Glucose homeostasis in abdominal obesity: hepatic hyperresponsiveness to growth hormone action

2004 ◽  
Vol 287 (1) ◽  
pp. E63-E68 ◽  
Author(s):  
M. M. Buijs ◽  
J. A. Romijn ◽  
J. Burggraaf ◽  
M. L. de Kam ◽  
M. Frölich ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Glucose Metabolism ◽  
Abdominal Obesity ◽  
Glucose Homeostasis ◽  
Premenopausal Women ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Normal Weight ◽  
Obese Women ◽  
Gh Secretion

It has been suggested that (abdominally) obese individuals are hypersensitive to growth hormone (GH) action. Because GH affects glucose metabolism, this may impact glucose homeostasis in abdominal obesity. Therefore, we studied the effect of GH on glucose metabolism in abdominally obese (OB) and normal-weight (NW) premenopausal women. A 1-h intravenous infusion of GH or placebo was randomly administered to six NW [body mass index (BMI) 21.1 ± 1.9 kg/m2] and six OB (BMI 35.5 ± 1.5 kg/m2) women in a crossover design. Insulin, glucagon, and GH secretion were suppressed by concomitant infusion of somatostatin. Glucose kinetics were measured using a 10-h infusion of [6,6-2H2]glucose. In both groups, similar physiological GH peaks were reached by infusion of GH. GH strongly stimulated endogenous glucose production (EGP) in both groups. The percent increase was significantly greater in OB than in NW women (29.8 ± 11.3 vs. 13.3 ± 7.4%, P = 0.014). Accordingly, GH responsiveness, defined as the maximum response of EGP per unit GH, was increased in OB vs. NW subjects (6.0 ± 2.1 vs. 2.2 ± 1.5 μmol·min−1·mU−1·l−1, P = 0.006). These results suggest that the liver is hyperresponsive to GH action in abdominally obese women. The role of the somatotropic ensemble in the control of glucose homeostasis in abdominal obesity is discussed.

scholarly journals The Decreased Growth Hormone Response to Growth Hormone Releasing Hormone in Obesity Is Associated to Cardiometabolic Risk Factors

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Fernando Cordido ◽  
Jesús Garcia-Buela ◽  
Susana Sangiao-Alvarellos ◽  
Teresa Martinez ◽  
Ovidio Vidal
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Cardiovascular Risk ◽  
Ldl Cholesterol ◽  
Premenopausal Women ◽  
Fasting Insulin ◽  
Risk Markers ◽  
Obese Women ◽  
Gh Secretion ◽  
The Metabolic Syndrome

The aim of the present study was to evaluate the relationship between GHRH-induced GH secretion in obese premenopausal women and cardiovascular risk markers or insulin resistance. Premenopausal obese women, aged 35–52 years, were studied. GH secretion, IGF-I, serum cardiovascular risk markers, insulin, leptin, mid-waist and hip circumference, total body fat, and truncal fat were measured. Subjects were classified as meeting the criteria for GH deficiency (GHD) when peak GH after stimulation with GHRH was≤3 μg/L. Mean total and LDL cholesterol, fasting insulin, and HOMA-IR were all higher, in subjects who would have been classified as GH-deficient compared with GH-sufficient. Peak GH secretion after stimulation was inversely associated with fasting insulin (R=−0.650,P=.012), HOMA-IR (R=−0.846,P=.001), total cholesterol (R=−0.532,P=.034), and LDL cholesterol (R=−0.692,P=.006) and positively associated with HDL cholesterol (R=0.561,P=.037). These data strongly suggest a role for insulin resistance in the decreased GH secretion of obesity and that the blunted GH secretion of central obesity could be the pituitary expression of the metabolic syndrome.

Estimation of growth hormone secretion rate: impact of kinetic assumptions intrinsic to the analytical approach

2001 ◽  
Vol 280 (1) ◽  
pp. R225-R232 ◽  
Author(s):  
Janneke G. Langendonk ◽  
Johannes D. Veldhuis ◽  
Jacobus Burggraaf ◽  
Rik C. Schoemaker ◽  
Adam F. Cohen ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Analytical Approach ◽  
Normal Weight ◽  
Secretion Rate ◽  
The Other ◽  
Upper Body ◽  
Metabolic Clearance ◽  
Obese Women ◽  
Gh Secretion ◽  
Plasma Gh

We compared four common mathematical techniques to determine daily endogenous growth hormone (GH) secretion rates from diurnal plasma GH concentration profiles in 24 women (16 upper- or lower-body obese and 8 normal-weight individuals). Two forms of deconvolution analysis and two techniques based on a priori determined GH clearance estimates were employed. Deconvolution analyses revealed significant differences in the 24-h GH secretion rate between normal-weight and upper-body obese women, whereas the other two techniques did not. Moreover, deconvolution analyses predicted that the reduction in mean plasma GH concentrations in upper-body obese women was accounted for by impaired GH secretion, whereas the other methods suggested that obesity increases GH metabolic clearance. Thus we infer that disparate conclusions concerning GH secretion can be drawn from the same primary data set. The different inferences likely reflect dissimilar kinetic assumptions and the particular limitations intrinsic to each analytical approach. Accordingly, we urge caution in the facile comparison of calculated GH secretion data in humans, especially when kinetic and secretion measurements are performed under different conditions. The most appropriate way to determine the GH secretion rate in humans must be balanced by the exact intent of the experiment and the acceptability of different assumptions in that context.

Basal and insulin-regulated free fatty acid and glucose metabolism in humans

2007 ◽  
Vol 292 (6) ◽  
pp. E1770-E1774 ◽  
Author(s):  
Samyah Shadid ◽  
Jill A. Kanaley ◽  
Michael T. Sheehan ◽  
Michael D. Jensen
Keyword(s):  
Glucose Metabolism ◽  
Body Fat ◽  
Premenopausal Women ◽  
Glucose Production ◽  
Normal Weight ◽  
Fat Free Mass ◽  
Glucose Disposal ◽  
Percent Body Fat ◽  
Class Iii ◽  
Glucose Flux

These studies were done to examine the effects of body composition, resting energy expenditure (REE), sex, and fitness on basal and insulin-regulated FFA and glucose metabolism. We performed 137 experiments in 101 nondiabetic, premenopausal women and men, ranging from low normal weight to class III obese (BMI 18.0–40.5 kg/m2). Glucose flux was measured using [6-2H2]glucose and FFA kinetics with [9,10-3H]oleate under either basal (74 experiments) or euglycemic hyperinsulinemic (1.0 mU·kg FFM−1·min−1) clamp conditions (63 experiments). Consistent with our previous findings, REE and sex independently predicted basal FFA flux, whereas fat-free mass was the best predictor of basal glucose flux; in addition, percent body fat was independently and positively associated with basal glucose flux (total r2 = 0.52, P < 0.0001). Insulin-suppressed lipolysis remained significantly associated with REE ( r = 0.25, P < 0.05), but percent body fat also contributed (total adjusted r2 = 0.36, P < 0.0001), whereas sex was not significantly related to insulin-suppressed FFA flux. Glucose disposal during hyperinsulinemia was independently associated with peak V̇o2, percent body fat, and FFA concentrations (total r2 = 0.63, P < 0.0001) but not with sex. We conclude that basal glucose production is independently related to both FFM and body fatness. In addition, hyperinsulinemia obscures the sex differences in FFA release relative to REE, but brings out the effects of fatness on lipolysis.

Influence of obesity and body fat distribution on growth hormone kinetics in humans

1999 ◽  
Vol 277 (5) ◽  
pp. E824-E829 ◽  
Author(s):  
Janneke G. Langendonk ◽  
A. Edo Meinders ◽  
Jacobus Burggraaf ◽  
Marijke Frölich ◽  
Corné A. M. Roelen ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Fat ◽  
Premenopausal Women ◽  
Human Growth ◽  
Fat Distribution ◽  
Normal Weight ◽  
Body Fat Distribution ◽  
Upper Body ◽  
Gh Secretion ◽  
Plasma Gh

We studied the kinetics of exogenous recombinant 22-kDa human growth hormone (rhGH) in premenopausal women with upper body obesity (UBO), lower body obesity (LBO), or normal body weight. A bolus of 100 mU rhGH was administered during a continuous infusion of somatostatin to suppress endogenous GH secretion. GH kinetics were investigated with noncompartmental analysis of plasma GH curves. GH peak values in response to GH infusion and plasma half-life of GH were not significantly different between normal weight and obese subjects. In contrast, GH clearance was 33% higher in LBO women and 51% higher in UBO women compared with clearance in normal weight controls. The difference in clearance between LBO and UBO was not statistically significant. Altered GH clearance characteristics contribute to low circulating GH levels in obese humans. Body fat distribution does not appear to affect GH kinetics.

scholarly journals Peak Growth Hormone-Releasing Hormone-Arginine-Stimulated Growth Hormone Is Inversely Associated with Intramyocellular and Intrahepatic Lipid Content in Premenopausal Women with Obesity

2009 ◽  
Vol 94 (10) ◽  
pp. 3995-4002 ◽  
Author(s):  
Miriam A. Bredella ◽  
Martin Torriani ◽  
Bijoy J. Thomas ◽  
Reza Hosseini Ghomi ◽  
Danielle J. Brick ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Growth Hormone ◽  
Premenopausal Women ◽  
Normal Weight ◽  
Visceral Adiposity ◽  
Gh Secretion ◽  
The Metabolic Syndrome ◽  
Intrahepatic Lipids ◽  
Peak Growth Hormone

Context: Visceral adiposity is a strong determinant of GH secretion, and low endogenous GH secretion is associated with increased insulin resistance, a key component of the metabolic syndrome. Increased fat accumulation in skeletal muscle and liver may play an etiological role in the development of insulin resistance and other complications of the metabolic syndrome. Little is known about the role of decreased endogenous GH secretion in the pathogenesis of insulin resistance in obesity. Objective: To investigate the relationship between intramyocellular lipids (IMCL), intrahepatic lipids, and peak-stimulated GH in premenopausal women with obesity. Design and Setting: We conducted a cross-sectional study at a clinical translational research center. Patients: Patients included 21 premenopausal women with obesity (mean body mass index, 34.0 ± 4.5 kg/m2) and 17 normal-weight controls (mean body mass index, 21.9 ± 2.0 kg/m2) of comparable mean age. Main Outcomes Measures: IMCL and intrahepatic lipids were measured with proton magnetic resonance spectroscopy (1H-MRS). Body composition was measured with magnetic resonance imaging. Peak GH was measured after stimulation with GHRH-arginine. Results: Obese subjects had higher IMCL, intrahepatic lipids, abdominal and thigh fat, and thigh muscle mass compared with normal-weight controls. There were strong inverse associations between peak GH and both IMCL and intrahepatic lipids independent of age and visceral adiposity. There were positive associations between IMCL and intrahepatic lipids with measures of insulin resistance and serum triglycerides. Conclusion: In premenopausal women with obesity, peak GH is inversely associated with IMCL and intrahepatic lipids independent of age and visceral adiposity. This suggests that low GH may contribute to insulin resistance in obesity through effects on muscle and intrahepatic lipids. Peak growth hormone after GHRH-arginine stimulation is inversely associated with intramyocellular and intrahepatic lipids in premenopausal women with obesity.

Acipimox enhances spontaneous growth hormone secretion in obese women

2004 ◽  
Vol 286 (4) ◽  
pp. R693-R698 ◽  
Author(s):  
Petra Kok ◽  
Madelon M. Buijs ◽  
Simon W. Kok ◽  
Inge H. A. P. van Ierssel ◽  
Marijke Frölich ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Normal Weight ◽  
Control Group ◽  
Time Interval ◽  
Obese Women ◽  
Double Blind ◽  
Deconvolution Analysis ◽  
Gh Secretion

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/m2) 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·lVd-1·24 h-1, P = 0.005, where lVd is liter of distribution volume). Acipimox considerably enhanced total (113 ± 50 vs. 66 ± 10 mU·lVd-1·24 h-1, P = 0.02) and pulsatile GH secretion (109 ± 49 vs. 62 ± 30 mU·lVd-1·24 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.

scholarly journals Growth hormone signaling and action in obese versus lean human subjects

2019 ◽  
Vol 316 (2) ◽  
pp. E333-E344 ◽  
Author(s):  
Morten Lyng Høgild ◽  
Ann Mosegaard Bak ◽  
Steen Bønløkke Pedersen ◽  
Jørgen Rungby ◽  
Jan Frystyk ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Human Subjects ◽  
Glucose Production ◽  
Relative Increase ◽  
Antagonistic Effect ◽  
Endogenous Glucose Production ◽  
Metabolic Adaptation ◽  
Igf I

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, −66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.

Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

2002 ◽  
Vol 282 (6) ◽  
pp. E1360-E1368 ◽  
Author(s):  
Thongchai Pratipanawatr ◽  
Wilailak Pratipanawatr ◽  
Clifford Rosen ◽  
Rachele Berria ◽  
Mandeep Bajaj ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Control Subjects ◽  
Igf I ◽  
Plasma Ffa ◽  
Type 2 Diabetic

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg−1 · min−1) clamp and a two-step euglycemic IGF-I (26 and 52 pmol · kg−1 · min−1) clamp with [3-3H]glucose, [1-14C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (Rd) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of Rd (second clamp step) in response to both insulin and IGF-I was reduced by ∼40–50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin ( P < 0.01–0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects ( P < 0.05–0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.

scholarly journals Insulin action in growth hormone-deficient and age-matched control rats: effect of growth hormone treatment

1999 ◽  
Vol 160 (1) ◽  
pp. 127-135 ◽  
Author(s):  
◽  
JL Laustsen ◽  
BS Hansen ◽  
EA Richter
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
Glucose Metabolism ◽  
Recombinant Human Growth Hormone ◽  
Normal Weight ◽  
Lower Amount ◽  
Control Group ◽  
Muscle Fibre Size ◽  
Igf I

The isolated effect of growth hormone on carbohydrate metabolism in rat skeletal muscle was studied in growth hormone-deficient dwarf rats (dw/dw) treated with either recombinant human growth hormone or saline for 10 days. In addition, age-matched heterozygous (DW/dw) (normal weight and plasma IGF-I) control rats were treated with saline. Growth hormone increased weight gain from 0.1+/-0.1 (s.e.m) to 3.6+/-0.1 g/day and plasma IGF-I concentration from 364+/-23 to 451+/-32 ng/ml. Glucose metabolism in skeletal muscle perfused with basal, submaximal and maximal concentrations (0, 600 and 60 000 pmol/l respectively) of insulin was not changed by growth hormone. No change could be detected in the total number of glucose transporters (GLUT1 and GLUT4) in the skeletal muscles, except from a lower amount of GLUT4 in the soleus muscle in the heterozygous control group. However, at submaximal insulin concentrations, skeletal muscle glucose uptake and transport were significantly lower in the heterozygous control group compared with the growth hormone-deficient group. This could indicate either a direct long-term effect of growth hormone or more likely a secondary effect attributable to the difference in body weight (205.2+/-3.1 vs 361. 6+/-5.9 g for dwarf rats and heterozygous controls respectively), and thereby muscle fibre size, between the groups probably resulting in lower average interstitial insulin and glucose concentrations at a given plasma concentration in the heterozygous rats. It is concluded that restoration of subnormal growth hormone concentrations for 10 days has no effect on insulin-stimulated glucose metabolism in skeletal muscle in vitro.

scholarly journals Central effects of thyronamines on glucose metabolism in rats

2009 ◽  
Vol 201 (3) ◽  
pp. 377-386 ◽  
Author(s):  
Lars P Klieverik ◽  
Ewout Foppen ◽  
Mariëtte T Ackermans ◽  
Mireille J Serlie ◽  
Hans P Sauerwein ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Plasma Glucose ◽  
Plasma Insulin ◽  
Low Dose ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Central Administration ◽  
Stable Isotope Dilution ◽  
Glucoregulatory Hormones ◽  
The Central Nervous System

Thyronamines are naturally occurring, chemical relatives of thyroid hormone. Systemic administration of synthetic 3-iodothyronamine (T1AM) and – to a lesser extent – thyronamine (T0AM), leads to acute bradycardia, hypothermia, decreased metabolic rate, and hyperglycemia. This profile led us to hypothesize that the central nervous system is among the principal targets of thyronamines. We investigated whether a low dose i.c.v. infusion of synthetic thyronamines recapitulates the changes in glucose metabolism that occur following i.p. thyronamine administration. Plasma glucose, glucoregulatory hormones, and endogenous glucose production (EGP) using stable isotope dilution were monitored in rats before and 120 min after an i.p. (50 mg/kg) or i.c.v. (0.5 mg/kg) bolus infusion of T1AM, T0AM, or vehicle. To identify the peripheral effects of centrally administered thyronamines, drug-naive rats were also infused intravenously with low dose (0.5 mg/kg) thyronamines. Systemic T1AM rapidly increased EGP and plasma glucose, increased plasma glucagon, and corticosterone, but failed to change plasma insulin. Compared with i.p.-administered T1AM, a 100-fold lower dose administered centrally induced a more pronounced acute EGP increase and hyperglucagonemia while plasma insulin tended to decrease. Both systemic and central infusions of T0AM caused smaller increases in EGP, plasma glucose, and glucagon compared with T1AM. Neither T1AM nor T0AM influenced any of these parameters upon low dose i.v. administration. We conclude that central administration of low-dose thyronamines suffices to induce the acute alterations in glucoregulatory hormones and glucose metabolism following systemic thyronamine infusion. Our data indicate that thyronamines can act centrally to modulate glucose metabolism.

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