Patients with active acromegaly are frequently insulin resistant, glucose intolerant, and at risk for developing overt type 2 diabetes. At the same time, these patients have a relatively lean phenotype associated with mobilization and oxidation of free fatty acids. These features are reversed by curative surgical removal of the growth hormone (GH)-producing adenoma. Mouse models of acromegaly share many of these characteristics, including a lean phenotype and proneness to type 2 diabetes. There are, however, also species differences with respect to oxidation rates of glucose and fat as well as the specific mechanisms underlying GH-induced insulin resistance. The impact of acromegaly treatment on insulin sensitivity and glucose tolerance depends on the treatment modality (e.g. somatostatin analogs also suppress insulin secretion, whereas the GH antagonist restores insulin sensitivity). The interplay between animal research and clinical studies has proven useful in the field of acromegaly and should be continued in order to understand the metabolic actions of GH.

Hyperinsulinemia, glucose intolerance, and overt diabetes mellitus are common features of active acromegaly [1], and it is assumed that these abnormalities contribute to the observed increase in cardiovascular morbidity and mortality [2].

The effects of growth hormone (GH) on glucose and fat metabolism in adult human subjects were discovered early on when purified human pituitary GH became available [3]. The most striking effect of a single GH pulse is a distinct increase in circulating levels of free fatty acids (FFA) and ketone bodies [4], which reflects stimulation of lipolysis that peaks after 2-3 h and lasts for up to 8 h [5]. During physiological conditions, the FFA surge occurs in response to an endogenous GH pulse, which is predominantly released in the night and in response to fasting and exercise [6]. During conditions of sustained elevations of GH into the postprandial periods, glucose intolerance (mainly as a consequence of impaired glucose uptake in skeletal muscle) is evident [6]. This phenomenon has been causally linked to the lipolytic effects, with Raben [3] stating, ‘It is tempting to seek a unified explanation in which the hyperglycemia as well as ketosis is related to the increased mobilisation and use of fat that occurs with growth hormone.' Experimental studies from the same period in healthy human subjects demonstrate that GH directly antagonizes insulin-stimulated glucose uptake in skeletal muscle and at the same time promotes muscle uptake of FFA derived from adipose tissue [7]. More recently, it was shown that the antagonistic effects of GH on insulin-stimulated glucose uptake in skeletal muscle are abrogated by concomitant suppression of lipolysis [8]. It is therefore conceivable that similar mechanisms operate in patients with active acromegaly and account for the high prevalence of insulin resistance and diabetes mellitus.

The treatment of acromegaly has undergone important changes and improvements over the last decades with the introduction of slow-release somatostatin analogs (SA) and the GH receptor (GHR) antagonist pegvisomant. This has also expanded our knowledge regarding glucose and fat metabolism before and after treatment. In this regard, it is interesting that SA suppress not only GH secretion from the adenoma but also the secretion of insulin from pancreatic β cells. In addition, somatostatin exerts direct effects on the liver and on skeletal muscle that may influence the overall therapeutic effects [9,10]. More recently, an SA with a high affinity for somatostatin receptor subtype 5 (SST5) has proven efficacious but is also associated with more pronounced hyperglycemia [11]. In addition to clinical studies, transgenic mouse lines overexpressing GH and a GH antagonist have been developed and contribute to our mechanistic understanding of the pathophysiology and treatment of acromegaly.

This review will focus on glucose and fat metabolism in mice models of GH excess and in patients with acromegaly before and after surgical and medical treatment.

Animal models can serve as an important source of in vivo information and allow a more invasive analysis of alterations of lipid and glucose metabolism. To that end, mice that express a GH transgene were first generated and described over 30 years ago [12] and share many features with the clinical condition of acromegaly. Male and female GH transgenic mice have elevated GH and IGF-1 levels, as one would expect [12,13,14,15]. They also exhibit accelerated growth as well as increased body weight and lean mass, which are apparent by approximately 3 weeks of age and continue throughout life [12,13]. Most striking is the drastic reduction (∼50%) in the lifespan of GH transgenic mice compared to nontransgenic controls [16]. Since there are no comprehensive end-of-life pathology studies in bovine GH (bGH) mice, we do not know the precise cause of death. However, based on cross-sectional analyses of various tissues, there are a number of specific pathological organ changes, including severe glomerulosclerosis and lipid accumulation in the kidney, fibrosis in the heart, and enhanced senescence in adipose tissue, as well as enlargement of most GH-sensitive tissues, with the liver and spleen experiencing the greatest disproportionate increase in size [17,18,19,20,21,22,23,24,25,26]. There is also evidence of impaired cardiac and vascular function [18,27,28,29,30], notable kidney damage [31,32], and a greater incidence and earlier onset of liver and mammary tumors [33,34]. We speculate that all of these pathologies likely contribute to the dramatically reduced lifespan at varying levels.

GH transgenic mice have notable alterations in glucose metabolism depending on the particular strain, age, and sex of the mice studied. Overall, energy expenditure, as determined by indirect calorimetry, is substantially greater in these mice [35]. However, this difference appears to be due to the increase in lean mass as energy expenditure data normalized to fat-free mass shows no significant difference [36]. Regardless, the respiratory exchange ratio is elevated in adult GH transgenic mice, indicating a preference for glucose oxidation at least at the age assessed [35]. Younger adult GH transgenic mice are hyperinsulinemic and glucose intolerant despite normal levels of glucose in most studies [14,15,18]. However, several studies have reported improvements in glucose intolerance with advancing age [18,37], and one study showed enhanced insulin sensitivity and glucose tolerance at all ages in one transgenic mouse strain [24]. Although the inconsistencies may be due to the particular mice studied or specific experimental procedures, it has been hypothesized that the accelerated aging in these mice and their established tissue dysfunction, particularly in tissues such as the liver and kidney, which are pivotal in glucose handling, their excessive levels of the insulin-sensitizing hormone IGF-1, or their disproportionate amount of lean mass and disease progression at older ages may explain this phenomenon [37]. As might be expected, calorie restriction improves glucose homeostasis as well as adipokine profiles in these mice [38], while high-fat feeding exacerbates the hyperinsulinemic state despite bGh mice being protected from diet-induced obesity [35,36]. The molecular mechanisms responsible for this altered glucose metabolism have been best studied mainly in muscle and liver. Transgenic mice have a reduced hepatic expression of genes important for glucose metabolism including glucose transporter 2, glucokinase, and enzymes involved in the glycogenic and gluconeogenic pathways [39]. There is also a decrease in insulin receptor binding as well as a loss of sensitivity to early events in the insulin-signaling pathway in the liver [40]. In skeletal muscle, the high GH levels in these mice have been associated with a reduction of insulin receptors and impairment of insulin signaling (reduced insulin receptor tyrosine and IRS-1 tyrosine phosphorylation as well as defective activation of PI 3-kinase by insulin) [15]. In general, the molecular alteration in glucose metabolism has only been addressed in tissue collected from younger mice when data regarding whole-body glucose homeostasis would suggest an insulin resistant state. It would be of interest to assess these parameters in older mice when at least some of the transgenic mouse lines exhibit reductions in glucose and insulin levels and determine the precise physiological changes that occur with aging in these mice.

Based on the well-documented role of GH on lipolysis and lipogenesis, it is not surprising that lipid metabolism and body composition are also altered in these mice. As noted previously, adult GH transgenic mice (after 4 months of age in males and 6 months in females) are leaner than littermate controls and have a reduction in the mass of all adipose tissue depots [13,36,41] (fig. 1). Interestingly, they tend to be fatter than littermate controls at earlier time points. Although not studied in these mice, we speculate that the hormonal/metabolic milieu at early ages favors the known function of high GH and IGF-1 in promoting the proliferation and differentiation of preadipocyte precursor cells, resulting in an increased tissue mass, as opposed to higher lipolytic/antilipogenic function in later life [42]. Of note, the body composition in GH transgenic mice is sex dependent with, males demonstrating a stronger phenotypic difference than females compared to sex-specific controls [13]. Furthermore, GH transgenic mice are resistant to developing obesity when fed a high-fat diet [36], preferentially partitioning the increase in energy consumption to lean tissues. On standard show, these mice have aberrant cytokine/adipokine profiles with increases in circulating IL-6, TNF-α, MCP-1, and resistin and reductions in circulating leptin and adiponectin [18,38,41]. Transgenic mice have marked alterations in circulating levels of lipids and lipoproteins, with decreased FFA, triglycerides, VLDL cholesterol, and VLDL-apoB but increases in cholesterol within the LDL and HDL lipoprotein fractions [14]. Regarding the hepatic contribution to this lipid profile, transgenic mice have decreased triglyceride secretion compared to littermate controls [14] and reduced expression of the hepatic genes involved in fatty acid activation, peroxisomal and mitochondrial β-oxidation, and the production of ketone bodies [43]. This latter paper suggests that this alteration is, in part, due to a decrease in PPARα activity. In addition to the contribution of the liver, these mice show increased lipoprotein lipase activity in adipose tissue, heart, and skeletal muscle but unchanged LDL receptor activity [14].

Fig. 1

Longitudinal weight and body composition measures of GH transgenic and GHA transgenic mice. The center image shows a representative male GH transgenic mouse, a wild-type (WT) mouse, and a GHA transgenic mouse at 6 months of age. To the left of the image, graphs showing body weight (top) and percent fat mass (bottom) from 4 to 52 weeks of age for GH transgenic and littermate controls are provided (adapted with permission from Palmer et al. [13]). To the right of the image, graphs showing body weight (top) and percent fat mass (bottom) from 4 to 82 weeks of age for GHA transgenic mice and littermate controls are provided (adapted with permission from Berryman et al. [63]). Note that bGH mice have a significantly greater body weight throughout life while GHA mice are relatively dwarf in early life but catch up in body weight by approximately 1 year of age. In terms of percent body fat, bGH mice initially have a greater percent fat mass but show no significant gains compared to the striking increase in fat mass for littermate controls. In contrast, GHA mice are relatively obese throughout life.

Fig. 1

Longitudinal weight and body composition measures of GH transgenic and GHA transgenic mice. The center image shows a representative male GH transgenic mouse, a wild-type (WT) mouse, and a GHA transgenic mouse at 6 months of age. To the left of the image, graphs showing body weight (top) and percent fat mass (bottom) from 4 to 52 weeks of age for GH transgenic and littermate controls are provided (adapted with permission from Palmer et al. [13]). To the right of the image, graphs showing body weight (top) and percent fat mass (bottom) from 4 to 82 weeks of age for GHA transgenic mice and littermate controls are provided (adapted with permission from Berryman et al. [63]). Note that bGH mice have a significantly greater body weight throughout life while GHA mice are relatively dwarf in early life but catch up in body weight by approximately 1 year of age. In terms of percent body fat, bGH mice initially have a greater percent fat mass but show no significant gains compared to the striking increase in fat mass for littermate controls. In contrast, GHA mice are relatively obese throughout life.

Close modal

Hepatic and peripheral insulin resistance and increased glucose turnover are known features of active acromegaly [44,45]. Insulin resistance in skeletal muscle in terms of reduced nonoxidative glucose disposal has also been documented with the forearm technique in combination with indirect calorimetry [46].

Møller et al. [47] studied substrate metabolism and insulin sensitivity in newly diagnosed acromegalic patients before and several months after successful adenomectomy. Basal levels of insulin and glucose were significantly elevated before surgery and became normalized afterwards. Active acromegaly was also accompanied by a reduced forearm uptake of glucose, an increased hepatic glucose output, and insulin resistance in skeletal muscle, all of which normalized after surgery [47]. A relationship between biochemical markers of disease activity and glucose homeostasis after surgery has also been reported in terms of a higher prevalence of glucose intolerance in patients with residual disease after surgery [48] and an inverse correlation between serum IGF-I values and insulin sensitivity [2].

Patients with active acromegaly are also characterized by increased levels of FFA and other lipid intermediates (e.g. glycerol and 3-hydroxybutyrate) together with markedly increased lipid oxidation rates and forearm uptake of 3-hydroxybutyrate despite compensatory hyperinsulinemia, all of which is reversed by surgical cure [47]. Assessment of turnover rates (fluxes) of FFA by means of tracer kinetics has not been conducted in patients with acromegaly, but it has been shown that GH administration in GH-deficient adults also increases the flux of [9, 10-3H]palmitate (a fatty acid) in concomitance with elevated palmitate levels and lipid oxidation rates [49].

Somatostatin Analogs

The impact of SA administration on glucose and fat metabolism is ambiguous due to the concomitant suppression of GH and suppressive effects on insulin and glucagon secretion [50,51]. Moreover, somatostatin may also improve insulin-stimulated muscle glucose uptake via direct peripheral effects [10,52]. The net effect is thus a balance between suppression of the insulin antagonistic effects of GH and glucagon, suppression of insulin secretion, and putative peripheral effects of somatostatin on glucose uptake.

Depot preparations of SA, which provide sustained and stable reductions in circadian GH levels, have been available for 15 years [53]. Based on routine assessments, this treatment is traditionally not considered to be associated with clinically significant effects on glucose homeostasis [53]. Measurements of insulin sensitivity by a euglycemic glucose clamp and glucose tolerance have been assessed before and after 6 months of treatment with depot preparations in 24 patients with active acromegaly [54]. Glucose tolerance deteriorates after SA treatment together with suppressed insulin secretion [54]. This deterioration is accompanied by a small but significant increase in HbA1c levels after treatment. By contrast, insulin sensitivity increased significantly and became normalized in these same patients [54]. In a retrospective survey including 110 patients treated with octreotide LAR for 18-54 months, no ‘clinically meaningful increase in fasting glucose levels was observed (data not shown)' [55]. By contrast, a recent retrospective 6-year follow-up study reported a deterioration in glucose tolerance in patients treated with long-acting SA compared to patients who were successfully treated with surgery alone [56]. Fasting plasma glucose levels, HbA1c levels, and plasma glucose levels during an oral glucose tolerance test rise during medical treatment irrespectively of the effect on GH status. In surgically ‘cured' patients, the corresponding glycemic indices are lower and remain stable [56]. However, insulin sensitivity, as indirectly estimated from basal and stimulated serum levels of glucose and insulin, increases in acromegaly controlled by SA [56]. Taken together, it appears that treatment with SA impairs glucose tolerance due to suppression of insulin and at the same time improves hepatic and peripheral insulin sensitivity due to suppression of GH. At the clinical level this seems to translate into a slight deterioration of glucose homeostasis in some but not all patients.

Data on the impact of SA administration on lipolysis and lipid oxidation are sparse. Theoretically, the net result is a balance between the suppression of both GH, which is lipolytic, and insulin, which is lipogenic and antilipolytic. A short-term study with octreotide recorded postprandial elevations in serum FFA levels in response to octreotide [57]. Accordingly, we have data to suggest that acromegalic patients well controlled during treatment with long-acting SA exhibit elevated fasting serum levels of FFA compared to surgically controlled patients [unpubl. data].

A long-acting SA with a particularly high affinity for SST5, Signifor LAR (pasiereotide) was recently approved worldwide for the treatment of acromegaly and Cushing's disease and is currently licensed for the treatment of acromegaly in the US [11]. It appears that pasiereotide overall is more efficacious in lowering GH and IGF-I levels in acromegalic patients, but this is accompanied by a more than 2-fold higher risk of developing hyperglycemia (∼30 %) and diabetes mellitus (∼25%) as compared to patients treated with conventional SA (14 and 8%, respectively) [11]. In fact, an experimental study in which healthy subjects were treated with pasireotide for 7 days revealed that the diabetogenic effects of the drug are mainly attributed to suppression of insulin and incretin hormones, whereas hepatic and peripheral insulin sensitivity are unaffected [58]. Taken together, it seems evident that pasireotide, owing to its high binding affinity to all SST (except SST4), is associated with a higher risk of glucose intolerance and diabetes mellitus. Further studies are needed to define the optimal role for this new treatment modality in patients with acromegaly; this will include data on the management of treatment-associated diabetes mellitus. It would be of particular interest to develop risk models to predict the à priori risk of developing clinically significant hyperglycemia.

Pegvisomant

Pegvisomant is a GH analog that functions as a specific GHR antagonist. It includes a single amino acid substitution at position 120, which corresponds to binding site 2 for the GHR, and 8 amino acid substitutions within binding site 1 in addition to polyethylene glycol moieties that increase the half-life of the molecule [59]. It binds to the GHR in competition with native GH and prevents conformational changes of the preformed GHR dimer, which are critical for signal transduction [59].

The discovery of pegvisomant was due to the development and characterization of a novel transgenic mouse strain with reduced GH action, i.e. the GHR antagonist (GHA) mouse, produced by the laboratory of John Kopchick [60] in 1991. GHA mice express a mutated GH transgene, which results in reduced GH action and a ∼25-50% reduction in serum IGF-I compared to controls [45,46,47]. GHA mice have an overall dwarf phenotype [60]. Interestingly, by approximately 11 months of age, the body weight of male GHA mice gradually catches up with that of controls [61,62]. The eventual weight gain is caused by marked increases in adiposity without major gains in lean mass [62], showing that these mice remain dwarf but become markedly obese with advancing age. Other reports have shown GHA mice to be obese [41] with specific enlargement of the subcutaneous fat pad, a trait shared among other mice with a reduction in GH action [63]. Regarding glucose metabolism, age appears to be an important consideration, which may be associated with the age-related changes in adiposity in these mice. That is, young GHA mice tend to have lower levels of glucose and insulin [61,62] but higher levels with advancing age [61,62]. Interestingly, young GHA mice, which are already obese, are susceptible to further adipose tissue expansion with a high-fat diet challenge but remain resilient to alterations in glucose homeostasis with high-fat diet feeding [64]. To date, studies have not systematically explored the molecular mechanisms for the alterations observed in glucose metabolism in these mice.

Pegvisomant therapy effectively normalizes IGF-I levels in more than 90% of patients, many of whom have been partially resistant to SA [65],and this is associated with a reduction in fasting plasma glucose concentrations[66] and HbA1c levels [67,68]. The beneficial effects of pegvisomant on glucose metabolism seem to involve improvement of glucose tolerance [69] as well as insulin sensitivity [70,71]. There is also data to support that glucose tolerance improves in patients partially resistant to SA if that treatment is combined with pegvisomant [69,72].

Published data on pegvisomant therapy and FA metabolism are ambiguous, with one study reporting a moderate suppression of lipolysis and nocturnal FFA levels [73], and another study recording no significant differences in FFA levels, lipolysis, or lipid oxidation [71]. It is conceivable that prolonged suppression of the lipolytic effects of GH (by pegvisomant) will increase fat mass, which in turn eventually will tend to cause elevations in FFA levels. It is, however, important to note that the pegvisomant-induced improvements in glucose tolerance and insulin sensitivity are maintained during long-term treatment [74].

Active acromegaly is associated with glucose intolerance despite compensatory hyperinsulinemia and hepatic as well as peripheral insulin resistance. It is assumed that these aberrations contribute to the excess mortality. Recent studies obtained from mice models of GH excess and the development of a specific GH antagonist (and a mice model overexpressing this molecule) have provided novel data regarding the interaction between GH status and glucose and fat metabolism. Moreover, a novel SA with a unique SSTR affinity pattern has drawn renewed attention to glucose metabolism as a function of acromegaly and its treatment.

Even though GH transgenic mice share many characteristics with acromegalic patients, important differences exist. The shared characteristics include elevated GH and IGF-I levels, a lean body composition, increased organ growth, and a reduced lifespan if left untreated. The reduced fat mass together with a relative resistance to the development of diet-induced obesity observed in GH transgenic mice would suggest enhanced lipolysis and lipid oxidation, yet reduced serum FFA levels [14] and increased glucose oxidation rates [75] have been recorded. These data contrast distinctly with those recorded in patients with active acromegaly [47]. It is also noteworthy that enhanced adipose LPL activity has been reported in GH transgenic mice [14], which should cause an increased uptake of circulating TG in adipose tissue and hence predispose to adiposity. It also contrasts with studies in acromegalic patients and obese human subjects, where GH exposure suppresses LPL activity in adipose tissue [76,77]. However, caution in comparing results is necessary as GH impacts adipose tissue in a depot-specific manner and the adipose depots used in these studies are not comparable between the human-derived and clinical data. The predisposition to insulin resistance and glucose intolerance is not uniform across all GH transgenic strains, although all GH transgenic mouse strains tested so far respond similarly to high-fat feeding and are characterized by more frequent development of diabetes mellitus concomitantly with resistance to the development of obesity [35,36,41]. Interestingly, a reciprocal response pattern occurs in GHA mice, i.e. increased susceptibility to obesity but resilience to diabetes mellitus [64]. These latter observations support the assumption of a mechanistic link between two effects of GH: stimulation of lipolysis/lipid oxidation and induction of insulin resistance. Along this line, one study in GH transgenic mice showed that insulin resistance in skeletal muscle was associated with impairment of basal and stimulated insulin-signaling mechanisms [15]. However, several studies in human subjects have failed to document a similar effect [78,79,80]. There is, nevertheless, evidence to suggest that GH-induced insulin resistance in human skeletal muscle is causally linked to the concomitant increase in lipolysis [8] and that this is mediated via substrate competition between intermediates of glucose and fatty acids [81] (fig. 2).

Fig. 2

Mechanisms underlying GH-induced insulin resistance in skeletal muscle. Data in human subjects indicate a causal association between GH-induced lipolysis and inhibition of glucose uptake, respectively; suppression of pyruvate dehydrogenase by GH has also been shown, which ultimately inhibits glucose oxidation. Data in mice indicate that GH may act by directly suppressing insulin-signaling pathways. UDP = Uridine diphosphate glucose; CoA = coenzyme A; PDH = pyruvate dehydrogenase; OOA = oxaloacetate.

Fig. 2

Mechanisms underlying GH-induced insulin resistance in skeletal muscle. Data in human subjects indicate a causal association between GH-induced lipolysis and inhibition of glucose uptake, respectively; suppression of pyruvate dehydrogenase by GH has also been shown, which ultimately inhibits glucose oxidation. Data in mice indicate that GH may act by directly suppressing insulin-signaling pathways. UDP = Uridine diphosphate glucose; CoA = coenzyme A; PDH = pyruvate dehydrogenase; OOA = oxaloacetate.

Close modal

The reasons for the observed metabolic differences between GH transgenic mice and patients with acromegaly are not established with certainty but are likely to be numerous. First, it is likely that species-specific differences exist regarding the metabolic effects of GH; for instance, one study observed that GH does not modulate the initial release of FFA during fasting in the mouse [82]. Likewise, the epididymal fat pad, which has been most commonly used for mouse studies, has no clinical equivalent, requiring one to use caution in interpreting the clinical relevance of these studies. Second, GH transgenic mice overexpress GH in several tissues that normally do not express GH, which might lead to ‘unusual' GH effects. In addition, the circulating GH levels measured in GH transgenic mice are much higher compared to those in patients with active acromegaly. Finally, the experimental design does not always allow one to directly compare as more invasive techniques and longitudinal studies can be more readily done with mice than with a clinical population. For example, it is interesting that the phenotype of GH transgenic mice appears to change markedly as a function of age [18,37]. It remains to be investigated whether something similar occurs in patients. Irrespectively of these unresolved discrepancies, mice models constitute a valuable research tool and the fascinating history of GHA mice reminds us that mice models can be instrumental for the development of new and effective treatments for patients.

It is generally assumed that the suppressive effects of conventional SA on insulin secretion do not constitute a clinically significant problem for patients treated with these compounds. This, however, is likely to change with the use of pasireotide. At the present stage, it remains uncertain how this drug will fit into the treatment algorithm and how the diabetogenic effects are best alleviated.

In conclusion, the metabolic aberrations observed in both GH transgenic mice and patients with acromegaly give important insight into the many actions of GH, which translates into a lean phenotype and a predisposition to diabetes mellitus among others. The degree to which these effects contribute to the overall morbidity and mortality in acromegaly remains to be further investigated. A better understanding will require continued research in mice and humans and may generate data of relevance for our understanding of more prevalent diseases such as obesity and type 2 diabetes.

For further reading on acromegaly in this issue, see [83,84,85,86,87,88,89,90,91,92].

1.
Sönksen PH, Greenwood FC, Ellis JP, Lowy C, Rutherford A, Nabarro JD: Changes of carbohydrate tolerance in acromegaly with progress of the disease and in response to treatment. J Clin Endocrinol Metab 1967;27:1418-1430.
2.
Puder JJ, Nilavar S, Post KD, Freda PU: Relationship between disease-related morbidity and biochemical markers of activity in patients with acromegaly. J Clin Endocrinol Metab 2005;90:1972-1978.
3.
Raben MS: Growth hormone. 1. Physiologic aspects. N Engl J Med 1962;266:31-35.
4.
Møller N, Jørgensen JO, Schmitz O, Møller J, Christiansen J, Alberti KG, et al: Effects of a growth hormone pulse on total and forearm substrate fluxes in humans. Am J Physiol 1990;258:E86-E91.
5.
Krag MB, Gormsen LC, Guo Z, Christiansen JS, Jensen MD, Nielsen S, et al: Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab 2007;292:E920-E927.
6.
Møller N, Jørgensen JOL: Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev 2009;30:152-77.
7.
Rabinowitz D, Klassen GA, Zierler KL: Effect of human growth hormone on muscle and adipose tissue metabolism in the forearm of man. J Clin Invest 1965;44:51-61.
8.
Nielsen S, Møller N, Christiansen JS, Jørgensen JO: Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes 2001;50:2301-2308.
9.
Murray RD, Kim K, Ren S-G, Chelly M, Umehara Y, Melmed S: Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest 2004;114:349-356.
10.
Krusenstjerna-Hafstrøm T, Vestergaard ET, Buhl M, Nielsen R, Clasen BF, Nielsen S, et al: Acute peripheral metabolic effects of intraarterial leg infusion of somatostatin in healthy young men. J Clin Endocrinol Metab 2011;96:2581-2589.
11.
Gadelha MR, Bronstein MD, Brue T, Coculescu M, Fleseriu M, Guitelman M, et al: Pasireotide versus Continued Treatment with Octreotide or Lanreotide in Patients with Inadequately Controlled Acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol 2014;2:875-884.
12.
Palmiter RD, Brinster RL, Hammer RE, Trumbauer ME, Rosenfeld MG, Birnberg NC, et al: Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature 1982;300:611-615.
13.
Palmer AJ, Chung M-Y, List EO, Walker J, Okada S, Kopchick JJ, et al: Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology 2009;150:1353-1360.
14.
Frick F, Bohlooly-Y M, Lindén D, Olsson B, Törnell J, Edén S, et al: Long-term growth hormone excess induces marked alterations in lipoprotein metabolism in mice. Am J Physiol Endocrinol Metab 2001;281:E1230-E1239.
15.
Dominici FP, Cifone D, Bartke A, Turyn D: Alterations in the early steps of the insulin-signaling system in skeletal muscle of GH-transgenic mice. Am J Physiol 1999;277:E447-E454.
16.
Bartke A: Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 2003;78:210-216.
17.
Wolf E, Kahnt E, Ehrlein J, Hermanns W, Brem G, Wanke R: Effects of long-term elevated serum levels of growth hormone on life expectancy of mice: lessons from transgenic animal models. Mech Ageing Dev 1993;68:71-87.
18.
Jara A, Benner CM, Sim D, Liu X, List EO, Householder LA, et al: Elevated systolic blood pressure in male GH transgenic mice is age dependent. Endocrinology 2014;155:975-986.
19.
Orian JM, Lee CS, Weiss LM, Brandon MR: The expression of a metallothionein-ovine growth hormone fusion gene in transgenic mice does not impair fertility but results in pathological lesions in the liver. Endocrinology 1989;124:455-463.
20.
Quaife CJ, Mathews LS, Pinkert CA, Hammer RE, Brinster RL, Palmiter RD: Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 1989;124:40-48.
21.
Shea BT, Hammer RE, Brinster RL: Growth allometry of the organs in giant transgenic mice. Endocrinology 1987;121:1924-1930.
22.
Machado MO, Hirata RDC, Sellitti DF, Iotti R, Iotti A, Cusumano AM, et al: Growth hormone promotes glomerular lipid accumulation in bGH mice. Kidney Int 2005;68:2019-2028.
23.
Yang CW, Striker LJ, Pesce C, Chen WY, Peten EP, Elliot S, et al: Glomerulosclerosis and body growth are mediated by different portions of bovine growth hormone: studies in transgenic mice. Lab Invest 1993;68:62-70.
24.
Yang CW, Striker LJ, Kopchick JJ, Chen WY, Pesce CM, Peten EP, et al: Glomerulosclerosis in mice transgenic for native or mutated bovine growth hormone gene. Kidney Int Suppl 1993;39:S90-S94.
25.
Liu ZH, Striker LJ, Phillips C, Chen NY, Chen WY, Kopchick JJ, et al: Growth hormone expression is required for the development of diabetic glomerulosclerosis in mice. Kidney Int Suppl 1995;51:S37-S38.
26.
Stout MB, Tchkonia T, Pirtskhalava T, Palmer AK, List EO, Berryman DE, et al: Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY) 2014;6:575-586.
27.
Izzard AS, Emerson M, Prehar S, Neyses L, Trainer P, List EO, et al: The cardiovascular phenotype of a mouse model of acromegaly. Growth Horm IGF Res 2009;19:413-419.
28.
Miquet JG, Giani JF, Martinez CS, Munoz MC, Gonzalez L, Sotelo AI, et al: Prolonged exposure to GH impairs insulin signaling in the heart. J Mol Endocrinol 2011;47:167-177.
29.
Bohlooly-Y M, Bohlooly M, Olsson B, Bruder CEG, Lindén D, Sjögren K, et al: Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia. Diabetes 2005;54:51-62.
30.
Bollano E, Omerovic E, Bohlooly-Y M, Kujacic V, Madhu B, Tornell J, et al: Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene 1. Endocrinology 2000;141:2229-2235.
31.
Doi T, Striker LJ, Kimata K, Peten EP, Yamada Y, Striker GE: Glomerulosclerosis in mice transgenic for growth hormone: increased mesangial extracellular matrix is correlated with kidney mRNA levels. J Exp Med 1991;173:1287-1290.
32.
Kumar D, Kumar S, Kohli S, Arya R, Gupta J: Antidiabetic activity of methanolic bark extract of Albizia odoratissima Benth. in alloxan induced diabetic albino mice. Asian Pac J Trop Med 2011;4:900-903.
33.
Miquet JG, Freund T, Martinez CS, González L, Díaz ME, Micucci GP, et al: Hepatocellular alterations and dysregulation of oncogenic pathways in the liver of transgenic mice overexpressing growth hormone. Cell Cycle 2013;12:1042-1057.
34.
Bartke A, Cecim M, Tang K, Steger RW, Chandrashekar V, Turyn D: Neuroendocrine and reproductive consequences of overexpression of growth hormone in transgenic mice. Proc Soc Exp Biol Med 1994;206:345-359.
35.
Olsson B, Bohlooly-Y M, Fitzgerald SM, Frick F, Ljungberg A, Ahrén B, et al: Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet. Endocrinology 2005;146:920-930.
36.
Berryman DE, List EO, Kohn DT, Coschigano KT, Seeley RJ, Kopchick JJ: Effect of growth hormone on susceptibility to diet-induced obesity. Endocrinology 2006;147:2801-2808.
37.
Boparai RK, Arum O, Khardori R, Bartke A: Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis. Biol Chem 2010;391:1149-1155.
38.
Wang Z, Masternak MM, Al-Regaiey KA, Bartke A: Adipocytokines and the regulation of lipid metabolism in growth hormone transgenic and calorie-restricted mice. Endocrinology 2007;148:2845-2853.
39.
Valera A, Rodriguez-Gil JE, Yun JS, McGrane MM, Hanson RW, Bosch F: Glucose metabolism in transgenic mice containing a chimeric P-enolpyruvate carboxykinase/bovine growth hormone gene. FASEB J 1993;7:791-800.
40.
Dominici FP, Balbis A, Bartke A, Turyn D: Role of hyperinsulinemia on hepatic insulin receptor concentration and autophosphorylation in the presence of high growth hormone levels in transgenic mice overexpressing growth hormone gene. J Endocrinol 1998;159:15-25.
41.
Berryman DE, List EO, Coschigano KT, Behar K, Kim JK, Kopchick JJ: Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res 2004;14:309-318.
42.
Nam SY, Lobie PE: The mechanism of effect of growth hormone on preadipocyte and adipocyte function. Obes Rev 2000;1:73-86.
43.
Olsson B, Bohlooly-Y M, Brusehed O, Isaksson OGP, Ahrén B, Olofsson S-O, et al: Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes. Am J Physiol Endocrinol Metab 2003;285:E504-E511.
44.
Karlander S, Vranić M, Efendić S: Increased glucose turnover and glucose cycling in acromegalic patients with normal glucose tolerance. Diabetologia 1986;29:778-783.
45.
Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R: Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action. Am J Physiol 1986;250:E269-E273.
46.
Foss MC, Saad MJ, Paccola GM, Paula FJ, Piccinato CE, Moreira AC: Peripheral glucose metabolism in acromegaly. J Clin Endocrinol Metab 1991;72:1048-1053.
47.
Møller N, Schmitz O, Jøorgensen JO, Astrup J, Bak JF, Christensen SE, et al: Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J Clin Endocrinol Metab 1992;74:1012-1019.
48.
Serri O, Beauregard C, Hardy J: Long-term biochemical status and disease-related morbidity in 53 postoperative patients with acromegaly. J Clin Endocrinol Metab 2004;89:658-661.
49.
Nørrelund H, Djurhuus C, Jørgensen JOL, Nielsen S, Nair KS, Schmitz O, et al: Effects of GH on urea, glucose and lipid metabolism, and insulin sensitivity during fasting in GH-deficient patients. Am J Physiol Endocrinol Metab 2003;285:E737-E743.
50.
Alberti KG, Christensen NJ, Christensen SE, Hansen AP, Iversen J, Lundbaek K, et al: Inhibition of insulin secretion by somatostatin. Lancet 1973;2:1299-1301.
51.
Davies RR, Miller M, Turner SJ, Goodship TH, Cook DB, Watson M, et al: Effects of somatostatin analogue SMS 201-995 in normal man. Clin Endocrinol (Oxf) 1986;24:665-674.
52.
Møller N, Bagger JP, Schmitz O, Jørgensen JO, Ovesen P, Møller J, et al: Somatostatin enhances insulin-stimulated glucose uptake in the perfused human forearm. J Clin Endocrinol Metab 1995;80:1789-1793.
53.
Sheppard MC: Primary medical therapy for acromegaly. Clin Endocrinol (Oxf) 2003;58:387-399.
54.
Baldelli R, Battista C, Leonetti F, Ghiggi M-R, Ribaudo M-C, Paoloni A, et al: Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment. Clin Endocrinol (Oxf) 2003;59:492-499.
55.
Cozzi R, Attanasio R, Montini M, Pagani G, Lasio G, Lodrini S, et al: Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results? J Clin Endocrinol Metab 2003;88:3090-3098.
56.
Ronchi CL, Varca V, Beck-Peccoz P, Orsi E, Donadio F, Baccarelli A, et al: Comparison between six-year therapy with long-acting somatostatin analogs and successful surgery in acromegaly: effects on cardiovascular risk factors. J Clin Endocrinol Metab 2006;91:121-128.
57.
George SR, Hegele RA, Burrow GN: The somatostatin analogue SMS 201-995 in acromegaly: prolonged, preferential suppression of growth hormone but not pancreatic hormones. Clin Invest Med 1987;10:309-315.
58.
Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S: Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab 2013;98:3446-3453.
59.
Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ: Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. Endocr Rev 2002;23:623-646.
60.
Chen WY, White ME, Wagner TE, Kopchick JJ: Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice. Endocrinology 1991;129:1402-1408.
61.
Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ: Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 2003;144:3799-3810.
62.
Berryman DE, Lubbers ER, Magon V, List EO, Kopchick JJ: A dwarf mouse model with decreased GH/IGF-1 activity that does not experience life-span extension: potential impact of increased adiposity, leptin, and insulin with advancing age. J Gerontol A Biol Sci Med Sci 2014;69:131-141.
63.
Berryman DE, List EO, Sackmann-Sala L, Lubbers E, Munn R, Kopchick JJ: Growth hormone and adipose tissue: beyond the adipocyte. Growth Horm IGF Res 2011;21:113-123.
64.
Yang T, Householder LA, Lubbers ER, List EO, Troike K, Vesel C, et al: Growth hormone receptor antagonist transgenic mice are protected from hyperinsulinemia and glucose intolerance despite obesity when placed on a HF diet. Endocrinology 2015;156:555-564.
65.
Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, et al: Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 2000;342:1171-1177.
66.
Van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, et al: Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 2001;358:1754-1759.
67.
Barkan AL, Burman P, Clemmons DR, Drake WM, Gagel RF, Harris PE, et al: Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant. J Clin Endocrinol Metab 2005;90:5684-5691.
68.
Rose DR, Clemmons DR: Growth hormone receptor antagonist improves insulin resistance in acromegaly. Growth Horm IGF Res 2002;12:418-424.
69.
Jørgensen JOL, Feldt-Rasmussen U, Frystyk J, Chen J-W, Kristensen LØ, Hagen C, et al: Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist. J Clin Endocrinol Metab 2005;90:5627-5631.
70.
Drake WM, Rowles S V, Roberts ME, Fode FK, Besser GM, Monson JP, et al: Insulin sensitivity and glucose tolerance improve in patients with acromegaly converted from depot octreotide to pegvisomant. Eur J Endocrinol 2003;149:521-527.
71.
Lindberg-Larsen R, Møller N, Schmitz O, Nielsen S, Andersen M, Orskov H, et al: The impact of pegvisomant treatment on substrate metabolism and insulin sensitivity in patients with acromegaly. J Clin Endocrinol Metab 2007;92:1724-1728.
72.
De Marinis L, Bianchi A, Fusco A, Cimino V, Mormando M, Tilaro L, et al: Long-term effects of the combination of pegvisomant with somatostatin analogs (SSA) on glucose homeostasis in non-diabetic patients with active acromegaly partially resistant to SSA. Pituitary 2007;10:227-232.
73.
Higham CE, Rowles S, Russell-Jones D, Umpleby AM, Trainer PJ: Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly. J Clin Endocrinol Metab 2009;94:2459-2463.
74.
Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, et al: Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. Eur J Endocrinol 2006;154:467-477.
75.
Baumann G: Growth hormone binding protein: the soluble growth hormone receptor. Minerva Endocrinol 2002;27:265-276.
76.
Simsolo RB, Ezzat S, Ong JM, Saghizadeh M, Kern PA: Effects of acromegaly treatment and growth hormone on adipose tissue lipoprotein lipase. J Clin Endocrinol Metab 1995;80:3233-3238.
77.
Richelsen B, Pedersen SB, Børglum JD, Møller-Pedersen T, Jørgensen J, Jørgensen JO: Growth hormone treatment of obese women for 5 wk: effect on body composition and adipose tissue LPL activity. Am J Physiol 1994;266:E211-E216.
78.
Jessen N, Djurhuus CB, Jørgensen JOL, Jensen LS, Møller N, Lund S, et al: Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion. Am J Physiol Endocrinol Metab 2005;288:E194-E199.
79.
Nielsen C, Gormsen LC, Jessen N, Pedersen SB, Møller N, Lund S, et al: Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. J Clin Endocrinol Metab 2008;93:2842-2850.
80.
Krusenstjerna-Hafstrøm T, Clasen BF, Møller N, Jessen N, Pedersen SB, Christiansen JS, et al: Growth hormone (GH)-induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults. J Clin Endocrinol Metab 2011;96:2548-2557.
81.
Nellemann B, Vendelbo MH, Nielsen TS, Bak AM, Høgild M, Pedersen SB, et al: Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity. Acta Physiol (Oxf) 2014;210:392-402.
82.
Steyn FJ, Leong JW, Huang L, Tan HY, Xie TY, Nelson C, et al: GH does not modulate the early fasting-induced release of free fatty acids in mice. Endocrinology 2012;153:273-282.
83.
de Herder WW: The history of acromegaly. Neuroendocrinology 2016;103:7-17.
84.
Schernthaner-Reiter MH, Trivellin G, Stratakis CA: MEN1, MEN4, and carney complex: pathology and molecular genetics. Neuroendocrinology 2016;103:18-31.
85.
Buchfelder M, Schlaffer S-M: Novel techniques in the surgical treatment of acromegaly: applications and efficacy. Neuroendocrinology 2016;103:32-41.
86.
Hannon MJ, Barkan AL, Drake WM: The role of radiotherapy in acromegaly. Neuroendocrinology 2016;103:42-49.
87.
Chanson P: Medical treatment of acromegaly with dopamine agonists or somatostatin analogs. Neuroendocrinology 2016;103:50-58.
88.
Neggers SJCMM, Muhammad A, van der Lely AJ: Pegvisomant treatment in acromegaly. Neuroendocrinology 2016;103:59-65.
89.
McCabe J, Ayuk J, Sherlock M: Treatment factors that influence mortality in acromegaly. Neuroendocrinology 2016;103:66-74.
90.
Powlson AS, Gurnell M: Cardiovascular disease and sleep-disordered breathing in acromegaly. Neuroendocrinology 2016;103:75-85.
91.
Claessen KMJA, Mazziotti G, Biermasz NR, Giustina A: Bone and joint disorders in acromegaly. Neuroendocrinology 2016;103:86-95.
92.
Webb SM, Badia X: Quality of life in acromegaly. Neuroendocrinology 2016;103:106-111.
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