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      Growth Hormone and Insulin Resistance

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          Background: Experimental data in human subjects demonstrate that growth hormone (GH) acutely inhibits glucose disposal in skeletal muscle. The insulin-antagonistic effects are clinically relevant since active acromegaly is accompanied by glucose intolerance, whereas children with GH deficiency may develop fasting hypoglycemia. At the same time, GH stimulates the turnover and oxidation of free fatty acids (FFAs), and there is experimental evidence to suggest a causal link between elevated FFA levels and insulin resistance in skeletal muscle. During fasting, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation, which seems to constitute a favorable metabolic adaptation. Conclusions: Observational data in GH-deficient adults do not indicate that GH replacement is associated with significant impairment of glucose tolerance; however, care should be taken to avoid overdosing and to monitor glycemic control.

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          Most cited references 12

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          Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly.

          An understanding of the events that occur during GH receptor (GHR) signaling has facilitated the development of a GHR antagonist (pegvisomant) for use in humans. This molecule has been designed to compete with native GH for the GHR and to prevent its proper or functional dimerization-a process that is critical for GH signal transduction and IGF-I synthesis and secretion. Clinical trials in patients with acromegaly show GHR blockade to be an exciting new mode of therapy for this condition, and pegvisomant may have a therapeutic role in diseases, such as diabetes and malignancy, in which abnormalities of the GH/IGF-I axis have been observed. This review charts the discovery and development of GHR antagonists and details the experience gained in patients with acromegaly.
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            Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist.

            Pegvisomant is a GH receptor antagonist that blocks the peripheral actions of GH in acromegaly. Pegvisomant, in contrast to somatostatin (SMS) analogs, does not suppress the activity of the GH-producing adenoma. We assessed the effects of cotreatment with pegvisomant and SMS in acromegaly on GH secretion, IGF-I levels, and glucose tolerance. Eleven patients with persistent disease despite previous therapy underwent the following fixed treatment algorithm: 1) on SMS therapy, 2) off therapy for 2 months, 3) 6-wk treatment with 10 mg/d pegvisomant, 4) 6-wk treatment with 15 mg/d pegvisomant, and 5) 3-month treatment with 15 mg pegvisomant plus SMS. Blood was sampled in the fasting state and during an oral glucose tolerance test. Total serum IGF-I levels (micrograms per liter) decreased after pegvisomant, but the lowest levels were obtained with cotreatment [458 +/- 67 (SMS), 562 +/- 78 (active), 376 +/- 51 (10 mg), 269 (15 mg), 195 +/- 24 (combined) (P < 0.0001)]. Free and bioactive IGF-I changed in a similar pattern. Steady-state pegvisomant levels (micrograms per liter) were obtained, but SMS cotreatment increased pegvisomant levels by 20% (P = 0.02) [2631 +/- 616 (10 mg), 6536 +/- 1413 (15 mg), 8030 +/- 1914 (combined)]. Pegvisomant increased endogenous GH levels (micrograms per liter), which was countered by SMS cotreatment [5.1 +/- 1.3 (SMS), 8.9 +/- 2.9 (active), 14.6 +/- 4.9 (10 mg), 19.7 +/- 6.5 (15 mg), 11.8 +/- 2.8 (combined) (P < 0.01)]. Plasma glucose levels (millimoles per liter) were highest during SMS and lowest during pegvisomant 15 mg [2-h oral glucose tolerance test: 10.3 +/- 0.7 (SMS), 8.9 +/- 0.7 (active), 7.2 +/- 0.7 (10 mg), 6.5 +/- 0.5 (15 mg), 8.0 +/- 0.8 (combined) (P = 0.02)]. Dual blockade of the GH axis with pegvisomant and a SMS analog is feasible in acromegaly.
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              Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure.

              Stimulation of lipolysis and the induction of resistance to insulin's actions on glucose metabolism are well-recognized effects of growth hormone (GH). To evaluate whether these two features are causally linked, we studied the impact of pharmacologically induced antilipolysis in seven GH-deficient patients (mean [+/- SE] age 37 +/- 4 years). Each subject was studied under four different conditions: during continuation of GH replacement alone (A), after discontinuation of GH replacement for 2 days (B), after GH replacement and short-term coadministration of acipimox (250 mg, p.o., b.i.d., for 2 days) (C), and after administration of acipimox alone (D). At the end of each study, total and regional substrate metabolisms were assessed in the basal state and after a 3-h hyperinsulinemic/euglycemic clamp. Serum levels of free fatty acids (FFAs) were elevated with GH alone (A) and suppressed with acipimox (C and D). Basal rates of lipid oxidation were highest with GH alone (A), and suppressed by 50% with acipimox (B versus D, P < 0.01; A versus C, P < 0.05). Basal glucose oxidation rates were lowest with GH alone (A) and highest with acipimox (C and D) (P = 0.01). Insulin-stimulated rates of total glucose turnover were significantly lower with GH alone as compared with all other conditions (P = 0.004). Insulin sensitivity as assessed by the M value (rate of glucose infusion) was reduced with GH alone as compared with all other conditions (M value in mg. kg(-1). min(-1): GH alone [A], 2.55 +/- 0.64; discontinuation of GH [B], 4.01 +/- 0.70; GH plus acipimox [C], 3.96 +/- 1.34; acipimox alone [D], 4.96 +/- 0.91; P < 0.01). During pharmacological antilipolysis, GH did not significantly influence insulin sensitivity (C versus D; P = 0.19). From our results, we reached the following conclusions: 1) Our data strongly suggest that the insulin antagonistic actions of GH on glucose metabolism are causally linked to the concomitant activation of lipolysis. 2) In addition, GH may induce residual insulin resistance through non-FFA-dependent mechanisms. 3) The cellular and molecular mechanisms subserving the insulin antagonistic effects of GH remain to be elucidated.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                February 2007
                15 February 2007
                : 67
                : Suppl 1
                : 33-36
                Medical Department M (Endocrinology and Diabetes) and Institute of Experimental Clinical Research, Aarhus University Hospital, Aarhus, Denmark
                97549 Horm Res 2007;67:33–36
                © 2007 S. Karger AG, Basel

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