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Traditional and novel aspects of the metabolic actions of growth hormone
YGHIR-01077; No of Pages 7 Growth Hormone & IGF Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Traditional and novel aspects of the metabolic actions of growth hormone Mark A. Sperling Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Children's Hospital, University of Pittsburgh School of Medicine, United States
a r t i c l e
i n f o
Article history: Received 5 June 2015 Accepted 5 June 2015 Available online xxxx Keywords: Growth hormone Growth hormone receptors Metabolism Carbohydrate Fat Protein
a b s t r a c t Growth hormone has been known to be diabetogenic for almost a century and it's diabetogenic properties fostered consideration of excessive and abnormal GH secretion as a cause of diabetes, as well as a role in the microvascular complications, especially retinopathy. However, besides inducing insulin resistance, GH also is lipolytic and a major anabolic hormone for nitrogen retention and protein synthesis. These actions are best illustrated at the extremes of GH secretion: Gigantism/acromegaly is characterized by excessive growth, CHO intolerance, hyperplasia of bone, little body fat and prominent muscle development, whereas total deficiency of GH secretion or action is associated with adiposity, poor growth, and poor muscle development. These actions also become apparent during puberty and pregnancy, times when GH secretion is increased and account for the characteristic changes in body composition and tendency to diabetes. More recently, tissue specific deletions of the GH receptor (GHR), have uncovered newer metabolic effects including it's essential role in triglyceride export from the liver when GHR is deleted in the liver, leading to hepatic steatosis and ultimately to hepatic adenoma formation, effects which may explain these findings in obesity, a state of diminished GH secretion and action. In addition deletion of GH action in muscle and fat is associated with specific patterns of disturbed phenotype and metabolic effects in CHO, fat, and protein metabolism affecting the specific tissue and whole body function. This chapter provides an overview of these classic and newer metabolic functions of GH, placing this hormone and its actions in a central role of body fuel economy in health and disease. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction A metabolic role for growth hormone (GH) has been postulated for over 80 years, one of the first being the Nobel laureate Bernardo Houssay, who showed in 1930 that hyperglycemia and other biochemical abnormalities improved after hypophysectomy in experimental-induced diabetes in dogs [1,2]. By contrast, injections of pituitary extracts, and later purified GH, resulted in hyperglycemia and frank diabetes, younger dogs being more resistant to these effects than adult dogs; complications of diabetes such as retinopathy improved after pituitary infarction during labor and delivery in pregnancy (Sheehan's syndrome). In humans, acromegaly was associated with a greater prevalence of diabetes which could be provoked by several days of GH administration [2]. So strong were these associations that it was believed for some time that GH, or other hormonal abnormalities, might be the cause of diabetes and contribute to the complications. Indeed, until the advent of laser therapy in the mid-1970s, the standard therapy for proliferative retinopathy associated with diabetes was pituitary ablation via surgery or implantation of radioactive yttrium into the pituitary fossa [3]. 2. Metabolic effects of infused growth hormone The availability of purified human GH extracted from cadaveric pituitaries, permitted a more detailed investigation of the metabolic effects of GH infused to healthy volunteers [4]. An intravenous
injection of 5 mg of GH (now known to be a pharmacological dose), resulted in a rise of free fatty acids (FFAs) and impairment of glucose disposal during an intravenous glucose tolerance test (Fig. 1a); the k value is the slope of glucose disappearance after an intravenous bolus so that the higher the slope, the more rapid the decline in glucose reflecting the effects of insulin. Notably, both the rise in FFA, as well as the diabetic k value take time to develop, and are preceded by an insulin-like effect as evident in the fall of FFA and initially higher K value. An infusion of GH at 2 mg/h for 5 h induced a rise in FFA, and a small rise in glucose after 2 h; oral glucose tolerance became frankly diabetic despite a large increment in insulin secretion, and the fall of FFA in response to the insulin was blunted (Fig. 1b). In other studies it was shown that GH stimulates amino acid uptake in muscle, even in vitro, suggesting a direct effect of GH [5]. Thus, GH is “diabetogenic” inducing insulin resistance and hyperglycemia, lipolytic and protein anabolic. In addition, it stimulates insulin release by enhancing insulin secretion from the pancreas and it stimulates growth of bone directly as well as indirectly via the generation of IGF-I primarily in the liver (Fig. 2). The significance of these effects is noted in patients who have growth hormone excess in infancy–childhood as exaggerated muscle and bone development, little fat and abnormal carbohydrate (CHO) metabolism; and in those with absent GH effects, as in Laron syndrome, with poor growth and poor muscle development with excessive fat deposits. In normal children, the effects of GH are noted during puberty.
http://dx.doi.org/10.1016/j.ghir.2015.06.005 1096-6374/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
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M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx
area under the glucose curve remain the same. However, the insulin response is 2–3 fold higher in puberty, irrespective of the amount of administered glucose [6]. Using the technique of the euglycemic glucose clamp, it was shown that the insulin sensitivity index is about twice as high in pre-pubertal as in pubertal children (Fig. 4). When a cohort of prepubertal children was followed longitudinally during puberty, the insulin sensitivity index measured via the euglycemic clamp approach fell by about 50%, whereas the first-phase insulin response, measured via the hyperglycemic clamp approach, doubled [7]. Thus, normal children compensate for insulin resistance during puberty by doubling their insulin response. Of the hormonal changes during puberty, it is not the sex steroids but increased GH secretion at night that is responsible for this change in insulin sensitivity and the resultant need for increased insulin secretion, a situation similar to that of the third trimester of pregnancy. Those who cannot achieve this required increase in insulin secretion, because they have a genetic defect such as MODY, or other defects in insulin secretion including ongoing autoimmune destruction, manifest that they have, or are developing diabetes. This explains why one of the peaks of presentation of diabetes is at puberty, and why gestational diabetes occurs during pregnancy, disappears after the separation of the placenta, and may reappear years later as the defect in insulin secretion becomes worse and cannot compensate for insulin resistance of obesity or other factors. 4. Protein metabolism during puberty Protein anabolism is markedly increased during puberty as a result of increased GH secretion together with increased insulin secretion, evident from increased rates of protein synthesis in the whole body, as well as the increased extraction of amino acids during infusions of glucose. Thus, during a hyperglycemic clamp, the extraction of the branched chain amino acids leucine, iso-leucine and valine, is greater in pubertal than in pre-pubertal children [8]. Treatment of GH deficient children with GH can restore whole body protein synthesis rates to the same levels as seen in normal age-matched controls, but treatment of such GH deficient children with IGF-I, does not restore normal rates of protein synthesis [9]. Thus, the increased body muscle mass during puberty in males and females, depends on the synergistic effects of GH and insulin, together with the sex steroids, estrogen in females and testosterone in males. The androgenic effects on muscle are greater than those of estrogens, contributing to the greater muscle mass formation in males; estrogens promote greater fat accumulation. 5. Lipid metabolism during puberty
Fig. 1. a. Effects of growth hormone (GH) on intravenous glucose tolerance and nonesterified fatty acids (NEFAs). Note that the k value, an index of insulin-like effects, increases shortly after the glucose bolus and NEFA declines 10 min after the bolus of GH. Thus, initially GH has an “insulin-like effect”. The k value steadily declines thereafter and NEFA levels rise, reflecting insulin resistance and lipolysis induced by GH. b. Oral glucose tolerance (OGTT) in the absence (control) and infusion of GH at 2 mg/h for 3 h before and 2 h after the oral glucose load. Note the induction of insulin resistance with frank diabetes despite a threefold increase in insulin. GH induces lipolysis but the uptake of fatty acids is not impaired during the OGTT when insulin is secreted.
3. Carbohydrate metabolism in children during puberty In normal children undergoing puberty, insulin resistance is manifest as a 2–3 fold increase in the insulin response to an oral glucose tolerance test, whether the dose of glucose is given at a dose of 1.75 g/kg, or “normalized” by giving 55 g/M2 (Fig. 3). In both of these methods of giving glucose, the fasting glucose concentration, peak glucose and
During puberty, rates of total body lipolysis, as reflected in the rates of glycerol turnover, increase by 30%–50%, associated with a 2–3 fold increase in the ratio of oxidation of lipid to the oxidation of glucose. As a result of increased oxidation of fat, caused by increased GH during puberty, fasting free fatty acid (FFA) levels decline. Thus, the effects of GH during puberty favor increased lipid turnover and oxidation, sparing glucose and amino-acids for anabolic growth and lowering fasting FFA. Similar changes also occur when peri-pubertal boys with idiopathic short stature are treated with standard doses of GH at 0.3 mg/kg/week [10]. Four months of such treatment resulted in a significant increase in fat free mass, as well as a decline in total fat mass and percent body fat; insulin as well as IGF-I levels increased, cholesterol and LDL levels declined, whereas HDL, FFA and triglycerides remained unchanged. Thus, treatment with GH for only 4 months in males with idiopathic short stature mimics puberty in significant changes of body composition as well as increasing insulin resistance and higher insulin secretion. In summary, increased GH secretion during puberty leads to: – Insulin resistance for carbohydrate metabolism, but not for protein metabolism.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx
Hypothalamus
Fat Lypolysis Pituitary G.H.
GHRH SRIF GHSRGHRELIN
Insulin Antagonism
Bone
Pituitary GH
Muscle Nitrogen Retention
3
IGF 1
Liver G.H. Receptor
Pancreas G.H. Binding Protein
β Cell Hyperplasia
Fig. 2. The metabolic effects of GH are summarized. GH is secreted in a pulsatile manner by the alternating effects of growth hormone releasing hormone (GHRH) and somatotropin release inhibiting factor (SRIF); a growth hormone secretagogue receptor for which ghrelin is the natural ligand also participates. GH induces insulin resistance in muscle and fat while at the same time facilitating nitrogen retention in the muscle and lipolysis in the fat tissue. The insulin resistance is overcome by increased insulin secretion which results in β-cell hyperplasia particularly in younger organisms. GH also induces growth in bones directly and via IGF-I generated in the liver after GH binds to its receptor (GHR); after binding GH, the extra cellular domain of the GHR is released into the circulation as GH binding protein.
– The resistance to insulin's effect on glucose is normally overcome by increased insulin secretion. – The increased insulin synergizes with growth hormone to enhance protein anabolism- sex steroids further enhance this effect (Testosterone N Estradiol). – Growth hormone enhances lipolysis and fat oxidation sparing glucose and amino acids for anabolism and growth.
degrees of glucose intolerance, explaining the peripubertal peak of incidence of diabetes, gestational diabetes, and the requirement for increasing the dose of insulin during puberty or pregnancy in those with diabetes. 1. Some newer recognized metabolic effects of growth hormone Recent studies using tissue-specific knockout of the GH receptor (GHR) have uncovered novel metabolic effects, when the GHR is deleted
Those who cannot compensate for the pubertal/pregnancy induced insulin resistance by increasing insulin secretion develop varying
P < 0.01
Insulin Sensitivity Index (mg/minxm2 /(logµm/mL))
P < 0.01
300 P < 0.05 Boys Girls 200
100
Prepubertal
Pubertal
Adapted from Bloch C, Clemens P, Sperling M. J Pediatrics . 1987; 110:481-87. Fig. 3. Impact of Puberty on glucose tolerance and insulin secretion during oral glucose tolerance tests. Two different doses of glucose were used, each showing that glucose tolerance remains unaltered, whereas insulin secretion increases markedly to overcome insulin resistance.
Fig 4. Changes in insulin sensitivity during puberty. The euglycemic clamp approach was used to demonstrate the higher insulin sensitivity in pre-pubertal children compared to pubertal children. Differences between boys and girls also are evident. See original reference for details of methodology.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
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M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx
in the liver, muscle or fat [11–18]. When GHR is deleted in the liver, circulating IGF-I concentrations decline by approximately 90–95%, but in the absence of the negative feedback effect of IGF-I, GH levels increase 3–4 fold from approximately 10 to 40 ng/ml [11]. There was no significant change in body size, length of bones such as the tibia, or difference in the width of the tibia growth plate [11]. IGF-I concentrations within the growth plate remained normal, because the high GH levels could act on the growth plate where the GHR was intact and functional. The high circulating GH levels induced insulin resistance as reflected in higher fasting insulin levels with normal glucose levels (Fig. 5). However, glucose tolerance after intraperitoneal (IP) glucose was clearly diabetic, and IP insulin demonstrated insulin resistance; there were no changes in the activities of key gluconeogenic enzymes, glucose-6-phosphatase (G6Pase), fructose 1–6 bisphosphonate (Fbp1), or phosphoenol carboxykinase 1 (Pck 1) (Fig. 5). Serum FFA levels were markedly higher, and the livers were enlarged and a paler color than normal, suggesting hepatic steatosis. Homogenization of the liver revealed a creamy layer at the surface confirming the excessive fat deposits in the liver, also
A
apparent after Oil-Red-O staining (Fig. 6). The 3 key enzymes involved in fat synthesis, sterol regulatory binding protein 1-C (Srb1c), fatty acid translocase (FAT) and PPRG were all markedly upregulated. Thus, there was increased fat synthesis within the liver. In addition, export of triglycerides was impaired so that less fat was being exported. Rescue of the GHR in the liver via an adenovirus which reconstituted GH action in the liver completely restored normal export of triglycerides (Fig. 6). Thus, GH action in the liver is essential for normal liver fat metabolism. This novel metabolic effect has now been demonstrated in other studies [17,18] and suggests the possibility of treating obese individuals with the metabolic syndrome and fatty liver with GH [17]. Moreover, in long-term follow up of mice with GHR deletion in the liver, about 30% go on to develop hepatic adenomas, preceded by evidence of inflammation and up-regulation of inflammatory and oncogenic pathways [13]. When GHR signaling is knocked out in muscle, mice lacking GHR develop metabolic features that were not observed in the IGF-1R knockouts including marked peripheral adiposity, insulin resistance, and
B
100
P<0.0005
80 60 40 20 0
GHRLD (n=6)
Control (n=8)
C 100
E 80 60 40 Control (n=9) GHRLD *** (n=9)
20 0 0
15
30
45
60
Minutes
D 600
Control (n=10) GHRLD *** (n=10)
500 400 300 200 100 0
Minutes
GHR-Effects on Glucose/Insulin Metabolism Fig. 5. GHR deletion in the liver: effects on glucose metabolism. Fasting glucose values are not significantly different (A), but insulin values are 2–3 fold higher suggesting resistance to insulin (B). Intra-peritoneal (IP) insulin injection demonstrates the extent of insulin resistance in the GHR liver-deleted animals (C), and IP glucose demonstrates diabetes (D). The three key glucogenic enzymes are not different, indicating that glucose clearance rather glucose production was responsible for the abnormalities in glucose. See text and reference [11] for details.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx
b
d
e
c
a
5
f
Fig. 6. GHR deletion in the liver: effects on lipid metabolism. Serum free fatty acids are increased (a) and livers are pale and larger, suggesting fat accumulation (b) evident as a creamy layer (arrow) after homogenization of the livers (c). Histology confirms fat accumulation especially with Oil-Red-O (d) staining. The expression of 3 key enzymes involved in triglyceride synthesis, Srebp-1c, FAT, and PPARγ, is increased about 5–10 fold (e). The export of triglycerides from the liver is diminished in the GHR liver after the expression of GHR is re-constituted via an adenovirus vector (f). Details of methodology can be found in reference [11].
glucose intolerance [12,15]. Insulin resistance in GHR-deficient myotubes was related to reduced Insulin Receptor protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101 [12]. The muscles of mice with GHR knockout demonstrate fat infiltration between and within muscle fibers (Fig. 7), making these mice weaker in activities requiring muscle strength. However, other investigators have not observed the same effects in their muscle specific GHR deletion studies [15]. When GHR is knocked out in fat tissue, there is a redistribution of fat with more going to subcutaneous sites and less formation of fat in visceral tissues (Figs. 8 and 9). The metabolic consequences of this adipose tissue redistribution are under investigation. For each of the tissues described, the deletion of GHR has resulted in novel changes in form (phenotype) and metabolic function of that tissue (metabolism), demonstrating that GH is a metabolic hormone,
essential for integrating metabolism and growth. Other recent reports also demonstrate novel effects of GHR deletion that may have a role in integrating immunity, inflammation and metabolism [19,20]. Conflict of interest statement No COI. References [1] J.D. Baird, W.M. Hunter, A.W. Smith, The relationship between human growth hormone and the development of diabetes mellitus and its complications, Postgrad. Med. J. 49 (Suppl. 1) (1973) 132–140. [2] R. Luft, R. Guillemin, Growth hormone and diabetes in man: old concepts—new implications, Diabetes 23 (9) (1974 Sep) 783–787.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
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Intermuscular infiltration of fat tissues in mice with muscle-specific GHR deletion
Fig. 7. Effects of GHR receptor deletion in muscle: intra-myocellular infiltration with fat is visible in the right photograph compared to the control on the left. Muscle function was weaker, movement diminished and obesity with impaired glucose tolerance was noted. Details are in reference [12].
Fig. 8. Effect of GHR deletion in fat tissue: deleting GHR in fat tissue results in re-distribution of fat from the visceral/supra-pubic fat pad (animal on left) to subcutaneous tissue (animal center). This is more evident in Fig. 9 which shows the ratios of visceral to sub-cutaneous fat tissue in control versus the GHR fat deletion (GHRFD) mice.
Ratio of fat weight (visceral to SubQ)
P<0.02 control vs GHRFD
Control
GHRFD
Fig. 9. Effect of GHR deletion in fat tissue: deleting GHR in fat tissue results in re-distribution of fat from the visceral/supra-pubic fat pad (animal on left) to subcutaneous tissue (animal center). This is more evident in this figure which shows the ratios of visceral to sub-cutaneous fat tissue in control versus the GHR fat deletion (GHRFD) mice.
[3] P.S. Sharp, T.J. Fallon, O.J. Brazier, L. Sandler, G.F. Joplin, E.M. Kohner, Long-term follow-up of patients who underwent yttrium-90 pituitary implantation for treatment of proliferative diabetic retinopathy, Diabetologia 30 (4) (1987 Apr) 199–207.
[4] W.H. Daughaday, D.M. Kipnis, The growth-promoting and anti-insulin actions of somatotropin, Recent Prog. Horm. Res. 22 (1966) 49–99. [5] N.A. Adamafio, R.J. Towns, J.L. Kostyo, Growth hormone receptors and action in BC3H-1 myocytes, Growth Regul. 1 (1) (1991 Mar) 17–22. [6] C.A. Bloch, P. Clemons, M.A. Sperling, Puberty decreases insulin sensitivity, J. Pediatr. 110 (3) (1987 Mar) 481–487. [7] T.S. Hannon, J. Janoski, S.A. Arslanian, Longitudinal study of physiologic insulin resistance and metabolic changes of puberty, Pediatr. Res. 60 (6) (2006 Dec) 759–763. [8] S. Caprio, G. Plewe, M.P. Diamond, D.C. Simonson, S.D. Boulware, R.S. Sherwin, W.V. Tamborlane, Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity, J. Pediatr. 114 (6) (1989 Jun) 963–967. [9] N. Mauras, K.M. Attie, E.O. Reiter, P. Saenger, J. Baptista, High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group, J. Clin. Endocrinol. Metab. 85 (10) (2000 Oct) 3653–3660. [10] T.S. Hannon, K. Danadian, C. Suprasongsin, S.A. Arslanian, Growth hormone treatment in adolescent males with idiopathic short stature: changes in body composition, protein, fat, and glucose metabolism, J. Clin. Endocrinol. Metab. 92 (8) (2007 Aug) 3033–3039. [11] Y. Fan, R.K. Menon, P. Cohen, D. Hwang, T. Clemens, D.J. DiGirolamo, J.J. Kopchick, D. LeRoith, M. Trucco, M. Sperling, Liver-specific deletion of the growth hormone receptor reveals essential role of GH signaling in hepatic lipid metabolism, J. Biol. Chem. 284 (30) (2009 Jul) 19937–19944. [12] M.D. Mavalli, D.J. DiGirolamo, Y. Fan, R.C. Riddle, K.S. Campbell, T. Van Groen, S.J. Frank, M.A. Sperling, K.A. Esser, M.M. Bammam, T.L. Clemens, Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice, J. Clin. Invest. 120 (11) (2010 Nov) 4007–4020. [13] Y. Fan, X. Fang, A. Tajima, X. Geng, S. Ranganathan, H. Dong, M. Trucco, M.A. Sperling, Evolution of hepatic steatosis to fibrosis and adenoma formation in liverspecific growth hormone receptor knockout mice, Front. Endocrinol. 5 (2014 Dec 18) 218. [14] E.O. List, D.E. Berryman, K. Funk, E.S. Gosney, A. Jara, B. Kelder, X. Wang, L. Kutz, K. Troike, N. Lozier, V. Mikula, E.R. Lubbers, H. Zhang, C. Vesel, R.K. Junnila, S.J. Frank, M.M. Masternak, A. Bartke, J.J. Kopchick, The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice, Mol. Endocrinol. 27 (3) (2013 Mar) 524–535. [15] A. Vijayakumar, Y. Wu, H. Sun, X. Li, Z. Jeddy, C. Liu, G.J. Schwartz, S. Yakar, D. LeRoith, Targeted loss of GHR signaling in mouse skeletal muscle protects against high-fat diet-induced metabolic deterioration, Diabetes 61 (1) (2012 Jan) 94–103. [16] E.O. List, D.E. Berryman, K. Funk, A. Jara, B. Kelder, F. Wang, M.B. Stout, X. Zhi, L. Sun, T.A. White, N.K. LeBrasseur, T. Pirtskhalava, T. Tchkonia, E.A. Jensen, W. Zhang, M.M. Masternak, J.L. Kirkland, R.A. Miller, A. Bartke, J.J. Kopchick, Liver-specific GH receptor gene-disrupted (LiGHRKO) mice have decreased endocrine IGF-I, increased local IGF-I, and altered body size, body composition, and adipokine profiles, Endocrinology 155 (5) (2014 May) 1793–1805. [17] J.L. Barclay, C.N. Nelson, M. Ishikawa, L.A. Murray, L.M. Kerr, T.R. McPhee, E.E. Powell, M.J. Waters, GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism, Endocrinology 152 (1) (2011 Jan) 181–192. [18] B.C. Sos, C. Harris, S.M. Nordstrom, J.L. Tran, M. Balázs, P. Caplazi, M. Febbraio, M.A. Applegate, K.U. Wagner, E.J. Weiss, Abrogation of growth hormone secretion rescues
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx fatty liver in mice with hepatocyte-specific deletion of JAK2, J. Clin. Invest. 121 (4) (2011 Apr) 1412–1423. [19] C. Lu, P. Kumar, Y. Fan, M.A. Sperling, R.K. Menon, A novel effect of GH on macrophage modulates macrophage-dependent adipocyte differentiation, Endocrinology 151 (5) (2010 May) 2189–2199.
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[20] C. Lu, P.A. Kuman, J. Sun, A. Aggarwal, Y. Fan, M.A. Sperling, C.N. Lumeng, R.K. Menon, Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity, J. Biol. Chem. 288 (22) (2013 May 31) 15725–15735.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Traditional and novel aspects of the metabolic actions of growth hormone Mark A. Sperling Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Children's Hospital, University of Pittsburgh School of Medicine, United States
a r t i c l e
i n f o
Article history: Received 5 June 2015 Accepted 5 June 2015 Available online xxxx Keywords: Growth hormone Growth hormone receptors Metabolism Carbohydrate Fat Protein
a b s t r a c t Growth hormone has been known to be diabetogenic for almost a century and it's diabetogenic properties fostered consideration of excessive and abnormal GH secretion as a cause of diabetes, as well as a role in the microvascular complications, especially retinopathy. However, besides inducing insulin resistance, GH also is lipolytic and a major anabolic hormone for nitrogen retention and protein synthesis. These actions are best illustrated at the extremes of GH secretion: Gigantism/acromegaly is characterized by excessive growth, CHO intolerance, hyperplasia of bone, little body fat and prominent muscle development, whereas total deficiency of GH secretion or action is associated with adiposity, poor growth, and poor muscle development. These actions also become apparent during puberty and pregnancy, times when GH secretion is increased and account for the characteristic changes in body composition and tendency to diabetes. More recently, tissue specific deletions of the GH receptor (GHR), have uncovered newer metabolic effects including it's essential role in triglyceride export from the liver when GHR is deleted in the liver, leading to hepatic steatosis and ultimately to hepatic adenoma formation, effects which may explain these findings in obesity, a state of diminished GH secretion and action. In addition deletion of GH action in muscle and fat is associated with specific patterns of disturbed phenotype and metabolic effects in CHO, fat, and protein metabolism affecting the specific tissue and whole body function. This chapter provides an overview of these classic and newer metabolic functions of GH, placing this hormone and its actions in a central role of body fuel economy in health and disease. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction A metabolic role for growth hormone (GH) has been postulated for over 80 years, one of the first being the Nobel laureate Bernardo Houssay, who showed in 1930 that hyperglycemia and other biochemical abnormalities improved after hypophysectomy in experimental-induced diabetes in dogs [1,2]. By contrast, injections of pituitary extracts, and later purified GH, resulted in hyperglycemia and frank diabetes, younger dogs being more resistant to these effects than adult dogs; complications of diabetes such as retinopathy improved after pituitary infarction during labor and delivery in pregnancy (Sheehan's syndrome). In humans, acromegaly was associated with a greater prevalence of diabetes which could be provoked by several days of GH administration [2]. So strong were these associations that it was believed for some time that GH, or other hormonal abnormalities, might be the cause of diabetes and contribute to the complications. Indeed, until the advent of laser therapy in the mid-1970s, the standard therapy for proliferative retinopathy associated with diabetes was pituitary ablation via surgery or implantation of radioactive yttrium into the pituitary fossa [3]. 2. Metabolic effects of infused growth hormone The availability of purified human GH extracted from cadaveric pituitaries, permitted a more detailed investigation of the metabolic effects of GH infused to healthy volunteers [4]. An intravenous
injection of 5 mg of GH (now known to be a pharmacological dose), resulted in a rise of free fatty acids (FFAs) and impairment of glucose disposal during an intravenous glucose tolerance test (Fig. 1a); the k value is the slope of glucose disappearance after an intravenous bolus so that the higher the slope, the more rapid the decline in glucose reflecting the effects of insulin. Notably, both the rise in FFA, as well as the diabetic k value take time to develop, and are preceded by an insulin-like effect as evident in the fall of FFA and initially higher K value. An infusion of GH at 2 mg/h for 5 h induced a rise in FFA, and a small rise in glucose after 2 h; oral glucose tolerance became frankly diabetic despite a large increment in insulin secretion, and the fall of FFA in response to the insulin was blunted (Fig. 1b). In other studies it was shown that GH stimulates amino acid uptake in muscle, even in vitro, suggesting a direct effect of GH [5]. Thus, GH is “diabetogenic” inducing insulin resistance and hyperglycemia, lipolytic and protein anabolic. In addition, it stimulates insulin release by enhancing insulin secretion from the pancreas and it stimulates growth of bone directly as well as indirectly via the generation of IGF-I primarily in the liver (Fig. 2). The significance of these effects is noted in patients who have growth hormone excess in infancy–childhood as exaggerated muscle and bone development, little fat and abnormal carbohydrate (CHO) metabolism; and in those with absent GH effects, as in Laron syndrome, with poor growth and poor muscle development with excessive fat deposits. In normal children, the effects of GH are noted during puberty.
http://dx.doi.org/10.1016/j.ghir.2015.06.005 1096-6374/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
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M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx
area under the glucose curve remain the same. However, the insulin response is 2–3 fold higher in puberty, irrespective of the amount of administered glucose [6]. Using the technique of the euglycemic glucose clamp, it was shown that the insulin sensitivity index is about twice as high in pre-pubertal as in pubertal children (Fig. 4). When a cohort of prepubertal children was followed longitudinally during puberty, the insulin sensitivity index measured via the euglycemic clamp approach fell by about 50%, whereas the first-phase insulin response, measured via the hyperglycemic clamp approach, doubled [7]. Thus, normal children compensate for insulin resistance during puberty by doubling their insulin response. Of the hormonal changes during puberty, it is not the sex steroids but increased GH secretion at night that is responsible for this change in insulin sensitivity and the resultant need for increased insulin secretion, a situation similar to that of the third trimester of pregnancy. Those who cannot achieve this required increase in insulin secretion, because they have a genetic defect such as MODY, or other defects in insulin secretion including ongoing autoimmune destruction, manifest that they have, or are developing diabetes. This explains why one of the peaks of presentation of diabetes is at puberty, and why gestational diabetes occurs during pregnancy, disappears after the separation of the placenta, and may reappear years later as the defect in insulin secretion becomes worse and cannot compensate for insulin resistance of obesity or other factors. 4. Protein metabolism during puberty Protein anabolism is markedly increased during puberty as a result of increased GH secretion together with increased insulin secretion, evident from increased rates of protein synthesis in the whole body, as well as the increased extraction of amino acids during infusions of glucose. Thus, during a hyperglycemic clamp, the extraction of the branched chain amino acids leucine, iso-leucine and valine, is greater in pubertal than in pre-pubertal children [8]. Treatment of GH deficient children with GH can restore whole body protein synthesis rates to the same levels as seen in normal age-matched controls, but treatment of such GH deficient children with IGF-I, does not restore normal rates of protein synthesis [9]. Thus, the increased body muscle mass during puberty in males and females, depends on the synergistic effects of GH and insulin, together with the sex steroids, estrogen in females and testosterone in males. The androgenic effects on muscle are greater than those of estrogens, contributing to the greater muscle mass formation in males; estrogens promote greater fat accumulation. 5. Lipid metabolism during puberty
Fig. 1. a. Effects of growth hormone (GH) on intravenous glucose tolerance and nonesterified fatty acids (NEFAs). Note that the k value, an index of insulin-like effects, increases shortly after the glucose bolus and NEFA declines 10 min after the bolus of GH. Thus, initially GH has an “insulin-like effect”. The k value steadily declines thereafter and NEFA levels rise, reflecting insulin resistance and lipolysis induced by GH. b. Oral glucose tolerance (OGTT) in the absence (control) and infusion of GH at 2 mg/h for 3 h before and 2 h after the oral glucose load. Note the induction of insulin resistance with frank diabetes despite a threefold increase in insulin. GH induces lipolysis but the uptake of fatty acids is not impaired during the OGTT when insulin is secreted.
3. Carbohydrate metabolism in children during puberty In normal children undergoing puberty, insulin resistance is manifest as a 2–3 fold increase in the insulin response to an oral glucose tolerance test, whether the dose of glucose is given at a dose of 1.75 g/kg, or “normalized” by giving 55 g/M2 (Fig. 3). In both of these methods of giving glucose, the fasting glucose concentration, peak glucose and
During puberty, rates of total body lipolysis, as reflected in the rates of glycerol turnover, increase by 30%–50%, associated with a 2–3 fold increase in the ratio of oxidation of lipid to the oxidation of glucose. As a result of increased oxidation of fat, caused by increased GH during puberty, fasting free fatty acid (FFA) levels decline. Thus, the effects of GH during puberty favor increased lipid turnover and oxidation, sparing glucose and amino-acids for anabolic growth and lowering fasting FFA. Similar changes also occur when peri-pubertal boys with idiopathic short stature are treated with standard doses of GH at 0.3 mg/kg/week [10]. Four months of such treatment resulted in a significant increase in fat free mass, as well as a decline in total fat mass and percent body fat; insulin as well as IGF-I levels increased, cholesterol and LDL levels declined, whereas HDL, FFA and triglycerides remained unchanged. Thus, treatment with GH for only 4 months in males with idiopathic short stature mimics puberty in significant changes of body composition as well as increasing insulin resistance and higher insulin secretion. In summary, increased GH secretion during puberty leads to: – Insulin resistance for carbohydrate metabolism, but not for protein metabolism.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx
Hypothalamus
Fat Lypolysis Pituitary G.H.
GHRH SRIF GHSRGHRELIN
Insulin Antagonism
Bone
Pituitary GH
Muscle Nitrogen Retention
3
IGF 1
Liver G.H. Receptor
Pancreas G.H. Binding Protein
β Cell Hyperplasia
Fig. 2. The metabolic effects of GH are summarized. GH is secreted in a pulsatile manner by the alternating effects of growth hormone releasing hormone (GHRH) and somatotropin release inhibiting factor (SRIF); a growth hormone secretagogue receptor for which ghrelin is the natural ligand also participates. GH induces insulin resistance in muscle and fat while at the same time facilitating nitrogen retention in the muscle and lipolysis in the fat tissue. The insulin resistance is overcome by increased insulin secretion which results in β-cell hyperplasia particularly in younger organisms. GH also induces growth in bones directly and via IGF-I generated in the liver after GH binds to its receptor (GHR); after binding GH, the extra cellular domain of the GHR is released into the circulation as GH binding protein.
– The resistance to insulin's effect on glucose is normally overcome by increased insulin secretion. – The increased insulin synergizes with growth hormone to enhance protein anabolism- sex steroids further enhance this effect (Testosterone N Estradiol). – Growth hormone enhances lipolysis and fat oxidation sparing glucose and amino acids for anabolism and growth.
degrees of glucose intolerance, explaining the peripubertal peak of incidence of diabetes, gestational diabetes, and the requirement for increasing the dose of insulin during puberty or pregnancy in those with diabetes. 1. Some newer recognized metabolic effects of growth hormone Recent studies using tissue-specific knockout of the GH receptor (GHR) have uncovered novel metabolic effects, when the GHR is deleted
Those who cannot compensate for the pubertal/pregnancy induced insulin resistance by increasing insulin secretion develop varying
P < 0.01
Insulin Sensitivity Index (mg/minxm2 /(logµm/mL))
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300 P < 0.05 Boys Girls 200
100
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Pubertal
Adapted from Bloch C, Clemens P, Sperling M. J Pediatrics . 1987; 110:481-87. Fig. 3. Impact of Puberty on glucose tolerance and insulin secretion during oral glucose tolerance tests. Two different doses of glucose were used, each showing that glucose tolerance remains unaltered, whereas insulin secretion increases markedly to overcome insulin resistance.
Fig 4. Changes in insulin sensitivity during puberty. The euglycemic clamp approach was used to demonstrate the higher insulin sensitivity in pre-pubertal children compared to pubertal children. Differences between boys and girls also are evident. See original reference for details of methodology.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
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in the liver, muscle or fat [11–18]. When GHR is deleted in the liver, circulating IGF-I concentrations decline by approximately 90–95%, but in the absence of the negative feedback effect of IGF-I, GH levels increase 3–4 fold from approximately 10 to 40 ng/ml [11]. There was no significant change in body size, length of bones such as the tibia, or difference in the width of the tibia growth plate [11]. IGF-I concentrations within the growth plate remained normal, because the high GH levels could act on the growth plate where the GHR was intact and functional. The high circulating GH levels induced insulin resistance as reflected in higher fasting insulin levels with normal glucose levels (Fig. 5). However, glucose tolerance after intraperitoneal (IP) glucose was clearly diabetic, and IP insulin demonstrated insulin resistance; there were no changes in the activities of key gluconeogenic enzymes, glucose-6-phosphatase (G6Pase), fructose 1–6 bisphosphonate (Fbp1), or phosphoenol carboxykinase 1 (Pck 1) (Fig. 5). Serum FFA levels were markedly higher, and the livers were enlarged and a paler color than normal, suggesting hepatic steatosis. Homogenization of the liver revealed a creamy layer at the surface confirming the excessive fat deposits in the liver, also
A
apparent after Oil-Red-O staining (Fig. 6). The 3 key enzymes involved in fat synthesis, sterol regulatory binding protein 1-C (Srb1c), fatty acid translocase (FAT) and PPRG were all markedly upregulated. Thus, there was increased fat synthesis within the liver. In addition, export of triglycerides was impaired so that less fat was being exported. Rescue of the GHR in the liver via an adenovirus which reconstituted GH action in the liver completely restored normal export of triglycerides (Fig. 6). Thus, GH action in the liver is essential for normal liver fat metabolism. This novel metabolic effect has now been demonstrated in other studies [17,18] and suggests the possibility of treating obese individuals with the metabolic syndrome and fatty liver with GH [17]. Moreover, in long-term follow up of mice with GHR deletion in the liver, about 30% go on to develop hepatic adenomas, preceded by evidence of inflammation and up-regulation of inflammatory and oncogenic pathways [13]. When GHR signaling is knocked out in muscle, mice lacking GHR develop metabolic features that were not observed in the IGF-1R knockouts including marked peripheral adiposity, insulin resistance, and
B
100
P<0.0005
80 60 40 20 0
GHRLD (n=6)
Control (n=8)
C 100
E 80 60 40 Control (n=9) GHRLD *** (n=9)
20 0 0
15
30
45
60
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D 600
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500 400 300 200 100 0
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GHR-Effects on Glucose/Insulin Metabolism Fig. 5. GHR deletion in the liver: effects on glucose metabolism. Fasting glucose values are not significantly different (A), but insulin values are 2–3 fold higher suggesting resistance to insulin (B). Intra-peritoneal (IP) insulin injection demonstrates the extent of insulin resistance in the GHR liver-deleted animals (C), and IP glucose demonstrates diabetes (D). The three key glucogenic enzymes are not different, indicating that glucose clearance rather glucose production was responsible for the abnormalities in glucose. See text and reference [11] for details.
Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005
M.A. Sperling / Growth Hormone & IGF Research xxx (2015) xxx–xxx
b
d
e
c
a
5
f
Fig. 6. GHR deletion in the liver: effects on lipid metabolism. Serum free fatty acids are increased (a) and livers are pale and larger, suggesting fat accumulation (b) evident as a creamy layer (arrow) after homogenization of the livers (c). Histology confirms fat accumulation especially with Oil-Red-O (d) staining. The expression of 3 key enzymes involved in triglyceride synthesis, Srebp-1c, FAT, and PPARγ, is increased about 5–10 fold (e). The export of triglycerides from the liver is diminished in the GHR liver after the expression of GHR is re-constituted via an adenovirus vector (f). Details of methodology can be found in reference [11].
glucose intolerance [12,15]. Insulin resistance in GHR-deficient myotubes was related to reduced Insulin Receptor protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101 [12]. The muscles of mice with GHR knockout demonstrate fat infiltration between and within muscle fibers (Fig. 7), making these mice weaker in activities requiring muscle strength. However, other investigators have not observed the same effects in their muscle specific GHR deletion studies [15]. When GHR is knocked out in fat tissue, there is a redistribution of fat with more going to subcutaneous sites and less formation of fat in visceral tissues (Figs. 8 and 9). The metabolic consequences of this adipose tissue redistribution are under investigation. For each of the tissues described, the deletion of GHR has resulted in novel changes in form (phenotype) and metabolic function of that tissue (metabolism), demonstrating that GH is a metabolic hormone,
essential for integrating metabolism and growth. Other recent reports also demonstrate novel effects of GHR deletion that may have a role in integrating immunity, inflammation and metabolism [19,20]. Conflict of interest statement No COI. References [1] J.D. Baird, W.M. Hunter, A.W. Smith, The relationship between human growth hormone and the development of diabetes mellitus and its complications, Postgrad. Med. J. 49 (Suppl. 1) (1973) 132–140. [2] R. Luft, R. Guillemin, Growth hormone and diabetes in man: old concepts—new implications, Diabetes 23 (9) (1974 Sep) 783–787.
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Intermuscular infiltration of fat tissues in mice with muscle-specific GHR deletion
Fig. 7. Effects of GHR receptor deletion in muscle: intra-myocellular infiltration with fat is visible in the right photograph compared to the control on the left. Muscle function was weaker, movement diminished and obesity with impaired glucose tolerance was noted. Details are in reference [12].
Fig. 8. Effect of GHR deletion in fat tissue: deleting GHR in fat tissue results in re-distribution of fat from the visceral/supra-pubic fat pad (animal on left) to subcutaneous tissue (animal center). This is more evident in Fig. 9 which shows the ratios of visceral to sub-cutaneous fat tissue in control versus the GHR fat deletion (GHRFD) mice.
Ratio of fat weight (visceral to SubQ)
P<0.02 control vs GHRFD
Control
GHRFD
Fig. 9. Effect of GHR deletion in fat tissue: deleting GHR in fat tissue results in re-distribution of fat from the visceral/supra-pubic fat pad (animal on left) to subcutaneous tissue (animal center). This is more evident in this figure which shows the ratios of visceral to sub-cutaneous fat tissue in control versus the GHR fat deletion (GHRFD) mice.
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Please cite this article as: M.A. Sperling, Traditional and novel aspects of the metabolic actions of growth hormone, Growth Horm. IGF Res. (2015), http://dx.doi.org/10.1016/j.ghir.2015.06.005