Krag MB, Gormsen LC, Guo Z, Christiansen JS, Jensen MD, Nielsen S, Jørgensen JO. Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab 292: E920 -E927, 2007. First published November 28, 2006; doi:10.1152/ajpendo.00374.2006.-The ability of growth hormone (GH) to stimulate lipolysis and cause insulin resistance in skeletal muscle may be causally linked, but the mechanisms remain obscure. We investigated the impact of GH on the turnover of FFA and VLDL-TG, intramuscular triglyceride content (IMTG), and insulin sensitivity (euglycemic clamp) in nine healthy men in a randomized double-blind placebo-controlled crossover study after 8 days treatment with (A) Placebo ϩ Placebo, (B) GH (2 mg daily) ϩ Placebo, and (C) GH (2 mg daily) ϩ Acipimox (250 mg ϫ 3 daily). In the basal state, GH (B) increased FFA levels (P Ͻ 0.05), palmitate turnover (P Ͻ 0.05), and lipid oxidation (P ϭ 0.05), but VLDL-TG kinetics were unaffected. Administration of acipimox (C) suppressed basal lipolysis but did not influence VLDL-TG kinetics. In the basal state, IMTG content increased after GH (B; P ϭ 0.03). Insulin resistance was induced by GH irrespective of concomitant acipimox (P Ͻ 0.001). The turnover of FFA and VLDL-TG was suppressed by hyperinsulinemia during placebo and GH, whereas coadministration of acipimox induced a rebound increase FFA turnover and VLDL-TG clearance. We conclude that these results show that GH-induced insulin resistance is associated with increased IMTG and unaltered VLDL-TG kinetics; we hypothesize that fat oxidation in muscle tissue is an important primary effect of GH and that circulating FFA rather than VLDL-TG constitute the major source for this process; and the role of IMTG in the development of GH-induced insulin resistance merits future research. acipimox; lipolysis; very-low-density lipoprotein-triglyceride kinetics; hyperinsulinemic euglycemic clamp; insulin sensitivity A REPRODUCIBLE EFFECT OF GROWTH HORMONE (GH) is mobilization of body fat and stimulation of lipid oxidation. Administration of a physiological GH bolus in the postabsorptive state increases circulating levels of free fatty acids (FFA) after a lag phase of 2 h, which is accompanied by suppression of the uptake and oxidation of glucose in skeletal muscle (35,36). Long-term GH administration translates into a significant reduction in fat mass, especially from the central compartments, and microdialysis studies demonstrate lipolysis directly in adipose tissue in vivo (10).The mechanisms underlying these effects of GH are not fully understood, but there is evidence to support that activation of the hormone-sensitive lipase is involved (9), and we (37) and others (41) have observed that coadministration of acipimox, a long-acting nicotinic acid analog, abrogates the GH-induced rise in FFA. Moreover, we have observed (38) that long-term administration of acipimox in GH-treated adult patients with GH deficiency did not af...

Patients with active acromegaly are insulin-resistant and glucose-intolerant, whereas children with growth hormone (GH) deficiency (GHD) are insulin-sensitive and may develop fasting hypoglycaemia. Surprisingly, however, hypopituitary adults with unsubstituted GHD tend to be insulin-resistant, which may worsen during GH substitution. During fasting, which may be considered the natural domain for the metabolic effects of GH, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation. In this particular context, insulin resistance appears to constitute a favourable metabolic adaptation. The problem is that GH substitution results in elevated circadian GH levels in non-fasting patients. The best way to address this challenge is to employ evening administration of GH and to tailor the dose. Insulin therapy may cause hypoglycaemia and GH substitution may cause hyperglycaemia. Such untoward effects should be minimized by carefully monitoring the individual patient.

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Measurement of serum insulin-like growth factor I (IGF-I) concentrations remains the single most important tool in the evaluation of growth hormone (GH) replacement in GH-deficient adults, and the therapeutic goal is to maintain the level within the age-adjusted normal range. In healthy adults, IGF-I levels do not differ between males and females, whereas spontaneous GH secretion is approximately twofold higher in females. Untreated GH-deficient women exhibit lower IGF-I levels compared with men, and the increase in serum IGF-I during GH replacement is also significantly less. Put together, these data suggest resistance to GH in women, which in healthy individuals is compensated for by increased GH secretion. Administration of oral oestrogen in healthy post-menopausal women suppresses hepatic IGF-I production and increases pituitary GH release, and oral oestrogen replacement in women with GH deficiency lowers IGF-I concentrations and increases the amount of GH necessary to obtain IGF-I target levels during treatment. These data clearly suggest that hepatic suppression of IGF-I production by oestrogen subserves the gender difference in GH sensitivity, but it is also likely that sex steroids may interact with the GH/IGF axis at further levels. There is also circumstantial evidence to indicate that testosterone stimulates IGF-I production, and it is speculated that a certain threshold level of androgens is essential to ensure hepatic IGF-I production. Whether these data should translate into earlier discontinuation of oestrogen replacement therapy in adult women with hypopituitarism merits consideration.

1) the increase in GH release during exercise is associated with the concomitant increase in body temperature, 2) GH stimulates sweat secretion and heat evaporation during exercise, which seems to be of distinct physiological significance, 3) ghrelin is not involved in exercise-induced GH release, 4) the impact of GH on substrate metabolism during exercise includes increased FFA turnover.