young Adult

We hypothesized that a high circulating free fatty acid (FFA) concentration is involved in the pathogenesis of hyposomatotropism associated with obesity. To evaluate this hypothesis, 10 healthy premenopausal women (body mass index 33.8 +/- 1.0 kg/m(2)) were studied in the follicular phase of their menstrual cycle at two occasions with a time interval of at least 8 wk, where body weight remained stable. Subjects were randomly assigned to treatment with either acipimox (an inhibitor of lipolysis, 250 mg orally 4 times daily) or placebo in a double-blind crossover design, starting 1 day before admission until the end of the blood sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of growth hormone (GH) concentrations, and GH secretion was estimated by deconvolution analysis. Identical methodology was used to study GH secretion in a historical control group of age-matched normal weight women. GH secretion was clearly blunted in obese women (total daily release 66 +/- 10 vs. lean controls: 201 +/- 23 mU x l(Vd)(-1) x 24 h(-1), P = 0.005, where l(Vd) is lite of distribution volume). Acipimox considerably enhanced total (113 +/- 50 vs. 66 +/- 10 mU x l(Vd)(-1) x 24 h(-1), P = 0.02) and pulsatile GH secretion (109 +/- 49 vs. 62 +/- 30 mU x l(Vd)(-1) x 24 h(-1), P = 0.02), but GH output remained lower compared with lean controls. Further analysis did not show any relationship between the effects of acipimox on GH secretion and regional body fat distribution. In conclusion, acipimox unleashes spontaneous GH secretion in obese women. It specifically enhances GH secretory burst mass. This might mean that lowering of systemic FFA concentrations by acipimox modulates neuroendocrine mechanisms that orchestrate the activity of the somatotropic ensemble.

Topics: Adipose Tissue; Adult; Body Composition; Entropy; Fatty Acids, Nonesterified; Female; Half-Life; Human Growth Hormone; Humans; Hypolipidemic Agents; Insulin-Like Growth Factor I; Obesity; Pyrazines

Obesity is associated with increased hepatic glycogen content. In vivo and in vitro data suggest that plasma free fatty acids (FFA) may cause this increase. In this study we investigated the effect of physiological plasma FFA levels on hepatic glycogen metabolism by studying intrahepatic glucose pathways in lean and obese subjects. Six lean and 6 obese males were studied twice during a 16- to 22-hour fast, once with and once without acipimox, an inhibitor of lipolysis. Intrahepatic glucose fluxes were measured by infusion of [2-(13C1)]glycerol, [1-(2H1)]galactose, and [U-(13C6)]glucose. Acetaminophen was administered as a glucuronate probe. In both lean and obese control studies, plasma FFA levels increased progressively, whereas acipimox completely suppressed plasma FFA levels for the whole study period. In lean males glycogenolysis did not change in the acipimox study, but decreased in the control study (P < .01). In lean males, neither glycogen synthesis, glycogen synthesis retained as glycogen, nor glycogen balance differed between control and acipimox studies. In obese males glycogenolysis did not change in the acipimox study, but decreased in the control study (P < .01). Glycogen synthesis did not change in either study. Glycogen synthesis retained as glycogen did not change in acipimox study, but increased in the control study (P = .03). Glycogen balance did not change in the acipimox study, but increased in the control study (P < .01). This study demonstrates that in obese males physiological levels of FFA contribute to the retention of hepatic glycogen during short-term fasting by inhibiting breakdown of glycogen and increasing glycogen synthesis retained as glycogen, whereas in lean males this effect was absent due to unaltered glycogen synthesis retained as glycogen.

Topics: Adult; C-Peptide; Fasting; Fatty Acids, Nonesterified; Gas Chromatography-Mass Spectrometry; Gluconeogenesis; Glucose; Hormones; Humans; Hypolipidemic Agents; Insulin; Liver Glycogen; Male; Middle Aged; Obesity; Pyrazines; Stimulation, Chemical

Several studies suggest that the hypothalamo-pituitary-adrenal (HPA) axis is exceedingly active in obese individuals. Experimental studies show that circulating free fatty acids (FFAs) promote the secretory activity of the HPA axis and that human obesity is associated with high circulating FFAs. We hypothesized that HPA axis activity is enhanced and that lowering of circulating FFAs by acipimox would reduce spontaneous secretion of the HPA hormonal ensemble in obese humans. To evaluate these hypotheses, diurnal ACTH and cortisol secretion was studied in 11 obese and 9 lean premenopausal women (body mass index: obese 33.5 +/- 0.9 vs. lean 21.2 +/- 0.6 kg/m(2), P < 0.001) in the early follicular stage of their menstrual cycle. Obese women were randomly assigned to treatment with either acipimox (inhibitor of lipolysis, 250 mg orally four times daily) or placebo in a double-blind crossover design, starting one day before admission until the end of the blood-sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of plasma ACTH and cortisol concentrations. ACTH and cortisol secretion rates were estimated by multiparameter deconvolution analysis. Daily ACTH secretion was substantially higher in obese than in lean women (7,950 +/- 1,212 vs. 2,808 +/- 329 ng/24 h, P = 0.002), whereas cortisol was not altered (obese 36,362 +/- 5,639 vs. lean 37,187 +/- 4,239 nmol/24 h, P = 0.912). Acipimox significantly reduced ACTH secretion in the obese subjects (acipimox 5,850 +/- 769 ng/24 h, P = 0.039 vs. placebo), whereas cortisol release did not change (acipimox 33,542 +/- 3,436 nmol/24 h, P = 0.484 vs. placebo). In conclusion, spontaneous ACTH secretion is enhanced in obese premenopausal women, whereas cortisol production is normal. Reduction of circulating FFA concentrations by acipimox blunts ACTH release in obese women, which suggests that FFAs are involved in the pathophysiology of this neuroendocrine anomaly.

Topics: Adrenocorticotropic Hormone; Adult; Circadian Rhythm; Cross-Over Studies; Double-Blind Method; Down-Regulation; Fatty Acids, Nonesterified; Female; Follicular Phase; Humans; Hydrocortisone; Hypolipidemic Agents; Hypothalamo-Hypophyseal System; Obesity; Pituitary-Adrenal System; Premenopause; Pyrazines; Reference Values; Statistics, Nonparametric

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

To evaluate the effects of long-term acipimox administration on glucose-induced insulin secretion and peripheral insulin sensitivity in polycystic ovarian syndrome (PCOS), 20 PCOS subjects (eight lean and 12 obese) and 14 body mass index-matched controls (seven lean and seven obese) were investigated.. Fasting blood samples were collected for basal hormone and lipoprotein assays, after which patients underwent an oral glucose tolerance test (OGTT). The following day a euglycaemic-hyperinsulinaemic clamp was performed. After 4-6 weeks of treatment with acipimox at a dose of 250 mg given orally three times a day, the patients repeated the study protocol.. No significant differences were found in the glucose, insulin or C-peptide responses to OGTT before and after anti-lipolytic drug administration in any group, nor was there any effect on insulin sensitivity. Concerning the lipid profile, acipimox administration led to a significant decrease of cholesterol and low-density lipoprotein levels in obese PCOS patients as well as in obese and lean controls. Lower triglycerides were found after the drug administration in both obese groups. Post-treatment free fatty acid levels were not significantly different when compared with basal values.. Acipimox does not appear to be an effective insulin-lowering drug in PCOS, even if it can be used in obese women with PCOS as an additional therapeutic agent to ameliorate the atherogenic lipid profile of the syndrome.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Hypolipidemic Agents; Insulin; Obesity; Pilot Projects; Polycystic Ovary Syndrome; Pyrazines; Thinness; Time Factors; Triglycerides

To evaluate the effects of acute lowering of FFAs on glucose-induced insulin secretion and GH response to GHRH in polycystic ovary syndrome (PCOS), 27 PCOS subjects (11 lean and 16 obese) and 17 body mass index-matched controls (8 lean and 9 obese) were investigated. Patients underwent an oral glucose tolerance test and a GHRH test before and after administration of the antilipolytic drug acipimox (250 mg orally 3 h and 1 h before the starting of the tests). Blood samples were collected for 2 h after GHRH bolus and for 4 h after the oral glucose tolerance test. Serum concentrations of GH, insulin, glucose, and c-peptide were assayed in each sample, and the results were expressed as area under the curve (AUC). No significant differences were found as to glucose, insulin, and c-peptide AUC before and after acute FFA plasma reduction in any of the investigated groups. Basally, lower GH-AUC was found in lean PCOS compared with body mass index-matched controls and in obese vs. lean controls; no significant differences were found as to the same variable between the two obese groups. The acipimox induced FFA suppression elicited in the four groups a sustained increase in the GH response to its trophic hormone; indeed, the GH-AUC nearly doubled with respect to basal evaluation in all the studied groups. However, the antilipolytic drug was not able to abolish the differences found between lean groups in basal conditions. In conclusion, the presented data confirm that FFAs have a main role in regulating GH secretion at the pituitary level; however, it does not seem that they could explain the GH as well as insulin dysfunction of PCOS.

Topics: Adult; Area Under Curve; Body Mass Index; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Growth Hormone-Releasing Hormone; Hormones; Human Growth Hormone; Humans; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipids; Obesity; Polycystic Ovary Syndrome; Pyrazines

GH release is increased by reducing circulating free fatty acids (FFAs). Aging is associated with decreased plasma GH concentrations. We evaluated GH releasing capacity in nine healthy elderly men after administration of GH-releasing peptide 2 (GHRP-2), with or without pretreatment with the antilipolytic drug acipimox, and compared the GHRP-2-induced GH release with the response to GHRH. The area under the curve (AUC) of the GH response after GHRP-2 alone was 4.8 times higher compared with GHRH alone (1834 +/- 255 vs. 382 +/- 78 microg/L.60 min, P: < 0.001). Acipimox, which reduced FFAs from 607 micromol/L to 180 micromol/L, increased the GH AUC to 1087 after GHRH and to 2956 microg/L.60 min after GHRP-2 (P: < 0.01). The AUC after acipimox/GHRP-2 were positively correlated with the AUC after GHRP-2 alone (r = 0.93, P: < 0.01); this was also observed between acipimox/GHRH and GHRH alone (r = 0.73, P: = 0.03). Significant negative correlations were observed between basal FFAs and AUC after GHRH or GHRP-2 after combining the data with and without acipimox (r = 0.58, P: = 0.01 and r = 0.48, P: = 0.04, respectively), and between basal FFAs and GH at t = 0 (r = -0.44, P: = 0.001). Interestingly, GHRP-2 administration was followed by a significant early rise in plasma FFAs by 60% (P = 0.01), indicating an acute lipolytic effect. In conclusion, reduction of circulating FFAs strongly enhances GHRP-2-stimulated GH release in elderly men. The data indicate that the decreased GH release associated with aging can be reversed by acipimox and that the pituitary GH secretory capacity in elderly men is still sufficient.

Topics: Aged; Area Under Curve; Blood Glucose; Fatty Acids, Nonesterified; Female; Growth Hormone-Releasing Hormone; Hormones; Human Growth Hormone; Humans; Hypolipidemic Agents; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Male; Obesity; Oligopeptides; Pyrazines

Obesity is commonly associated with elevated plasma free fatty acid (FFA) levels, as well as with insulin resistance and hyperinsulinemia, two important cardiovascular risk factors. What causes insulin resistance and hyperinsulinemia in obesity remains uncertain. Here, we have tested the hypothesis that FFAs are the link between obesity and insulin resistance/hyperinsulinemia and that, therefore, lowering of chronically elevated plasma FFA levels would improve insulin resistance/hyperinsulinemia and glucose tolerance in obese nondiabetic and diabetic subjects. Acipimox (250 mg), a long-acting antilipolytic drug, or placebo was given overnight (at 7:00 P.M., 1:00 A.M., 7:00 A.M.) to 9 lean control subjects, 13 obese nondiabetic subjects, 10 obese subjects with impaired glucose tolerance, and 11 patients with type 2 diabetes. Euglycemic-hyperinsulinemic clamps and oral glucose tolerance tests (75 g) were performed on separate mornings after overnight Acipimox or placebo treatment. In the three obese study groups, Acipimox lowered fasting levels of plasma FFAs (by 60-70%) and plasma insulin (by approximately 50%). Insulin-stimulated glucose uptake during euglycemic-hyperinsulinemic clamping was more than twofold higher after Acipimox than after placebo. Areas under the glucose and insulin curves during oral glucose tolerance testing were both approximately 30% lower after Acipimox administration than after placebo. We conclude that lowering of elevated plasma FFA levels can reduce insulin resistance/hyperinsulinemia and improve oral glucose tolerance in lean and obese nondiabetic subjects and in obese patients with type 2 diabetes.

Topics: Adult; Basal Metabolism; Diabetes Mellitus; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypolipidemic Agents; Insulin Resistance; Male; Obesity; Oxidation-Reduction; Pyrazines

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Serum leptin concentrations increase in correlation with the percentage of body fat, but besides that little is known about the physiological actions of leptin in humans. The aim of this study was to assess the influence of changes in circulating free-fatty acids on serum leptin levels. Increases in plasma FFA levels (p < 0.02) were obtained in a group of normal subjects following the administration of intralipid plus heparin (250 ml 10% Intralipid plus 5000 U heparin). FFA reduction was achieved through the administration of acipimox (250 mg, orally, at 0 min and at 210 min), a lipid-lowering drug devoid of side effects, to a group of normal (p < 0.02) and obese subjects (p < 0.05). An increase in circulating FFA levels in normal subjects (n = 6), following administration of a lipid-heparin infusion, failed to modify plasma leptin levels as assessed by the area under the curve (AUC; mean +/- SE 892 +/- 168 for placebo vs 896 +/- 260 following intralipid plus heparin). Similarly, whereas acipimox pretreatment induced a reduction in FFA levels compared to placebo in normal (n = 6) and obese subjects (n = 8), it also failed to modify plasma leptin levels at any time-point studied. The results indicate that short-term reduction or increase in circulating FFA are not associated to changes in plasma leptin levels.

Topics: Adult; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Heparin; Humans; Hypolipidemic Agents; Kinetics; Leptin; Male; Obesity; Placebos; Proteins; 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

Obesity is associated with an impairment of normal growth hormone (GH) secretion and blunted responses to all stimuli. A high plasma free fatty acid (FFA) level is frequently observed in obesity. FFA participates in the regulation of pituitary GH secretion. To determine whether the derangement of GH secretion in obesity is associated with high plasma FFA levels, tests with GH-releasing hormone (GHRH) and acipimox (ACX), an antilipolytic agent able to decrease FFA, were undertaken in six obese subjects and seven normal control subjects. In addition, the effect of prolonged suppression of FFA level on GH response to GHRH after administration of ACX for 1 month was also examined in each of the obese subjects. The GH response in obese subjects (median, 9.1 microg/L) to GHRH (1-29) (1 microg/kg intravenously [IV]) was significantly blunted as compared with normal control subjects (23.5 microg / L, P < .05). Basal FFA levels were higher in obese subjects (855.2 microEq / L than in normal control subjects (514.6 microEq / L, P < .05). One-dose ACX (500 mg) decreased FFA levels in both obese and normal subjects: the lowest FFA levels in obese subjects (158.3 microEq/L 2 to 2.5 hours after ACX were similar to those of normal control subjects (108.7 microEq/L). One-dose ACX potentiated GHRH-stimulated GH response in both obese and normal subjects. GH responses potentiated by ACX in obese subjects (27.1 microg/L) were similar to GH responses to GHRH in normal control subjects, but lower than in normal subjects treated with ACX plus GHRH (58.5 microg / L, P < .05). Thereafter, all of the obese subjects were treated with ACX for 1 month, after which the ACX plus GHRH tests were repeated. After 1 month of acipimox administration in the obese subjects, GH responses (38.8 microg/L) were significantly higher than those of obese subjects treated with GHRH and one-dose ACX plus GHRH (P < .05). They were similar to GH responses of normal control subjects receiving the one-dose ACX plus GHRH test. In conclusion, in obesity the prolonged suppression of FFA levels induced by long-term administration of ACX potentiated somatotrope responsiveness, likely acting at the pituitary level, suggesting that the duration of FFA suppression had an important relation to the magnitude of GH response.

Topics: Adult; Fatty Acids, Nonesterified; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Hypolipidemic Agents; Male; Obesity; Pyrazines

GH secretion in response to provocative stimuli is blunted in obese patients. On the other hand, increases in plasma free fatty acids (FFA) inhibit the GH response to a variety of stimuli, and FFA levels in plasma are increased with obesity. To ascertain whether FFA might be responsible for the GH secretory alterations of obesity, we studied spontaneous and stimulated GH secretion in 31 obese patients after FFA reduction by acipimox, a lipid-lowering drug devoid of serious side-effects. Each subject underwent two paired tests. In one, acipimox was administered orally at a dose of 250 mg at -270 min and at a dose of 250 mg at -60 min; in the matched test, placebo was given at similar intervals. To induce GH release, three stimuli acting through different mechanisms were used: pyridostigmine (60 mg, orally, at -60 min), GHRH (100 micrograms, iv, at 0 min), and GHRH plus GH-releasing peptide (GHRP-6; His-D-Trp-Ala-Trp-D-Phe-Lys-NH2; both at a dose of 100 micrograms, iv, at 0 min). GH secretion was analyzed as the area under the secretory curve (AUC; mean +/- SE; micrograms per L/60 min). Acipimox pretreatment alone (n = 13) induced a large reduction in FFA levels compared with placebo treatment. The FFA reduction led to a slight GH rise (AUC, 123 +/- 47), not different from that in the placebo group (61 +/- 15). In the pyridostigmine-treated group (n = 6), the acipimox-pyridostigmine AUC (408 +/- 107) was significantly higher (P < 0.05) than that in the placebo-pyridostigmine group (191 +/- 25). Furthermore, the GHRH-mediated (n = 6) AUC of GH secretion in the placebo test (221 +/- 55) was tripled by FFA reduction due to acipimox, with an AUC of (691 +/- 134; P < 0.05). Even the most potent GH stimulus known to date, i.e. GHRH plus GHRP-6, was enhanced by FFA suppression. In fact, the placebo-GHRH-GHRP-6 AUC was 1591 +/- 349, lower (P < 0.05) than that in the acipimox-GHRH-GHRP-6 test (2373 +/- 242). The enhancing effects of FFA lowering on GHRH-mediated and GHRH- plus GHRP-6-mediated GH release were synergistic. These results indicate that in obese subjects, unlike normal weight subjects. FFA reduction per se does not stimulate GH secretion. A reduction in FFA with acipimox, however, increased pyridostigmine-. GHRH-, and even GHRH- plus GHRP-6-mediated GH release, suggesting that FFA reduction operates through a different mechanism from that of these three stimuli. The abnormally high FFA levels may be a contributing factor for the disrupted GH secretory me

Topics: Adolescent; Adult; Fatty Acids, Nonesterified; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Hypolipidemic Agents; Male; Middle Aged; Obesity; Oligopeptides; Pyrazines; Pyridostigmine Bromide

GH induces lipolysis in vivo, increasing plasma free fatty acid (FFA) levels; in turn, FFA are able to reduce GH release, and acipimox, a nicotinic acid analog able to block lipolysis, enhances in normal subjects the GH response to GHRH. Obesity and old age are characterized by a blunted GH response to several stimuli, including GHRH; reports also indicate high plasma FFA levels in obesity and sometimes in the elderly. The aim of this study was to evaluate the possible role of FFA in GH release in obese and elderly subjects. According to a randomized, single blind, cross-over protocol, six healthy subjects, six obese subjects, and six elderly subjects received on 2 different days, with a 1-week interval, placebo or acipimox (250 mg, orally) at 0700 and 1100 h; GHRH [GHRH-(1-44)NH2; 50 micrograms in healthy subjects and in elderly subjects, 100 micrograms in obese subjects] was injected iv at 1300 h, and blood samples for evaluation of plasma FFA, blood glucose, serum insulin (IRI), and serum GH levels were taken from 1200 to 1500 h. Plasma FFA levels were always lower (P < 0.05) after acipimox than after placebo (0.03 +/- 0.01 vs. 0.13 +/- 0.02 g/L in healthy subjects, 0.09 +/- 0.01 vs. 0.27 +/- 0.02 g/L in obese, 0.02 +/- 0.005 vs. 0.17 +/- 0.01 g/L in elderly subjects); serum IRI levels were also lower (P < 0.05) after acipimox than after placebo in the three groups of subjects (16 +/- 3 vs. 30 +/- 5, 120 +/- 30 vs. 181 +/- 32, and 21 +/- 3 vs. 49 +/- 9 pmol/L); both FFA (P < 0.05) and IRI levels (P < 0.05) were higher in obese than in healthy or elderly subjects after placebo and acipimox. Blood glucose levels were not different in the three groups of subjects after either placebo or acipimox. The integrated GH response to GHRH-(GH delta area) was always greater (P < 0.05) after acipimox than after placebo (4677 +/- 633 vs. 1599 +/- 373 in healthy, 1469 +/- 230 vs. 343 +/- 114 in obese, 2304 +/- 759 vs. 325 +/- 133 micrograms/L.120 min in elderly subjects); after both placebo and acipimox, the GH delta area was greater (P < 0.05) in healthy subjects than in obese or elderly subjects. The GH delta area of elderly and obese subjects after acipimox was not different from the GH delta area of healthy subjects after placebo. Changes in GH delta areas were not significantly related to changes in FFA or IRI induced by acipimox; in contrast, absolute values of FFA and IRI as well as basal GH levels were all significantly related to the GH delta area. At multip

Topics: Adult; Aged; Aging; Blood Glucose; Cross-Over Studies; Fatty Acids, Nonesterified; Female; Gonadotropin-Releasing Hormone; Human Growth Hormone; Humans; Hypolipidemic Agents; Insulin; Lipolysis; Male; Obesity; Pyrazines; Single-Blind Method

Obesity is associated with blunted growth hormone (GH) levels and pulsatility and elevated plasma free fatty acids (FFA) levels. To evaluate whether the two phenomena are correlated, in the present study we investigated the effects of an acute pharmacologic blockade of lipolysis on nocturnal GH levels and pulsatility in 10 obese and 10 control subjects. At 9 PM on two different nights with a 1-night interval in between, all subjects received either a single oral tablet of placebo or acipimox slow release (ACX-SR, 500 mg) in randomized order. Blood samples were drawn from 10 PM to 6 AM for evaluation of FFA, glycerol, GH, immunoreactive insulin (IRI), glucose, and insulin-like growth factor-I (IGF-I) levels. After placebo, FFA and glycerol levels were higher (P < .02) and GH levels, areas, peak amplitude, and peak increment (assessed by the Cluster algorithm) were lower in obese than in control subjects (P < .01). After ACX-SR, FFA and glycerol levels were reduced in both groups (P < .02 v placebo), and in obese subjects they became similar to those observed in control subjects after placebo. ACX-SR had no effect on GH levels and pulsatility in control subjects. GH levels, areas, peak, amplitude, peak increment, and interpeak valley levels were all increased after ACX-SR in obese subjects (P < .05 or less v placebo) and became similar to those observed in normal subjects after placebo, but no correlation was found between the reduction in FFA levels and the increase in GH levels and pulsatility.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Blood Glucose; Body Mass Index; Circadian Rhythm; Cross-Over Studies; Delayed-Action Preparations; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glycerol; Growth Hormone; Humans; Hypolipidemic Agents; Insulin; Insulin-Like Growth Factor I; Lipolysis; Male; Middle Aged; Obesity; Pulsatile Flow; Pyrazines

NEFAs characteristically are elevated in obese NIDDM patients in both the basal state and after insulin. This elevation might aggravate glycemic control both by decreasing peripheral glucose disposal (glucose-fatty acid cycle), and by increasing HGO. Thus, lowering plasma NEFA levels might improve carbohydrate metabolism. We therefore measured HGO and fuel use (by indirect calorimetry) both in the basal state and during the last 30 min of a hyperinsulinemic clamp (0.025U.kg-1.h-1) in 8 obese NIDDM patients (BMI 34.8 +/- 1.0 kg/m2) after complete overnight suppression of plasma NEFA levels with acipimox, a new nicotinic acid analogue. After acipimox, mean basal plasma NEFA and glycerol levels were lower than control values (0.11 +/- 0.02 vs. 0.65 +/- 0.04 mM, P < 0.001; and 16 +/- 3 vs. 68 +/- 7 microM, P = 0.004, respectively) and were accompanied by a fall in lipid oxidation (acipimox vs. placebo: 16.1 +/- 1.2 vs. 38.8 +/- 2.4 mg.m-2 x min-1; P < 0.001) and a rise in glucose oxidation (91.1 +/- 6.2 vs. 54.1 +/- 9.0 mg.m-2 x min-1; P = 0.002). Basal HGO and fasting plasma glucose levels were lower (94.1 +/- 9.2 vs. 118.5 +/- 9.5 mg.m-2 x min-1, P = 0.01; and 8.3 +/- 1.2 vs. 9.8 +/- 1.2 mM; P < 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Alanine; Blood Glucose; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glycerol; Humans; Hydroxybutyrates; Hypolipidemic Agents; Insulin; Lactates; Male; Middle Aged; Obesity; Pyrazines; Pyruvates; Triglycerides

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

Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) (1)H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.

Topics: Adult; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Humans; Hypolipidemic Agents; Insulin Resistance; Liver; Male; Middle Aged; Mitochondria; Obesity; Pyrazines; Reactive Oxygen Species

Smoking is a major risk factor for diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The health risk associated with smoking can be exaggerated by obesity. We hypothesize that nicotine when combined with a high-fat diet (HFD) can also cause ectopic lipid accumulation in skeletal muscle, similar to recently observed hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD and received twice-daily ip injections of nicotine (0.75 mg/kg body weight) or saline for 10 weeks. Transmission electron microscopy of the gastrocnemius muscle revealed substantial intramyocellular lipid accumulation in close association with intramyofibrillar mitochondria along with intramyofibrillar mitochondrial swelling and vacuolization in nicotine-treated mice on an HFD compared with mice on an HFD treated with saline. These abnormalities were reversed by acipimox, an inhibitor of lipolysis. Mechanistically, the detrimental effect of nicotine plus HFD on skeletal muscle was associated with significantly increased oxidative stress, plasma free fatty acid, and muscle triglyceride levels coupled with inactivation of AMP-activated protein kinase and activation of its downstream target, acetyl-coenzyme A-carboxylase. We conclude that 1) greater oxidative stress together with inactivation of AMP-activated protein kinase mediates the effect of nicotine on skeletal muscle abnormalities in diet-induced obesity and 2) adipose tissue lipolysis is an important contributor of muscle steatosis and mitochondrial abnormalities.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Fatty Acids, Nonesterified; Lipolysis; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria; Muscle Fibers, Skeletal; Muscle, Skeletal; Nicotine; Obesity; Oxidative Stress; Pyrazines; Risk Factors; Smoking; Triglycerides

Topics: Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Humans; Insulin Resistance; Male; Mitochondria; Obesity; Pyrazines

Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IBα protein (an indication of decreased IB kinase-nuclear factor B signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

Topics: Administration, Oral; Adult; Case-Control Studies; Ceramides; Chemokine CCL2; Diabetes Mellitus, Type 2; Diglycerides; Fatty Acids, Nonesterified; Female; Glucose; Humans; Hypolipidemic Agents; I-kappa B Kinase; Insulin; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Male; Middle Aged; Muscle, Skeletal; Obesity; Pyrazines; Signal Transduction; Toll-Like Receptor 4

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

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A(1c) (379 +/- 34 vs. 326 +/- 30 pmol x kg(-1) x min(-1) without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Dietary Proteins; Energy Intake; Exercise; Fasting; Fatty Acids; Female; Glucagon; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertriglyceridemia; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Proinsulin; Pyrazines

We previously reported that long-term treatment of Zucker diabetic fatty (ZDF) rats with the selective beta(3) agonist CL-316243 normalizes glycemia, decreases plasma free fatty acids (FFA) concentration, improves insulin responsiveness, and increases glucose uptake, not only in brown and white adipose tissues, but also in skeletal muscles. Because muscles do not express typical beta(3) adrenoceptors, we postulated that the muscle effect was indirect and that it was possibly mediated by an activation of the glucose-fatty acid cycle. To test this hypothesis, we investigated the effects of Acipimox, a potent inhibitor of lipolysis in adipose tissue. Similar to CL-316243, Acipimox (150 mg/kg orally) markedly decreased plasma FFA, glucose, and insulin concentrations and improved glucose tolerance while reducing the insulin response in obese (350 to 400 g) ZDF rats. Plasma FFA concentrations were significantly correlated with plasma glucose and insulin concentrations (r =.72 and.83, respectively; P <.01), indicating strong metabolic relationships between these parameters. Euglycemic-hyperinsulinemic clamps combined with the 2-[(3)H]deoxyglucose method revealed that Acipimox markedly improved insulin responsiveness and significantly increased glucose uptake (Rg') in the diaphragm, the heart, and various skeletal muscles. Unlike CL-316243, Acipimox did not increase glucose use in brown or white adipose tissues. This selectivity shows that it is possible to improve diabetes in obese ZDF rats without necessarily stimulating thermogenesis in adipose tissues. Thus, decreasing plasma FFA with 2 drugs (Acipimox or CL-316243) that act via different mechanisms (acute inhibition of lipolysis or chronic stimulation of FFA oxidation) is associated with increased glucose uptake in muscles and enhanced insulin responsiveness. These observations support the hypothesis that CL-316243 may indirectly stimulate glucose uptake in muscles of type II diabetic rats by first stimulating brown adipose tissue (increasing uncoupling protein content and fatty acid oxidation) and progressively decreasing the levels of circulating FFA, resulting in activation of the glucose-fatty acid cycle or other mechanisms regulating insulin responsiveness in skeletal muscles.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dioxoles; Fatty Acids, Nonesterified; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Male; Obesity; Pyrazines; Rats; Rats, Zucker

Two studies were performed to assess the entero-insular axis in simple obesity and the possible effect of variations in the level of circulating non-esterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7-36) amide]. In the first study, we compared the entero-pancreatic hormone response to oral carbohydrate in obese and lean women. Obese subjects demonstrated hyperinsulinaemia and impaired glucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 (GLP-1). These findings therefore provide no support for the hypothesis that overactivity of the entero-insular axis contributes to the hyperinsulinaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observations. In the second study, in which carbohydrate-stimulated GLP-1 responses were again evaluated in obese and lean women, circulating NEFA levels were modulated using either heparin (to increase serum NEFA) or acipimox (to reduce serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to carbohydrate alone or to carbohydrate plus heparin. We suggest that higher fasting and postprandial NEFA levels in obesity may tonically inhibit nutrient-mediated GLP-1 secretion, and that this results in attenuation of the GLP-1 response to carbohydrate. However, although serum NEFA levels post-acipimox were similarly suppressed in both lean and obese subjects, the GLP-1 response was again significantly lower in obese subjects, suggesting the possibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insulinotropic effect and to its postulated role as a satiety factor.

Topics: Adult; Analysis of Variance; Area Under Curve; Case-Control Studies; Dietary Carbohydrates; Fatty Acids, Nonesterified; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Heparin; Humans; Insulin; Models, Biological; Neurotransmitter Agents; Obesity; Peptide Fragments; Postprandial Period; Pyrazines; Triglycerides

Circulating non-esterified fatty acids (NEFAs) have been causally associated with impairment of glucose metabolism, although their effect on the entero-insular axis, either in obesity or health, is unknown.. Glucose, insulin, glucagon-like peptide-1 (7-36 amide) (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to 100 g of carbohydrate in 400 mL water were evaluated during simultaneous modulation of circulating non-esterified fatty acids (NEFAs). A total of 10,000 units of heparin (to increase serum NEFAs) and 500 mg of acipimox (2 h before oral carbohydrate ingestion to reduce serum NEFAs) were administered to seven obese [mean +/- SEM: age 40 +/- 3.7 years; body mass index (BMI) 38.9 +/- 2.1 kg m-2] and seven lean (age 39.6 +/- 3.6 years; BMI 22.4 +/- 0.4 kg m-2) women.. Higher fasting levels and post-heparin total integrated NEFAs (P < 0.05) and glycerol (P < 0.05) responses were seen in the obese than in the lean group. Incremental integrated GLP-1 responses to oral carbohydrate post-heparin in lean (P < 0.01) and obese (P < 0.05) subjects were significantly lower than after acipimox. Total integrated GIP (P < 0.05) and glucose (P < 0.01) responses were higher post heparin than after acipimox in obese subjects only.. The inverse relationship in GIP and GLP-1 responses in the obese group after modulation of NEFAs indicates that reciprocal changes between these two hormones may exist to ensure constancy of B-cell stimulation. Our results suggest that in obese subjects compensatory secretion of GIP was incomplete and could not prevent impairment in glucose tolerance after heparin-induced rise in NEFAs. These results may be important in understanding the role of the insulinotropic hormones in carbohydrate metabolism characterized by high NEFA levels such as obesity and diabetes mellitus.

Topics: Adult; Blood Glucose; Dietary Carbohydrates; Fatty Acids, Nonesterified; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Heparin; Humans; Insulin; Intestines; Islets of Langerhans; Obesity; Peptide Fragments; Protein Precursors; Pyrazines

We have recently presented experimental evidence indicating that insulin has a physiologic inhibitory effect on growth hormone (GH) release in healthy humans. The aim of the present study was to determine whether in obesity, which is characterized by hyperinsulinemia and blunted GH release, insulin contributes to the GH defect. To this aim, we used a simplified experimental protocol previously used in healthy humans to isolate the effect of insulin by removing the interference of free fatty acids (FFAs), which are known to block GH release. Six obese subjects (four men and two women; age, 30.8 +/- 5.2 years; body mass index, 36.8 +/- 2.8 kg/m2 [mean +/- SE]) and six normal subjects (four men and two women; age, 25.8 +/- 1.9 years; body mass index, 22.7 +/- 1.1 kg/m2) received intravenous (i.v.) GH-releasing hormone (GHRH) 0.6 microg/kg under three experimental conditions: (1) i.v. 0.9% NaCl infusion and oral placebo, (2) i.v. 0.9% NaCl infusion and oral acipimox, an antilipolytic agent able to reduce FFA levels (250 mg at 6 and 2 hours before GHRH), and (3) euglycemic-hyperinsulinemic clamp (insulin infusion rate, 0.4 mU x kg(-1) x min(-1)). As expected, after placebo, the GH response to GHRH was lower for obese subjects versus normals (488 +/- 139 v 1,755 +/- 412 microg/L x 120 min, P < .05). Acipimox markedly reduced FFA levels and produced a mild reduction of insulin levels; under these conditions, the GH response to GHRH was increased in both groups, remaining lower in obese versus normal subjects (1,842 +/- 360 v 4,871 +/- 1,286 microg/L x 120 min, P < .05). In both groups, insulin infusion yielded insulin levels usually observed under postprandial conditions and reduced circulating FFA to the levels observed after acipimox administration. Again, the GH response to GHRH was lower for obese subjects versus normals (380 +/- 40 v 1,075 +/- 206 microg/L x 120 min, P < .05), and in both groups, it was significantly lower than the corresponding response after acipimox. In obese subjects, as previously reported in normals, the GH response to GHRH was inversely correlated with the mean serum insulin (r = -.70, P < .01). In conclusion, our data indicate that in the obese, as in normal subjects, the GH response to GHRH is a function of insulin levels. The finding that after both the acipimox treatment and the insulin clamp the obese still show higher insulin levels and a lower GH response to GHRH than normal subjects suggests that hyperinsulinemia is a major d

Topics: Adult; Body Mass Index; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hyperinsulinism; Hypolipidemic Agents; Insulin; Male; Obesity; Pyrazines

Increased free fatty acid (FFA) levels of obese patients are likely involved in the pathogenesis of the growth hormone (GH) hyposecretion of obesity. To clarify their role, we studied the influence of inhibition of plasma FFA levels, induced by 500 mg oral acipimox (ACX), an antilipolytic drug, on the GH response to GH-releasing hormone (GHRH) alone or combined with arginine ([ARG] study A) in six normal women ([NS] aged 24 to 37 years; body mass index, 22.4 +/- 0.9 kg/m2) and six obese women ([OB] aged 21 to 40 years; body mass index 39.5 +/- 3.2 kg/m2). In a group of seven OB patients (aged 18 to 58 years; body mass index, 35.8 +/- 1.3 kg/m2), the effect of ACX on either GHRH- or GHRH+ARG-stimulated GH increase was also studied after a 4-day treatment with the same drug at 250 mg three times daily (study B). OB patients had baseline FFA levels higher than NS (0.77 +/- 0.06 v 0.44 +/- 0.09 mmol/L, P<.05). In study A, ACX reduced FFA levels to the same nadir in both groups (0.11 +/- 0.02 and 0.12 +/- 0.03 mmol/L, NS and OB subjects, respectively). In NS, ACX failed to significantly potentiate the GH response to either GHRH (1,371.9 +/- 425.2 v 1,001.8 +/- 229.0 micrograms/L x min) or GHRH+ARG (3558.4 +/- 1,513.7 v 3,045.9 +/- 441.8 micrograms/L x min), while in OB patients it increased the GH response to GHRH (797.6 +/- 277.3 v 353.8 +/- 136.7 micrograms/L x min, P<.01) and did not modify the response to ARG+GHRH (1,010.5 +/- 253.1 v 821.1 +/- 222.0 micrograms/L x min). In study B, ACX reduced FFA levels in OB patients (nadir, 0.09 +/- 0.04 mmol/L). This treatment strikingly increased the GH response to GHRH (1,734.0 +/- 725.4 v 271.5 +/- 112.8 micrograms/L x min, P<.01) and significantly potentiated that to ARG+GHRH (2,371.9 +/- 571.3 v 1,020.0 +/- 343.2 micrograms/L x min, P<.05). In conclusion, our present findings indicate that an acute reduction of plasma FFA levels in OB patients restores their somatotrope responsiveness, whereas it does not affect GH secretion in lean subjects. After prolonged treatment, ACX further improves GHRH-stimulated GH secretion in OB patients, suggesting that elevated FFA levels play a leading role in the GH hyposecretory state of obesity.

Topics: Adult; Arginine; Fatty Acids, Nonesterified; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Hypolipidemic Agents; Obesity; Pyrazines

Obesity is associated with an impairment of normal GH secretion and blunted responses to all stimuli. Recent reports suggest that increased somatostatinergic activity is the basis for the GH derangement of obesity. However, the basic mechanism of this alteration is still being debated. The high plasma free fatty acid (FFA) is frequently observed in obesity. FFA participates in the regulation of pituitary GH secretion. To determine whether the derangement of GH secretion in obesity is associated with high plasma FFA levels, several tests with GHRH with or without pyridostigmine (PYR) and acipimox (ACX), antilipolytic agents able to decrease FFA, were undertaken in six obese and seven normal control subjects. In obese subjects, the GH response (mean peak +/- SEM: 8.9 +/- 1.1 ug/L) to GHRH-(1-29) (1 ug/kg, i.v.) was significantly blunted when compared with the response in normal control subjects (25.7 +/- 1.8 ug/L; P < 0.05). After PYR (120 mg), the response to GHRH was enhanced in the obese subjects (21.4 +/- 4.9 ug/L; P < 0.05) and was similar to that of the controls with GHRH only, but remained significantly reduced compared with controls treated with PYR plus GHRH (43.2 +/- 6.0 ug/L; P < 0.05). Basal FFA levels were higher than those of normal controls (P < 0.05). ACX (500 mg) decreased FFA levels in both obese and normal subjects; the lowest FFA levels of obese subjects at 15 min were similar to those of normal controls. ACX also potentiated GHRH-stimulated GH response in both obese and normal subjects. The GH responses potentiated by ACX in obesity (22.7 +/- 5.5 ug/L) were similar to those of PYR plus GHRH in obese subjects and GHRH in normal controls, but they were lower than those of control treated with ACX plus GHRH (50.8 +/- 6.7 ug/L; P < 0.05). After the combined pretreatment with ACX and PYR, GH responses in obesity (44.1 +/- 6.0 ug/L) were significantly higher than those in GHRH test, PYR plus GHRH, and ACX plus GHRH in obese subjects (P < 0.05), and they were similar to PYR plus GHRH or ACX plus GHRH in normal controls. However their enhanced GH responses were reduced compared with the control with ACX plus PYR plus GHRH (64.9 +/- 4.5 ug/L; P < 0.05). Our results are in agreement with the hypothalamic hypothesis: an increase in somatostatinergic tone is responsible for the blunted GH response to GHRH in obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Cohort Studies; Drug Synergism; Fatty Acids, Nonesterified; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Hypolipidemic Agents; Kinetics; Male; Obesity; Pyrazines; Reference Values; Time Factors