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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1197
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 3 710-714
Copyright © 2008 by The Endocrine Society

Microalbuminuria in Insulin Sensitivity in Patients with Growth Hormone-Secreting Pituitary Tumor

Roberto Baldelli, Laura De Marinis, Antonio Bianchi, Rosario Pivonello, Valentina Gasco, Renata Auriemma, Giuseppe Pasimeni, Vincenzo Cimino, Marialuisa Appetecchia, Mauro Maccario, Gaetano Lombardi, Alfredo Pontecorvi, Annamaria Colao and Silvia Grottoli

Endocrinology Unit (R.B., G. P., M. A.), Regina Elena Cancer Institute, 00128 Rome, Italy; Endocrinology (L.d.M., A.B., V.C., A.P.), Catholic University of Sacred Heart, 00168 Rome, Italy; Department of Molecular and Clinical Endocrinology and Oncology (R.P., R.A., G.L., A.C.), University "Federico II", 80125 Naples, Italy; and Department of Internal Medicine, Endocrinology, and Metabolic Diseases (V.G., M.M., S.G.), University of Turin, 10153 Turin, Italy

Address all correspondence and requests for reprints to: Roberto Baldelli, M.D., Ph.D., Endocrinology Unit, Regina Elena Cancer Institute-IRCCS, Via Elio Chianesi 53, 00128 Roma, Italy. E-mail: baldelli{at}ifo.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Impaired glucose tolerance and diabetes mellitus are frequently present in acromegalic patients in whom the degree of impaired glucose metabolism seems directly correlated with GH levels. Microalbuminuria is reported to be directly correlated with insulin resistance, and both conditions predict cardiovascular disease mortality.

Objective: Our objective was to investigate the microalbuminuria levels as a marker of endothelial dysfunction in acromegalic patients.

Design: We conducted an observational, multicenter, open prospective study.

Subjects: Subjects included 74 patients with active acromegaly (52 with normal glucose tolerance, 16 with impaired glucose tolerance, and six with diabetes), and 50 healthy subjects matched for age, gender, and body mass index were studied as controls.

Results: In the whole group, mean GH and IGF-I levels were 24.2 ± 3.9 ng/ml and 700.1 ± 23.0 µg/liter, respectively. The insulin sensitivity index (ISI) in the patients was lower than in the controls (P < 0.0005). In impaired glucose tolerance and diabetic patients, microalbuminuria was higher than in normal glucose tolerance patients (P < 0.05 and P < 0.0005 respectively). Hypertensive patients had higher levels of microalbuminuria than normotensive ones (P < 0.005). The levels of microalbuminuria related to creatinine were directly correlated with fasting glucose levels (r = 0.27; P = 0.0019), fasting insulin levels (r = 0.28; P = 0.017), and insulin after 90 (r = 0.26; P = 0.027) and 120 min after glucose load (r = 0.26; P = 0.023) and indirectly correlated with ISI composite (P < 0.0001; r = –0.48). By a multivariate analysis, the log-ISI composite was the strongest predictor of microalbuminuria (t = –3.19; P = 0.0021).

Conclusions: Impairment of glucose tolerance in acromegaly is associated with high levels of microalbuminuria. For this reason, microalbuminuria should be part of cardiovascular risk assessment in these patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
GH and IGF-I receptors are generally expressed in the adult rat kidney (1). IGF-I is even synthesized in this tissue, suggesting a specific local role for GH and IGF-I (1).

Little information is, however, available on the human kidney. Both GH and IGF-I increase glomerular hemodynamics, and all GH effects appear to be systemically mediated by circulating IGF-I (1). Patients with acromegaly show elevated plasma volume associated with remarkable changes of glomerular filtration rate and plasma renal flow (1). Glucose homeostasis is also frequently altered in these patients, and impaired glucose tolerance (IGT) and diabetes mellitus (DM) are often present (2, 3).

Both pancreatic β-cell dysfunction and insulin resistance have been postulated in the pathogenesis of glucose intolerance in acromegaly (2). GH may cause insulin resistance in the liver, skeletal muscle, and adipose tissue (4, 5, 6), and hyperinsulinemia may play an important role in increasing the cardiovascular risk of acromegalic patients (2, 4, 7, 8, 9, 10). Aside from this, hyperinsulinemia is known to induce increased glomerular filtration rate and renal vasodilatation, which result in a rise of plasma flow and hydrostatic pressure gradient in normal rats (11). It is assumed that the pressure elevation in glomerular vessels is involved in increased albumin excretion (12). Indeed, microalbuminuria seems to cluster directly with the metabolic syndrome, and both conditions predict cardiovascular disease mortality (13). Glomerular hyperfiltration occurs frequently in acromegaly, but it is uncertain whether albuminuria is elevated in this disease (14) and whether it is related to GH excess or metabolic alterations (i.e. DM and hypertension). Among acromegalic patients, the excretion of albumin seems to be related to GH and IGF-I (14, 15).

This study aimed at investigating the levels of microalbuminuria as a marker of endothelial dysfunction in active acromegalic patients and at correlating this variable with those related to glucose tolerance.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Seventy-four patients with active acromegaly, 34 males and 40 females, aged 47.1 ± 11.9 yr (mean ± SD), with body mass index (BMI) of 31.4 ± 0.5 kg/m2, were included in an observational, multicenter, open prospective study. At study entry, acromegaly was clinically diagnosed on the basis of acral enlargement, patient interview, and comparison of photographs taken during a one- to two-decade span to date the onset of acral enlargement.

The biochemical diagnosis was performed in keeping with plasma GH levels higher than 2.5 ng/ml, not suppressible less than 1 ng/ml after oral glucose tolerance test (OGTT 75 g), and elevated IGF-I values for age (16). An OGTT was performed in all patients to assay blood glucose, insulin, and GH levels every 30 min for 2 h.

All patients gave their informed consent to the study, which was approved by all local ethical committees.

Controls

Fifty healthy subjects, matched for age (48.9 ± 11.8 yr), gender (25 men and 25 women), and BMI (30.8 ± 0.6 kg/m2) were studied as control group. In all patients at baseline, spontaneous GH secretion (six blood samples at 30-min intervals) and IGF-I were evaluated, and a general clinical examination was performed.

Methods

The diagnosis of DM or IGT was made according to the recent World Health Organization criteria (17). Blood glucose was determined by autoanalyzer using a glucose oxidase method (Beckman Instruments, Fullerton, CA). Serum GH and IGF-I levels were assayed by immunoassays using commercially available kits. The following age-corrected IGF-I (lower than 97th centile) were considered normal: 380 µg/liter or less (20–39 yr), 289.7 µg/liter or less (40–59 yr), and 218.4 µg/liter or less (60–80 yr). A 24-h urinary collection was used to determine the urine albumin concentrations using an automated immunoturbidity method (Dade Boehring, Marburg, Germany), with sensitivity of 2.3 mg/liter and inter- and intraassay coefficients of variation of 4.4 and 4.3%, respectively. We used the average of the two readings to determine the final albumin urinary excretion as normoalbuminuria (<20 mg/liter), microalbuminuria (20–200 mg/liter), and macroalbuminuria (>200 mg/liter). Data are shown as raw albuminuria and as creatinine ratio. Glycosylated hemoglobin (HbA1c) was performed using available commercial kits, and the average of three measurements was considered according to the recommendations of the report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (17). The insulin sensitivity index (ISI) has been calculated using the following formula: 10.000/{surd}(fasting plasma glucose x fasting plasma insulin) x (mean OGTT glucose concentration x mean OGTT insulin concentration) (18). According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (19), the severity of hypertension was classified as mild (stage 1) when the systolic blood pressure (SBP) and diastolic blood pressure (DBP) were between 140 and 159 mm Hg and between 90 and 99 mm Hg, respectively or severe (stage 2) when the SBP and DBP were higher than 160 and higher than 100 mm Hg, respectively; pre-hypertension was defined as SBP between 120 and 140 and DBP between 80 and 90 mm Hg.

Statistical analysis

Statistical analysis was made using a Statview 5 software for Windows. Data are presented as mean ± SE (Kruskal-Wallis test), followed by the Dunn’s test, the Mann-Whitney U test, or the Wilcoxon matched paired test when appropriate. A P < 0.05 was considered significant. Categorical data were analyzed by the {chi}2 test. Correlations between albuminuria (raw and creatinine ratio) and patients’ age, disease duration, GH, IGF-I, basal and postglucose glucose and insulin levels, ISI composite, and HbA1c, in the controls and in the patients, separately, were evaluated by calculating the Spearman coefficient. Multiple correlation analysis was performed to evaluate which parameter better predicted albuminuria among those showing a Spearman r < 0.01. The variables nonnormally distributed were plotted after natural-log transformation.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Mean spontaneous GH and IGF-I levels in all patients were 24.2 ± 3.9 ng/ml and 700.1 ± 23.0 µg/liter, respectively (Table 1Go). In all patients, basal fasting glucose levels were 5.38 ± 0.11 mmol/liter; 52 had normal glucose tolerance (NGT), 16 had IGT, and six had DM (Table 1Go). In the patients, basal plasma insulin levels were significantly higher (35.3 ± 4.0 vs. 10.1 ± 0.5 mUI/liter; P < 0.0005), and ISI composite during OGTT was significantly lower (3.2 ± 0.2 vs. 6.1 ± 0.2; P < 0.0005) than that of control group (Table 1Go). The levels of albuminuria as raw data (32.2 ± 2.5 vs. 16.3 ± 1.0 mg/liter; P < 0.029) or creatinine ratio (24.4 ± 1.7 vs. 18.6 ± 0.5; P < 0.05) were significantly higher in the patients than in control group (Table 1Go); microalbuminuria was detected in 41 patients (55.4%) and in none of controls (<0.0001). No difference was found in albuminuria levels associated with gender or with BMI. The patients with hypertension (n = 24) showed higher levels of albuminuria (P < 0.005) (Fig. 1Go). The levels of albuminuria were, as expected, higher in IGT and DM patients than in NGT patients (P < 0.05 and P < 0.0005, respectively) (Fig. 1Go).


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  		TABLE 1. Patient and control profiles

 

Figure 1
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  		FIG. 1. Microalbuminuria levels. A, NT, IGT, and DM patients (*, P < 0.05 vs. NT; **, P <0.0005 vs. NT). B, Hypertensive and normotensive patients (*, P < 0.005).

 
In the patient group, the levels of albuminuria as raw data were correlated with patient age (r = 0.25; P < 0.034), disease duration (r = 0.30; P = 0.0097), and ISI composite (r = –0.38; P = 0.0008); the levels of albuminuria/creatinine ratio were correlated with GH (r = 0.25; P < 0.030), glucose levels at time 0 (r = 0.10; P = 0.0019) and time 120 (r = 0.26; P = 0.027), insulin levels at time 0 (r = 0.28; P = 0.017), time 90 (r = 0.26; P = 0.027), and time 120 (r = 0.26; P = 0.023), and ISI composite (r = –0.35; P < 0.0001) (Fig. 2Go and Table 2Go). No correlation was found between the levels of albuminuria and IGF-I levels. The ISI composite was the strongest predictor of microalbuminuria (t = –3.19; P = 0.0021).


Figure 2
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  		FIG. 2. Correlation between albuminuria/creatinine ratio and log-ISI composite in the 74 patients and 50 controls. Dashed lines indicate the 95% confidence limits.

 

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  		TABLE 2. Multiple linear regression analysis between microalbuminuria and ISI, glucose time 0 in acromegalic patients (n = 74)

 
In the control group, the levels of albuminuria/creatinine ratio were correlated with glucose levels at time 30 (r = –0.30; P = 0.024) and insulin levels time at 120 (r = –0.42; P = 0.002) but not log-ISI composite (r = 0.08; P = 0.58) (Fig. 2Go).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Acromegaly is associated with higher levels of microalbuminuria than the normal population. To explain this observation, the presence of different components of the metabolic syndrome such as hypertension, insulin resistance, and alteration of glucose metabolism is hypothesized (14, 15).

The cardiometabolic syndrome is associated with cardiovascular disease and includes a variety of risk factor such as insulin resistance, hyperinsulinemia, dyslipidemia, and microalbuminuria (20). Active acromegaly is frequently associated with alterations in glucose homeostasis, such as insulin resistance, hyperinsulinemia, IGT, or DM (3).

In this context, microalbuminuria is an early indicator of renal disease and is frequently associated with insulin resistance. This condition contributes to elevated blood pressure through several mechanisms, one of which is the action of tissue angiotensin II and aldosterone, leading to vascular resistance to the effects of insulin (20, 21, 22, 23, 24, 25, 26). Moreover, insulin may increase nephron perfusion and filtration through IGF-I receptors to which it has affinity. In our series, we indeed found that hypertensive patients had higher levels of microalbuminuria than normotensive ones; in this context, hypertension is believed to contribute to renal disease by increasing glomerular capillary pressure, proteinuria, endothelial dysfunction, and sclerosis, leading to nephron damage (22).

Furthermore, the alterations of glucose tolerance can also exert a direct toxic effect on nephrons through glycosylation of glomerular proteins, as previously reported (27, 28, 29). In our patients, a strict relationship between microalbuminuria and insulin resistance was found; this correlation confers an important value to microalbuminuria as a direct marker of metabolic derangement. Hyperinsulinemia is able to induce renal vasodilatation, resulting in increased plasma flow and increased glomerular filtration rate. This localized elevated pressure in the glomerular vessels possibly could be also involved in increased albumin excretion (1). Acromegalic patients can be considered at high risk of metabolic derangements, and the clustering of risk factors attributed to insulin resistance and microalbuminuria may all be features of damage to different aspects of endothelial function.

In conclusion, we found high levels of microalbuminuria, alterations in glucose metabolism, and insulin resistance/hyperinsulinemia in acromegaly. The persistence of insulin resistance and suboptimal control of associated cardiometabolic abnormalities cause renal injury with functional as well as structural nephron loss contributing to elevated blood pressure. This condition leads to further renal injury, thereby setting off a vicious circle of events. More studies should investigate the effects of treatment of acromegaly in the control of such microalbuminuria impairment.


   Footnotes
 
Disclosure Summary: A.C. received lecture fees from Ipsen, Novartis, and Pfizer. G.L. received lecture fees from Ipsen and Novartis. R.B., G.P., M.A., L.d.M., A.B., V.C., A.P., R.P., R.A., V.G., M.M., A.C., and S.G. have nothing to declare.

First Published Online December 26, 2007

Abbreviations: BMI, Body mass index; DBP, diastolic blood pressure; DM, diabetes mellitus; IGT, impaired glucose tolerance; ISI, insulin sensitivity index; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SBP, systolic blood pressure.

Received May 30, 2007.

Accepted December 19, 2007.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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