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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5448-5453
Copyright © 2004 by The Endocrine Society

Serum Adiponectin Is Reduced in Acromegaly and Normalized after Correction of Growth Hormone Excess

Karen Siu-Ling Lam, Aimin Xu, Kathryn Choon-Beng Tan, Lai-Ching Wong, Sau-Cheung Tiu and Sidney Tam

Department of Medicine, University of Hong Kong (K.S.-L.L., A.X., K.C.-B.T., L.-C.W.); Department of Medicine, Queen Elizabeth Hospital (S.-C.T.); and Clinical Biochemistry Unit, Queen Mary Hospital (S.T.), Hong Kong

Address all correspondence and requests for reprints to: Dr. Karen Lam, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. E-mail: ksllam{at}hkucc.hku.hk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Adiponectin, an adipocyte-derived hormone, possesses insulin-sensitizing, antiinflammatory, and antiatherogenic properties. We hypothesized that hypoadiponectinemia was present in acromegaly, as in other conditions with increased insulin resistance and cardiovascular risk. Using an in-house RIA, serum adiponectin was determined in 35 patients with active acromegaly and 35 age-, sex-, and body mass index-matched healthy controls. Twenty-five patients were restudied after GH-lowering therapies. Serum adiponectin was significantly reduced in the acromegalic patients (4.3 ± 1.8 vs. 6.7 ± 1.8 µg/ml in controls; P < 0.001), but was increased after treatment with Sandostatin LAR, a long-acting somatostatin analog (5.8 ± 2.6 vs. 3.8 ± 1.6 µg/ml pretreatment; P < 0.001; n = 15) or transsphenoidal surgery (6.5 ± 2.7 vs. 3.9 ± 1.5 µg/ml preoperation; P < 0.01; n = 10). Fasting insulin was an independent determinant of serum adiponectin levels (P < 0.01) in control subjects, contributing to 11.7% of the variance in circulating adiponectin. In cultured 3T3-L1 adipocytes, adiponectin mRNA levels were decreased by insulin (1.5 µM; P < 0.005) or IGF-I (1 µg/ml; P < 0.05), but not by GH (1 µM) or somatostatin (1 µM). In conclusion, hypoadiponectinemia is present in active acromegaly, probably secondary to the inhibitory effect of high circulating insulin levels. Hypoadiponectinemia, reversible with GH-lowering therapies, may contribute to the increased insulin resistance and cardiovascular risk in patients with acromegaly.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADIPONECTIN, AN ADIPOCYTE-derived hormone, has been shown to possess insulin-sensitizing (1), antiatherogenic (2), and antiinflammatory properties (3). Circulating levels of adiponectin correlate strongly with insulin sensitivity, as evaluated by glucose disposal rate (4). Reduced adiponectin levels have been reported in various components of the metabolic syndrome, also known as the insulin resistance syndrome (5), including obesity (especially visceral obesity), diabetes, dyslipidemia, and hypertension (6, 7). Furthermore, hypoadiponectinemia has been found in patients with coronary artery disease (8) and was predictive of cardiovascular mortality in a study of patients with end-stage renal failure (9). On the basis of these findings, adiponectin has been proposed to be a key player in the metabolic syndrome (6).

Patients with active acromegaly have increased cardiovascular mortality (10), attributed to the increased presence of diabetes mellitus or impaired glucose tolerance, hypertension, and lipid abnormalities. GH excess is associated with insulin resistance and hyperinsulinemia, which improve with GH-lowering therapies (11, 12, 13), accompanied by amelioration of the metabolic disorders (11, 13). Although GH excess is associated with reduced fat mass, the ratio of visceral fat to sc fat has been reported to be increased in some patients with acromegaly, attributed to the greater sensitivity of visceral fat to the effect of hyperinsulinism (14). Thus, active acromegaly has many features of the metabolic syndrome. It is tempting to speculate that hypoadiponectinemia, which has been implicated in the pathogenesis of the metabolic syndrome (6), is also involved in the pathogenesis of the insulin resistance and related metabolic disorders present in active acromegaly. Indeed, hypoadiponectinemia has been found in a transgenic mouse model of acromegaly (15). In contrast, adiponectin levels in acromegalic patients have been reported variably as higher than (16) or similar to (17) those in normal controls. The effect of GH-reducing therapy on serum adiponectin levels has not been studied.

In this study we investigated the effect of GH excess on circulating adiponectin levels in patients with active acromegaly before and after treatment with a somatostatin analog or transsphenoidal surgery. The effects of high levels of GH, insulin, IGF-I, and somatostatin on adiponectin mRNA expression in adipocytes were also studied in vitro.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Thirty-five patients with acromegaly, recruited from the Endocrine Clinic, Queen Mary Hospital, were studied. All had evidence of active disease, as indicated by symptoms of acromegaly, elevated IGF-I levels, and a lack of suppression of serum GH to less than 2 ng/ml during a 75-g oral glucose tolerance test. Seven patients had diabetes mellitus, of whom three were taking insulin. All had otherwise normal pituitary function or had been taking stable hormonal replacement therapy for hypopituitarism for at least 6 months. Eighteen patients had previous transsphenoidal surgery and/or radiotherapy and were receiving bromocriptine for residual disease; bromocriptine was stopped for at least 4 wk before the study. Plasma glucose, serum adiponectin, insulin, and IGF-I (mean of two samples, 1 h apart) were checked after 12-h overnight fasting, and GH secretion was assessed from the mean of five samples taken at 1-h intervals. Plasma glucose, serum adiponectin, and insulin were also assessed in 35 age-, sex-, and body mass index (BMI)-matched nondiabetic healthy subjects. All subjects were studied after giving their informed consent according to a protocol approved by the human ethics committee of the Medical Faculty, University of Hong Kong.

Fifteen of the acromegalic patients were restudied after two injections of Sandostatin LAR (Novartis Pharma AG, Basel, Switzerland), a long-acting somatostatin analog, at 20 mg, im, every 4 wk. Another 10 patients were restudied 6 months after transsphenoidal surgery.

In vitro studies

3T3-L1 fibroblast cells were grown in DMEM containing 25 mM glucose and 10% fetal bovine serum. After the cells reached 100% confluence, differentiation to adipocytes was initiated by incubation with 10 µg/ml insulin, 0.25 µM dexamethasone, and 0.5 mM isobutylmethylxanthine for 2 d, then with 10 µg/ml insulin for another 2 d. After an additional 2 d in culture medium, more than 90% of the cells had accumulated lipid droplets. The cells were then incubated for 40 h in serum-free DMEM containing 1 µg/ml (0.13 µM) IGF-I, 1 µM GH, 1.5 µM insulin, or 1 µM somatostatin (Sigma-Aldrich Corp., St. Louis, MO).

RNA isolation and Northern blot analysis

Total RNA from 3T3-L1 adipocytes was prepared with TRIzol reagent according to the manufacturer’s instructions (Invitrogen Life Technologies, Carlsbad, CA) and quantified by measuring the absorbance at 260 nm. Ten micrograms of total RNA from each sample were denatured and subjected to electrophoresis on a 1.2% agarose gel containing 2.2 M formaldehyde and transferred to a nylon membrane (Pharmacia Biotech, Uppsala, Sweden). The blot was probed with a specific 32P-labeled cDNA probe for mouse adiponectin as described previously (7). The mRNA abundance of the adiponectin gene was quantitated by phosphorimaging and normalized against 28S RNA.

Assay methods

Serum adiponectin was determined with an in-house RIA assay, using a rabbit polyclonal antibody against human adiponectin (18, 19). Intra- and interassay coefficients of variation were 5.2% and 5.7%, respectively. Serum GH and total IGF-I (Nicholas Institute Diagnostics, San Juan Capistrano, CA) were determined using commercial RIA kits. Age-specific, but not sex-specific, ranges for IGF-I levels were available from the manufacturer. Serum insulin was assayed by microparticle enzyme immunoassay (Abbott Laboratories, Tokyo, Japan). Homeostasis model assessment index of insulin resistance [HOMA-IR = fasting glucose (mmol/liter) x fasting insulin (mIU/liter) /22.5] was calculated.

Statistical analysis

Results are expressed as the mean ± SD. Differences between groups were tested by independent sample t test. Pearson’s correlations were used to test the relationship between variables. Comparison of values before and after treatment was made using paired t test. Multiple linear regression analysis was used to assess the relationship of adiponectin with other variables. For the in vitro study, the results represent data from three independent experiments, with n being the number of wells (two per treatment in each experiment). All analyses were performed using SPSS 11.0 for Windows (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical and biochemical characteristics of the acromegalic patients and control subjects are shown in Table 1Go. There was no significant difference in age, sex distribution, or BMI between the two groups. Serum adiponectin was significantly lower in the acromegalic patients (P < 0.001 vs. controls; Fig. 1Go). The association of hypoadiponectinemia with active acromegaly was demonstrated even when the seven patients with diabetes mellitus were excluded from analysis (4.41 vs. 6.84 µg/ml in controls; P = 0.001; n = 28 in each group). Patients with active acromegaly also had higher fasting serum insulin (P = 0.013 vs. controls) and, in those not receiving insulin, higher HOMA-IR (P = 0.007 vs. controls; n = 32 in each group).


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  		TABLE 1. Clinical and biochemical parameters in acromegalic patients and controls

 


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  		FIG. 1. Scattergram showing the serum adiponectin levels of individual acromegalic patients and control subjects. *, P < 0.001 vs. mean level in controls.

 
In the healthy controls, serum adiponectin levels were inversely related to BMI (r = –0.374; P = 0.027); serum insulin (r = –0.402; P = 0.017), and HOMA-IR (r = –0.415; P = 0.013) and were higher in women (9.12 ± 3.26 vs. 5.29 ± 1.22 µg/ml in men; P < 0.001). On multiple linear regression, gender and fasting serum insulin, but not age, BMI, or HOMA-IR, were independently associated with serum adiponectin, contributing 43% (P < 0.001) and 11.7% (P = 0.007), respectively, to the variance in circulating adiponectin levels. Serum adiponectin levels in the 35 acromegalic patients showed no significant correlation with BMI, HOMA-IR, serum GH, insulin, or IGF-I and no significant gender difference (4.98 ± 1.94 vs. 3.83 ± 1.55 µg/ml in men; P = 0.55).

The hormonal responses to medical or surgical treatment in the acromegalic patients are summarized in Table 2Go. After two doses of Sandostatin LAR, marked reductions (P < 0.0001) in mean serum GH, IGF-I, and insulin were seen in the 15 patients, accompanied by a rise in mean serum adiponectin (Fig. 2AGo; P = 0.001; n = 15). There was no significant change in the waist/hip ratio (0.827 ± 0.060 vs. 0.829 ± 0.050 at baseline; P = 0.68). In the 10 patients treated surgically, reductions in mean serum GH (P = 0.016), IGF-I (P = 0.002), and insulin (P = 0.024) were also associated with increases in serum adiponectin levels (Fig. 2BGo; P = 0.009; n = 10). In these 25 patients (18 men and seven women), the percent increase in adiponectin showed a trend toward an inverse relationship with the percent reduction in serum insulin (r = –0.346; P = 0.09), but not with the percent reduction in mean GH (P = 0.55) or IGF-I (P = 0.53). An inverse relationship of serum adiponectin with BMI was seen (r = –445; P < 0.05) at the time of restudy, but the gender difference in adiponectin levels remained nonsignificant (7.22 ± 3.41 vs. 5.70 ± 2.33 µg/ml in men; P = 0.3).


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  		TABLE 2. Hormonal changes in acromegalic patients treated medically or surgically

 


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  		FIG. 2. Serum adiponectin levels in individual acromegalic patients before and after medical (A) and surgical (B) treatment. IGF-I levels in nanograms per milliliter are shown in parentheses in order of the corresponding adiponectin levels. Conversion factor to Systeme Internationale units: x 0.131 = nmol/liter.

 
The effects of incubation with high doses of GH, insulin, somatostatin, and IGF-I on adiponectin gene expression were investigated in 3T3-L1 adipocytes. As shown in Fig. 3Go, a significant reduction in adiponectin mRNA levels vs. levels after incubation in control medium was seen after incubation with insulin (P = 0.004; n = 6) and IGF-I (n = 0.045; n = 6), but not with GH or somatostatin.



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  		FIG. 3. Adiponectin mRNA levels in 3T3-L1 adipocytes incubated for 40 h in serum-free medium containing GH (10–6 M), insulin (Ins; 1.5 x 10–6 M); somatostatin (SS; 10–6 M), IGF-I (1.3 x 10–7 M), or control (C) medium. For quantitation, adiponectin mRNA abundance was normalized against 28S RNA (28S). A, Representative Northern blots; B, adiponectin mRNA levels in arbitrary density units. *, P < 0.05; **, P < 0.005 (vs. control). n = 6 in each group.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study patients with active acromegaly were shown to have significantly lower serum adiponectin levels, compared with age-, sex-, and BMI-matched healthy controls. The reversal of hypoadiponectinemia by GH-lowering therapies suggests that the reduced adiponectin levels in these patients occurred as a result of GH excess. However, as in a previous study (20), our results showed that excess GH was not associated with any significant reduction in adiponectin gene expression in vitro. Serum adiponectin also showed no significant relationship to serum GH levels in the acromegalic patients. These findings suggest that other changes caused by GH excess, rather than GH itself, may be responsible for the hypoadiponectinemia observed in active acromegaly. In one of the medically treated patients, a paradoxical reduction in serum adiponectin of over 2 µg/ml was seen. This woman had a dramatic reduction in mean GH levels to only 0.32 ng/ml, necessitating a reduction in Sandostatin LAR dosage for subsequent clinical management. Interestingly, a recent study has reported a rise in serum adiponectin after GH treatment in GH-deficient women (21). This may be explained by the dose-dependent effect of GH on adiponectin gene expression, which has been demonstrated in cultured 3T3-L1 adipocytes (22). In that study, treatment with GH at 10–11–10–7 M significantly increased adiponectin mRNA expression in these cells. The dose-dependent stimulating effect of GH reached a maximum at 10–8 M and decreased at higher concentrations, so that in cells treated with GH 10–6 M, the adiponectin mRNA levels were similar to those in untreated cells (22).

GH excess is known to be associated with resistance to the action of insulin (11), although the mechanism is not well understood. Hyperinsulinemia, consequent to increased insulin resistance, is therefore commonly seen in patients with active acromegaly. Insulin has been shown to reduce adiponectin mRNA levels in 3T3-L1 cells, at concentrations ranging from 10–8 (20, 22) to 1.5 x 10–6 M, as used in this study. Indeed, at a concentration as low as 10–8 M, insulin can completely abolish the stimulation of adiponectin expression elicited by GH at the optimal dosage of 10–8 M (22). The inhibitory effect of insulin on adiponectin expression can be partially reversed by pretreatment with pharmacological inhibitors of the phosphatidylinositol 3-kinase and p70S6 kinase (20). These two pathways, which are major mediators of the metabolic actions of insulin, have been demonstrated to be inhibitory to adiponectin gene expression in cultured adipocytes (22). The role of insulin as a negative regulator of adiponectin production is also supported by the finding of increased plasma adiponectin levels in mice with adipose tissue-specific knock-out of the insulin receptor (23) and the reduction in serum adiponectin levels after insulin infusion in healthy men during a hyperinsulinemic euglycemic clamp (24). We propose, therefore, that hyperinsulinemia is likely to be the cause of hypoadiponectinemia observed in our patients with active acromegaly. The rise in serum adiponectin after successful GH-lowering therapy, either medical or surgical, may be attributed to a reduction in circulating insulin levels consequent to the reduction of GH-induced insulin resistance. In patients treated medically in this study, the rise in circulating adiponectin levels also resulted from a direct inhibition of insulin secretion by Sandostatin LAR. The trend toward an inverse relationship between the percent changes in serum adiponectin and fasting insulin in the patients restudied after GH-lowering therapy was in keeping with these possibilities. This hypothesis is also supported by the finding that fasting insulin, independent of BMI and insulin resistance, was a significant determinant of circulating adiponectin levels in the healthy controls of this study.

Our in vitro data suggest that in addition to hyperinsulinemia, high levels of IGF-I may also suppress adiponectin gene expression and potentially contribute to the hypoadiponectinemia in active acromegaly. Whether this action is exerted via the insulin receptors or IGF-I receptors on the adipocytes (25) remains to be investigated. The lack of a statistical relationship between serum IGF-I and adiponectin levels in the acromegalic patients in this study is not supportive of a significant role of elevated IGF-I in the hypoadiponectinemia observed in active acromegaly. The regulation of adiponectin expression by IGF-I, suggested by our preliminary in vitro findings, remains to be confirmed by additional studies.

Hypoadiponectinemia has also been observed in a transgenic mouse model of acromegaly (15). In that study, long-term GH excess in transgenic mice overexpressing bovine GH was associated with insulin resistance and a 45% reduction in serum adiponectin levels compared with the wild-type littermates. In contrast, increased, rather than decreased, adiponectin levels were found in a study involving 18 patients with acromegaly compared with BMI- and sex-matched controls (16). In that study, insulin resistance and fasting serum were not significantly different between the acromegalic patients and control subjects, with fasting insulin in the patients being only 24% higher than that in controls. In contrast, the patients in our study were significantly more insulin resistant and had insulin levels that were 86% higher than the healthy controls. The discrepancies in serum insulin and adiponectin levels in active acromegaly between our study and that by Silha et al. (16) may be related to the difference in sample size between the two studies. As the researchers themselves pointed out, their sample size was small and, with multiple comparisons being involved, the borderline significant results should be interpreted with caution (16). In another study, which reported no significant changes in adiponectin levels in patients with acromegaly (17), details about the age, sex, and BMI of the 25 control subjects were not available from the abstract, and a direct comparison with our study is not possible. The effects of GH-lowering therapy on serum adiponectin levels were not examined in any of the above studies (15, 16, 17).

The inverse relationship of serum adiponectin with insulin resistance and BMI, an index of overall obesity, observed in the healthy controls, has been well reported (6, 19, 26, 27, 28). In the presence of active acromegaly, the inverse relationship of serum adiponectin with insulin resistance may have been masked by the confounding effect of high circulating GH on insulin action. GH excess also causes alterations in body compositions, leading to reduced fat mass, but increased lean body mass, which are reversible with treatment for acromegaly (29). This may explain the absence of a significant relationship between serum adiponectin and BMI in active acromegaly, because BMI is probably not a good measurement of overall obesity in the presence of altered body compositions. Although we did not measure fat mass in this study, we and others have previously shown that treatment with octreotide or Sandostatin LAR is accompanied by an increase in total body fat (13, 29). Because the serum adiponectin level has been shown to vary inversely with total body fat in large population-based studies (30) regardless of sex, age or degree of adiposity (31), it seems unlikely that the treatment-induced increase in body fat could account for the rise in adiponectin after treatment for acromegaly. In contrast, increased visceral obesity has been previously reported in a proportion of patients with active acromegaly (14), attributed to the greater sensitivity of visceral fat to the effect of hyperinsulinemia. Because in our patients, hyperinsulinemia was present before treatment, an increase in visceral fat may explain in part the hypoadiponectinemia observed in these patients.

Serum adiponectin levels are known to be higher in women (28, 32) than in men; this is attributed to differences in body fat distribution and insulin sensitivity (28) and perhaps also the actions of sex hormones on adiponectin expression, conflicting findings for which have been reported (27, 32). A definite gender difference could not be demonstrated in the acromegalic patients, probably because of the confounding effects of GH excess and related hormonal changes on insulin sensitivity, body fat distribution, and adiponectin expression. The number of patients restudied after GH-lowering therapies, especially the female patients, was too small to adequately address the effect of GH lowering on the gender difference in adiponectin expression.

In conclusion, we have shown for the first time that patients with active acromegaly have hypoadiponectinemia, which is reversible with GH-lowering therapies. Because adiponectin is known to have beneficial effects on insulin sensitivity, atherogenesis, and inflammation of the arterial wall, this reduction in adiponectin expression may contribute to the increased cardiovascular risk in patients with acromegaly.


   Acknowledgments
 
We thank Dr. K. W. Lo for the referral of patients, and Novartis Pharma AG (Basel, Switzerland) for the supply of Sandostatin LAR.


   Footnotes
 
This work was supported by a grant from the Hong Kong Research Grant Council (HKU 7426/03).

Abbreviations: BMI, Body mass index; HOMA-IR, homeostasis model assessment index of insulin resistance.

Received November 20, 2003.

Accepted August 15, 2004.


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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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