Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss.

Short sleep appears to be strongly associated with obesity and altered metabolic function, and sleep and growth hormone (GH) secretion seems interlinked. In obesity, both the GH-insulin-like-growth-factor-I (GH-IGF-I) axis and sleep have been reported to be abnormal, however, no studies have investigated sleep in relation to the GH-IGF-I axis and weight loss in obese subjects. In this study polygraphic sleep recordings, 24-h GH release, 24-h leptin levels, free-IGF-I, total-IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), cortisol and insulin sensitivity were determined in six severely obese subjects (BMI: 41+/-1 kg/m(2), 32+/-2 years of age), cross-sectional at baseline, and longitudinal after a dramatically diet-induced weight loss (36+/-7 kg). Ten age- and gender-matched nonobese subjects served as controls. Sleep duration (360+/-17 vs. 448+/-15 min/night; P<0.01), 24-h GH (55+/-9 vs. 344+/-55 mU/l.24 h; P<0.01), free-IGF-I (2.3+/-0.42 vs. 5.7+/-1.2 microg/l; P<0.01), and total-IGF-I (186+/-21 vs. 301+/-18 microg/l; P<0.01) were significantly decreased and 24-h leptin levels were increased (35+/-5 vs. 12+/-3 microg/l; P<0.01) in obese subjects at pre-weight loss compared with nonobese subjects After diet-induced weight loss the differences in GH, free IGF-I, and leptin were no longer present between previously obese and nonobese subjects, whereas a significant difference in sleep duration and total IGF-I levels persisted. Rapid eye movement (REM) sleep, non-REM sleep, IGFBP-3, ALS, and cortisol levels were similar in obese and nonobese subjects. Sleep duration, 24-h GH, and IGF-I levels were decreased and 24-h leptin levels were increased in obese subjects. We conclude that hyposomatotropism and hyperleptinemia in obesity are transient phenomena reversible with weight loss, whereas short sleep seems to persist after weight has been reduced dramatically.

Effect of weight loss on free insulin-like growth factor-I in obese women with hyposomatotropism.

OBJECTIVE: It has been hypothesized that increased free insulin-like growth factor (IGF)-I levels generated from an increase in IGF-binding protein (IGFBP) protease activity could be the inhibitory mechanism for the decreased growth hormone (GH) secretion observed in obese subjects. RESEARCH METHODS AND PROCEDURES: In this study, we determined basal and 24-hour levels of free IGF-I and -II, total IGF-I and -II, IGFBP-1, as well as basal IGFBP-2, -3, and -4, acid-labile subunit (ALS), IGFBP-1, -2, and -3 protease activity, and 24-hour GH release in obese women before and after a diet-induced weight loss. Sixteen obese women (age, 29.5+/-1.4 years) participated in a weight loss program and 16 age-matched non-obese women served as controls. RESULTS: Circulating free IGF-I and 24-hour GH release were significantly decreased in obese women at before weight loss compared with non-obese women (1.29+/-0.12 vs. 0.60+/-0.09 microg/L; p<0.001 and 862+/-90 vs. 404+/-77 mU/24 hours; p<0.001, respectively). Free IGF-I and 24-hour GH release were not inversely correlated to each other. IGFBP-1 and -2 levels were decreased, whereas ALS, IGFBP-3 and -4, and IGFBP-1, -2, and -3 protease activity were similar in obese and non-obese women. Eight of the 16 obese women achieved an average weight loss of 30+/-5 kg during 26 to 60 weeks of dieting. After the considerable weight loss, significant differences in free IGF-I, GH release, and IGFBP-1 and -2 levels were no longer present between previously obese and non-obese women. DISCUSSION: We showed that circulating free IGF-I is markedly decreased in severely obese women and does not per se mediate the concomitant hyposomatotropism. The decreased levels of free IGF-I seem to be transient and restored to normal levels after weight loss.

Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction.

BACKGROUND: Plasma tryptophan concentrations and the ratio of tryptophan to other large neutral amino acids (plasma tryptophan ratio) are reportedly low in obese subjects. The plasma tryptophan ratio predicts brain tryptophan uptake and serotonin production. If this ratio is low in obese subjects, serotonin function may also be low. Plasma tryptophan concentrations and ratios have been measured only at single time points in obese subjects; it is not known whether low values for these 2 variables persist throughout a 24-h period. OBJECTIVE: Our objective was to determine whether plasma tryptophan concentrations and ratios in obese subjects are lower than those in normal-weight subjects throughout a 24-h period and whether they increase when body weight is reduced. DESIGN: Plasma tryptophan concentrations and ratios were examined in obese subjects before and after weight loss and in nonobese control subjects. Blood samples were drawn frequently throughout the 24-h period. An insulin tolerance test was also used to determine whether weight loss altered the ability of insulin to modify plasma concentrations of tryptophan and of the other large neutral amino acids. RESULTS: Plasma tryptophan concentrations and ratios in obese subjects were low at all times; these effects persisted after weight reduction. Plasma concentrations of all the large neutral amino acids decreased during insulin infusion in all the groups. CONCLUSIONS: The low 24-h plasma tryptophan ratios in obese and formerly obese subjects suggest that brain tryptophan uptake may be continuously diminished and may remain below normal despite weight reduction.

A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate.

OBJECTIVE: NN703 (tabimorelin) is an orally active growth hormone (GH) secretagogue intended for use as an alternative to daily injections of GH. In vitro studies in human liver microsomes have indicated that NN703 is a mechanism-based inhibitor of CYP3A4. The aim of the present study was to investigate in man the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4. METHODS: Seventeen adult male subjects were enrolled in the study, and each received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day 1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day 9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam and its main metabolite, alpha-hydroxymidazolam, were investigated. RESULTS: Following a single dose of NN703 (day 3), the AUC of both midazolam and alpha-hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both). After repeated NN703 dosing (day 9), NN703 levels reached steady state, and midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas alpha-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline (n.s.). Following the washout period (day 16), midazolam AUC decreased to values lower than those on day 3 and day 9, but still significantly (45%) higher than baseline levels (P=0.0001). The C(max) values of midazolam and alpha-hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect following repeated NN703 dosing was more pronounced. The t(1/2) of midazolam increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady state on day 9. CONCLUSION: This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.