Effect of pituitary surgery in patients with acromegaly on adiponectin serum concentrations and alanine aminotransferase activity

doi:10.1016/j.cccn.2004.09.022

Clinica Chimica Acta

Volume 352, Issues 1–2, February 2005, Pages 175-181

https://doi.org/10.1016/j.cccn.2004.09.022 Get rights and content

Abstract

Background

Thiazolidinediones increase adiponectin concentrations, improve insulin sensitivity and fatty liver disease (reflected by decreased alanine aminotransferase [ALT] activity) in type 2 diabetes. This study was performed to test the effect of neurosurgery in acromegaly (sharing at baseline insulin resistance but not increased visceral fat with type 2 diabetes) on insulin sensitivity, adiponectin concentrations and ALT activity.

Methods

Sixteen patients with acromegaly undergoing pituitary surgery (and 16 patients with type 2 diabetes treated with pioglitazone) were included. Insulin sensitivity, adiponectin concentrations and ALT activity were determined at baseline and after 4 months.

Results

Pituitary surgery in acromegalic patients increased adiponectin concentrations from mean (±S.D.) 9.3±3.8 to 10.2±4.4 mg/L (p<0.05). HOMA scores fell from 6.8±4 at baseline to 3.5±0.9 following neurosurgery (p<0.005) and ALT activity decreased from median (range) 21 (13–30) to 13 (10–42) U/L (p<0.05). In type 2 diabetics, pioglitazone treatment increased adiponectin concentrations; HOMA scores and ALT activity fell significantly.

Conclusion

Pituitary surgery in patients with acromegaly led to a marked increase in insulin sensitivity and a slight increase in adiponectin serum concentrations, whereas ALT activity significantly decreased.

Introduction

Adiponectin is an adipocyte-specific glycoprotein that sensitises liver and skeletal muscle to the action of insulin [1], [2]. Circulating adiponectin concentrations have been shown to be positively correlated with insulin sensitivity and thus, decreased adiponectin concentrations have been described in insulin resistant subjects including patients with type 2 diabetes and obesity [3], [4], [5]. In patients with type 2 diabetes, an increased hepatic fat content was found to be an important determinant of decreased hepatic insulin sensitivity [6], [7]. Thiazolidinediones increase adiponectin gene expression and plasma levels [8], [9]. In patients with type 2 diabetes, treatment with pioglitazone reduced visceral fat, hepatic fat content, and alanine aminotransferase (ALT) enzyme activity [7], [10]. The decrease in hepatic fat and improvement in hepatic insulin sensitivity were closely associated with the increase in plasma adiponectin concentrations [7]. Moreover, treatment with recombinant adiponectin alleviated nonalcoholic steatohepatitis (NASH) in mice and pioglitazone treatment improved NASH in non-diabetic humans [11].

Patients with acromegaly and type 2 diabetes share many common features including insulin resistance, impaired glucose tolerance and increased incidence of macrovascular complications [12]. However, whereas visceral fat is increased in patients with type 2 diabetes, it is decreased in patients with acromegaly [6], [13]. To the best of our knowledge, only one cross-sectional study investigated adiponectin serum concentrations in patients with acromegaly [14]. Despite decreased insulin sensitivity in acromegalic subjects, adiponectin concentrations were found to be increased when compared to healthy controls.

The aim of this study was to assess the effect of pituitary surgery in patients with acromegaly and the effect of pioglitazone therapy in patients with type 2 diabetes on insulin sensitivity, adiponectin serum concentrations, and ALT activity.

Section snippets

Materials and methods

Sixteen consecutive patients with newly diagnosed acromegaly at the University Hospital of Zurich were included. Three acromegalic patients were excluded: one because of insulin-dependent diabetes mellitus, one because of an oesophageal cancer undergoing surgery and one because of a salmonella-induced coxitis. Diagnosis of acromegaly was established by clinical findings, elevated IGF 1 concentrations and lack of growth hormone (GH) suppression to <1 μg/L during an 75 g oral glucose tolerance

Results

Baseline characteristics of all 32 patients are shown in Table 1. No significant differences were found between patients with acromegaly and type 2 diabetes concerning gender, duration of disease, BMI, body weight, fasting insulin concentration, HOMA score, triglycerides, HDL-cholesterol and ALT activity. Patients with type 2 diabetes were significantly older (61±9 years) compared to the patients with acromegaly (48±16 years). Waist circumference, plasma glucose and HbA1c were significantly

Discussion

Our data confirm that thiazolidinedione drugs increase circulating adiponectin concentrations and improve insulin sensitivity in patients with type 2 diabetes, as illustrated by the drop of HOMA scores [18]. Although we did not measure body composition and visceral fat in our study, the increase in waist circumference following pioglitazone therapy might be assigned to an increase in subcutaneous rather than visceral fat because the latter usually decreases [18]. In a previous study,

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Cited by (19)

Soluble delta-like 1 homolog decreases in patients with acromegaly following pituitary surgery: A potential mediator of adipogenesis suppression by growth hormone?
2019, Growth Hormone and IGF Research
Citation Excerpt :
Longitudinal assessment of both sDlk1 and body composition in context (in the same patients) deserves attention in future studies that may check whether our data on sDlk1 are reproducible and whether these levels are related to changes in fat mass. Previous studies have unequivocally shown an increase of fat mass within 3 months after pituitary surgery [1,34–36] as well as an immediate decrease in insulin resistance [37–39]. According to our own preliminary findings, the decrease in serum sDlk1 appears to occur rapidly after surgery and therefore precedes a detectable decrease in body fat mass.
GH excess in acromegaly leads to lower fat mass and insulin resistance; both reverse following pituitary surgery. Soluble delta like-1 homolog (sDlk1) inhibits adipocyte differentiation and may mediate the antiadipogenic effects of GH. It is released into the circulation by ectodomain shedding through ‘A Disintegrin And Metalloproteinase domain 17’ (ADAM17), which also sheds soluble α-Klotho (sKlotho). Klotho is a transmembrane protein, which influences life span. sKlotho inhibits insulin signalling, and is markedly elevated in acromegaly and decreases after surgery. Therefore, we examined if sDlk1 parallels the course of sKlotho, which could explain the well-known changes in fat mass in patients with acromegaly after surgery.
We measured serum levels of GH, IGF-1, sDlk1 and sKlotho (both by ELISA) in 42 treatment-naïve acromegaly patients (20 females/22 males) before and 1–3 months after transsphenoidal surgery. Data are presented as median(interquartile range).
GH decreased in all patients postoperatively (in 32/42 to <1 ng/ml during oral glucose tolerance testing). Likewise, IGF-1 and sKlotho decreased in all patients, from 587 (432–708) to 195 (133–270) ng/ml, and from 4.0 (2.7–5.9) to 0.7 (0.6–1.2) ng/ml, respectively; sDlk1 fell in 40/42 subjects, from 10.7 (5.8–13.4) to 7.1 (3.7–10.4) ng/ml following pituitary surgery. P < 0.0001 for all parameters.
sDlk1 declined after pituitary surgery in our patients with acromegaly, but to a lesser extent than sKlotho. It remains to be seen whether this may contribute to the well-known postoperative changes in body composition. Our findings may extend beyond the scope of acromegaly, and thus further elucidate mechanisms in the fields of obesity and anti-ageing.
Phosphatidylinositol-3-phosphate clearance plays a key role in autophagosome completion
2012, Current Biology
Citation Excerpt :
The knockout of both YMR1 and SJL3, however, caused an almost complete block in autophagy (Figure 1A). Autophagy was additionally tested with the quantitative Pho8Δ60 assay [22]. This enzymatic assay confirmed the GFP-Atg8 processing assay data and also revealed that autophagy was not reduced, but upregulated, when SJL2 was deleted (Figure 1B).
The biogenesis of autophagosomes, the hallmark of autophagy, depends on the function of the autophagy-related (Atg) proteins and the generation of phosphatidylinositol-3-phosphate (PtdIns3P) at the phagophore assembly site (PAS), the location where autophagosomes arise. The current model is that PtdIns3P is involved primarily in the recruitment of Atg proteins to the PAS and that once an autophagosome is complete, the Atg machinery is released from its surface back into the cytoplasm and reused for the formation of new vesicles.
We have identified a PtdIns3P phosphatase, Ymr1, that is essential for the normal progression of both bulk and selective types of autophagy. This protein is recruited to the PAS at an early stage of formation of this structure through a process that requires both its GRAM domain and its catalytic activity. In the absence of Ymr1, Atg proteins fail to dissociate from the limiting membrane of autophagosomes, and these vesicles accumulate in the cytoplasm.
Our data thus reveal a key role for PtdIns3P turnover in the regulation of the late steps of autophagosome biogenesis and indicate that the disassembly of the Atg machinery from the surface of autophagosomes is a requisite for their fusion with the vacuole.
Endocrine diseases and the liver
2011, Clinics in Liver Disease
Citation Excerpt :
These data highlight the role of growth hormone and insulinlike growth factor 1 in the pathogenesis of MS and oxidative stress within the liver. However, excess secretion of growth hormone, as seen in acromegaly, is associated with DM, insulin resistance (without increased visceral fat accumulations), elevated liver enzyme levels, and low adiponectin levels that are reversible after pituitary surgery.68 Acromegaly has also been associated with an increased predisposition to gallstones.
Increase of classic and nonclassic cardiovascular risk factors in patients with acromegaly
2007, Endocrine Practice
Citation Excerpt :
In the series reported by Oscarsson et al (45), the levels of triglycerides and Lp(a) decreased postoperatively. Two other groups reported that successful surgical intervention resulted in considerable improvement of insulin sensitivity (64,65) and normalization of glucose tolerance (64). On evaluation of medical treatment of acromegaly, somatostatin analogue therapy has been shown to decrease insulin resistance, to induce favorable changes in the lipid profile, and to reduce levels of Lp(a), insulin, and fibrinogen (12-15,51,53).
To evaluate the prevalence of classic and nonclassic cardiovascular risk factors in patients with acromegaly.
Sixty-two patients with acromegaly (50 with active disease and 12 with controlled acromegaly) and 36 healthy persons (the control group) underwent measurement of lipids, fasting plasma glucose, homeostasis model assessment of insulin resistance (HOMA-IR) index, Lp(a), high-sensitivity C-reactive protein (hsCRP), homocysteine, and variables primarily related to thrombogenesis (fibrinogen, antithrombin III, protein C, and protein S).
In comparison with control subjects, patients with active acromegaly had significantly higher mean values of fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein (VLDL) cholesterol, triglycerides, Lp(a), HOMA-IR, and fibrinogen as well as lower mean levels of high-density lipoprotein cholesterol and protein S. In both groups, homocysteine, antithrombin III, protein C, and hsCRP levels were similar. Moreover, patients with active acromegaly, in comparison with those who had controlled acromegaly, presented with significantly higher values of fasting plasma glucose, HOMA-IR, triglycerides, VLDL cholesterol, Lp(a), and fibrinogen, whereas hsCRP and protein S were significantly lower. Finally, low levels of high-density lipoprotein cholesterol and protein S as well as elevated values of VLDL cholesterol, triglycerides, HOMA-IR, and fasting plasma glucose were more prevalent in patients with active acromegaly than in the other groups.
Our findings demonstrate that, in comparison with control subjects and patients with controlled acromegaly, patients with active acromegaly had a higher frequency of classic and nonclassic cardiovascular risk factors. These findings are potentially very important because acromegaly is associated with a 2- to 3-fold increase in mortality rate, predominantly related to cardiovascular disease. (Endocr Pract. 2007;13:363-372)
Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in coronary patients with predominantly normal or mildly impaired renal function
2007, Clinica Chimica Acta
Citation Excerpt :
A variety of endocrine mediators secreted by white adipose tissue has been described, such as tumor-necrosis factor-alpha (TNF-α) and interleukins (e.g., IL-6, IL-8, IL-10), which play important roles in the process of inflammation [1]. Adipokines such as adiponectin, leptin, and resistin interact in the pathogenesis of diseases constituting the metabolic syndrome and have been described to be associated with cardiovascular risk [2–5]. Adiponectin is a protein coded on chromosome 3 and consists of 244 amino acids [6–8].
Due to their molecular weight, it is possible that the adipokines adiponectin, resistin and leptin accumulate when glomerular filtration rate (GFR) is decreased. In reduced renal clearance, altered serum concentrations of these proteins might affect cardiovascular risk. The objective of the study was to investigate the relationship between adipokine concentrations and GFR.
The association between GFR, as determined by the abbreviated MDRD equation, and the concentrations of the adipokines adiponectin, resistin and leptin was assessed in a cohort of coronary patients (n = 538; 363 male, 165 female). After calculation of correlations between GFR and adipokine concentrations, the association was further assessed by analysis of covariance following adjustment for age, gender, BMI, presence of type 2 diabetes, presence of hypertension, history of smoking as well as for serum lipid concentrations.
Mean GFR in our study population was 68.74 ± 15.27 ml/min/1.73 m². 74.3% of the patients had a GFR > 60 ml/min/1.73 m², 24% of the patients had a GFR between 30 and 60 ml/min/1.73 m², and 1.7% of the patients had a GFR < 30 ml/min/1.73 m². There were significant inverse correlations between adiponectin (r = − 0.372; p < 0.001), resistin (r = − 0.227; p < 0.001) and leptin (r = − 0.151; p = 0.009) concentrations and GFR. After multivariate adjustment, the associations remained significant for adiponectin and resistin. Subgroup analysis in patients with GFR > 60 ml/min/1.73 m² showed a significant correlation between GFR and adiponectin as well as leptin concentrations. However, after adjustment, these associations no longer were significant.
There is an independent association between GFR and the serum concentrations of adiponectin and resistin. However, this association is not present at GFR > 60 ml/min/1.73 m². This finding suggests that adipokine concentrations in mildly impaired and normal renal function are influenced by factors other than GFR.
Evaluation of two fully automated novel enzyme-linked immunosorbent assays for the determination of human adiponectin in serum
2006, Clinica Chimica Acta
In contrast to RIA, recently available ELISAs provide the potential for fully automated analysis of adiponectin. To date, studies reporting on the diagnostic characteristics of ELISAs and investigating on the relationship between ELISA- and RIA-based methods are rare.
Thus, we established and evaluated a fully automated platform (BEP 2000; Dade-Behring, Switzerland) for determination of adiponectin levels in serum by two different ELISA methods (competitive human adiponectin ELISA; high sensitivity human adiponectin sandwich ELISA; both Biovendor, Czech Republic). Further, as a reference method, we also employed a human adiponectin RIA (Linco Research, USA). Samples from 150 patients routinely presenting to our cardiology unit were tested.
ELISA measurements could be accomplished in less than 3 h, measurement of RIA had a duration of 24 h. The ELISAs were evaluated for precision, analytical sensitivity and specificity, linearity on dilution and spiking recovery. In the investigated patients, type 2 diabetes, higher age and male gender were significantly associated with lower serum adiponectin concentrations. Correlations between the ELISA methods and the RIA were strong (competitive ELISA, r = 0.82; sandwich ELISA, r = 0.92; both p < 0.001). However, Deming regression and Bland–Altman analysis indicated lack of agreement of the 3 methods preventing direct comparison of results. The equations of the regression lines are: Competitive ELISA = 1.48 × RIA − 0.88; High sensitivity sandwich ELISA = 0.77 × RIA + 1.01.
Fully automated measurement of adiponectin by ELISA is feasible and substantially more rapid than RIA. The investigated ELISA test systems seem to exhibit analytical characteristics allowing for clinical application. In addition, there is a strong correlation between the ELISA methods and RIA. These findings might promote a more widespread use of adiponectin measurements in clinical research.

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Effect of pituitary surgery in patients with acromegaly on adiponectin serum concentrations and alanine aminotransferase activity

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Results

Discussion

Biochem. Biophys. Res. Commun.

Metabolism

Am. J. Kidney Dis.

The adipocyte-secreted protein Acrp30 enhances hepatic insulin action

Nat. Med.

Cloning of adiponectin receptors that mediate antidiabetic metabolic effects

Nature

Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients

Arterioscler. Thromb. Vasc. Biol.

Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia

J. Clin. Endocrinol. Metab.

Insulin resistance and body fat distribution

Diabetes Care

Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients

J. Clin. Endocrinol. Metab.

PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein

Diabetes

The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects

Diabetes

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis

Hepatology