Impact of Long-Acting Somatostatin Analogues on Glucose Metabolism in Acromegaly: A Hospital-Based Study

Shen, Ming; Wang, Meng; He, Wenqiang; He, Min; Qiao, Nidan; Ma, Zengyi; Ye, Zhao; Zhang, Qilin; Zhang, Yichao; Yang, Yeping; Cai, Yanjiao; ABuDuoReYiMu, Yakupujiang; Lu, Yun; Lu, Bin; Shou, Xuefei; Wang, Yongfei; Ye, Hongying; Li, Yiming; Li, Shiqi; Zhao, Yao; Cao, Xiaoyun; Zhang, Zhaoyun

doi:https://doi.org/10.1155/2018/3015854

International Journal of Endocrinology

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Volume 2018 | Article ID 3015854 | https://doi.org/10.1155/2018/3015854

Impact of Long-Acting Somatostatin Analogues on Glucose Metabolism in Acromegaly: A Hospital-Based Study

Ming Shen,¹Meng Wang,²Wenqiang He,¹Min He,²Nidan Qiao,¹Zengyi Ma,¹Zhao Ye,¹Qilin Zhang,¹Yichao Zhang,¹Yeping Yang,²Yanjiao Cai,²and Yakupujiang ABuDuoReYiMu³ et al.

Academic Editor: Mario Maggi

Received13 Jul 2017

Accepted13 Dec 2017

Published26 Apr 2018

Abstract

Purpose. To evaluate the change in glucose tolerance in treatment-naïve patients with acromegaly after administration of SSA and to identify predictive factors of glucose impairment during SSA therapy. Methods. Oral glucose tolerance testing (OGTT) was performed on 64 newly diagnosed and treatment-naïve patients with acromegaly both at pretreatment and 3 months after initiation of treatment with long-acting SSA. Insulin resistance (IR) was assessed by homeostatic model assessment- (HOMA-) IR and IS_OGTT. Insulin secretion was assessed by HOMA-β, INS₀/BG₀, IGI (insulinogenic index), IGI/IR, ISSI2, and AUC_INS/AUC_BG. Receiver-operating characteristic (ROC) curves were generated to determine the optimal cutoffs to predict the impact of SSA on glucose metabolism. Results. Pretreatment, 19, 24, and 21 patients were categorized as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM), respectively. Posttreatment, IR, represented by IS_OGTT, was significantly improved in all 3 groups. Insulin secretion, represented by HOMA-β, declined in the NGT and IGT groups, but was unaltered in the DM group. The glucose tolerance status deteriorated in 18 (28.1%) patients, including 13 patients in the NGT group and 5 patients in the IGT group. Deterioration was associated with lower baseline BG₁₂₀ (plasma glucose 120 min post-OGTT), less reduction of growth hormone (GH), and greater reduction of insulin secretion after SSA therapy. BG₁₂₀ greater than 8.1 mmol/l provided the greatest sensitivity and specificity in predicting the stabilization and/or improvement of glucose tolerance status after SSA treatment (PPV 90.7%, NPV 66.7%, ). Conclusions. The deterioration of glucose metabolism induced by SSA treatment is caused by the less reduction of GH and the more inhibition of insulin secretion, which can be predicted by the baseline BG₁₂₀ during OGTT.

1. Introduction

Acromegaly is an insidious disease associated with a 1.72 times increased mortality risk [1]. Cardiovascular, respiratory, and metabolic complications are the main causes of death in acromegaly. Disturbances of carbohydrate metabolism are the major type of metabolic disorder [2]. Overt type 2 diabetes mellitus is reported in 19–56% and impaired glucose tolerance (IGT) in 16–46% of patients with acromegaly [3]. GH-mediated insulin resistance (IR) is the major cause of impaired glucose metabolism in active acromegaly [4].

Although transsphenoidal surgery is the first-line therapy for GH-secreting adenomas, for those who are not in remission after surgery or for whom surgery is contraindicated, long-acting somatostatin analogues (SSA) are generally considered to be first-line therapy [5]. However, the impact of SSA on glucose metabolism has not been fully elucidated and previous results from small series are conflicting [6–9]. This may be due to the fact that SSA inhibits GH and glucagon secretion while also suppressing the release of insulin [10, 11]. The aim of our study was to investigate the effects of SSA on glucose homeostasis and to determine whether there are any variables that could predict the influence of SSA on glucose metabolism in patients with active acromegaly.

2. Subjects and Methods

2.1. Patients

This was a retrospective study of prospectively obtained data from patients seen between July 2012 and August 2014 at a tertiary referral center in the East of China. Sixty-four newly diagnosed and untreated patients with acromegaly (38 females and 26 males, mean age 41.7 ± 13.0 years) were recruited. Clinical and biochemical findings of the patients are summarized in Supplementary Tables 1–4. The diagnosis of active disease was based on the clinical features of acromegaly, failure of GH suppression to below 1 μg/l in response to a 75 g oral glucose tolerance test (OGTT), plasma IGF-1 levels above the age-appropriate reference range, and radiological evidence of a pituitary tumor. The mean GH (GH_m) was obtained as the average level of 5 samples drawn within a 2 h period (every 30 min from 0700 to 0900 h) [12]. Before and after SSA treatment, glycosylated hemoglobin (HbA_1c) was obtained. Glucose tolerance was evaluated by OGTT. Briefly, after an overnight fasting, blood samples were drawn for baseline blood glucose (BG) and insulin (INS). Then, 75 g of glucose was administered orally. Sampling for BG and insulin was performed 30, 60, 120, and 180 min later. Three months after initiation of long-acting SSA treatment, octreotide LAR, 20 mg every 4 weeks (), and lanreotide SR, 40 mg every 2 weeks (), patients were reevaluated. The diagnosis of type 2 diabetes mellitus or impaired glucose tolerance was made according to World Health Organization criteria [13].

Informed consent was obtained by each individual. Our study was approved by the ethics committee at our hospital and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

2.2. Evaluation of Insulin Resistance and β-Cell Function

Homeostatic model assessment (HOMA) (including HOMA-IR and HOMA-β) was used to estimate insulin resistance (IR) and β-cell function [14]. Insulin sensitivity was also assessed by calculating IS_OGTT (the OGTT insulin sensitivity index) [15]. INS₀/BG₀, IGI (insulinogenic index), IGI/IR, and ISSI2 (the OGTT insulin secretion sensitivity index-2) were also used to estimate β-cell function [14, 16–22]. The areas under the curve of glucose (AUC_BG) and insulin (AUC_INS) during OGTT were calculated using the trapezoidal rule [9, 23]. AUC_INS/AUC_BG, which is an indicator of insulin secretion, was also calculated [20].

2.3. Abbreviated Variables and Formulas

BG₀ was the baseline blood glucose value during the OGTT. BG₃₀, BG₆₀, BG₁₂₀, and BG₁₈₀ were the blood glucose values from 30 min to 180 min during the OGTT. INS₀, INS₃₀, INS₆₀, INS₁₂₀, and INS₁₈₀ were the insulin values from basal to 180 min during the OGTT. BG_mean and INS_mean represent the mean insulin and glucose concentrations during the OGTT. AUC_BG = (BG₀ + BG₃₀) × 15 + (BG₃₀ + BG₆₀) × 15 + (BG₆₀ + BG₁₂₀) × 30 + (BG₁₂₀ + BG₁₈₀) × 30. AUC_INS = (INS₀ + INS₃₀) × 15 + (INS₃₀ + INS₆₀) × 15 + (INS₆₀ + INS₁₂₀) × 30 + (INS₁₂₀ + INS₁₈₀) × 30. HOMA-IR = (BG₀ × INS₀)/22.5. HOMA-β = (20 × INS₀)/(BG₀ – 3.5) × 100%. IS_OGTT (the OGTT insulin sensitivity index) = 10,000/SQRT (BG₀ × INS₀ × BG_mean × INS_mean). IGI (insulinogenic index) = (INS₃₀ − INS₀)/(BG₃₀ − BG₀) = △INS₃₀/△BG₃₀. IGI/IR = IGI/HOME-IR. ISSI2 (the OGTT insulin secretion sensitivity index-2) = (AUC_INS/AUC_BG) × IS_OGTT.

2.4. Biochemical Measurements

GH was measured by a two-site chemiluminescent immunometric assay (AutoDELFIA® hGH, PerkinElmer Life and Analytical Sciences, Wallac Oy), intra-assay CV: 5.3–6.5%, interassay CV: 5.7–6.2%, and sensitivity: up to 0.01 μg/l (0.026 mU/l).

IGF-1 was measured with the IMMULITE 2000 solid-phase, enzyme-labeled chemiluminescent immunometric assay (Siemens Healthcare Diagnostic Products Limited, UK); normal age-appropriate ranges are as follows: 1–6 years: 49–327 μg/l; 7–11 years: 57–551 μg/l; 12–13 years: 143–850 μg/l; 14–16 years: 220–996 μg/l; 17–18 years: 163–731 μg/l; 19–20 years: 127–483 μg/l; 21–35 years: 115–358 μg/l; 36–50 years: 94–284 μg/l; >50 years: 55–238 μg/l; intra-assay CV: 2.3–3.5%; interassay CV: 7.0–7.1%; and sensitivity: 20 μg/l. IGF-1 limit of normal range (ULN) [24].

Insulin was measured by chemiluminescence immunoassay (ADVIA Centaur XP, Siemens, USA). BG was measured by a Hitachi 7600 Biochemical Analyzer (Tokyo, Japan). HbA_1c was detected with high-performance liquid chromatography (Tosoh HLC-723 G8 HPLC Analyzer, Japan).

2.5. Statistics Analysis

Data are presented as (or median with interquartile range) for continuous variables normally (or not normally) distributed, respectively, and as frequency for categorical variables. Normality was tested using the Kolmogorov-Smirnov test. The change of variables between pre- and post-SSA treatment within one group was compared using the paired -test when data distribution was normal or by the Wilcoxon rank-sum (Mann–Whitney) test when variables were not normally distributed. One-way ANOVA with LSD post hoc analysis (or the Kruskal-Wallis test followed by Bonferroni post hoc test) was used for comparisons among multiple groups. For categorical variables, differences were analyzed by the chi-square test. Univariate regression analysis was performed, and Spearman rank correlation coefficients are reported. After construction of receiver-operating characteristic (ROC) curves, Youden indices were calculated to determine the optimal cutoffs for variables to predict the change in glucose metabolism after SSA treatment (sensitivity, specificity, PPV, and NPV). Statistical analysis was performed with SPSS 16.0 statistical software. A two-tailed was considered significant.

3. Results

3.1. Baseline Characteristics among NGT/IGT/DM Groups

Pretreatment, patients were categorized into three groups: normal glucose tolerance (NGT) group (19 patients, 8 females/11 males), impaired glucose tolerance (IGT) group (24 patients, 15 females/9 males), and diabetes mellitus (DM) group (21 patients, 15 females/6 males). 8 patients in the DM group were known to have diabetes and were treated with oral antidiabetic drugs prior to taking part in this study. For these patients, OGTT was only performed when fasting plasma glucose (FPG) was below 8 mmol/l (previously diagnosed diabetic patients with FPG above 8 mmol/l was excluded from this study). The other 13 diabetic patients were diagnosed at baseline OGTT along with the diagnosis of acromegaly. During the study, 10 patients were treated with oral antidiabetic drugs and 11 patients were given advice about lifestyle/dietary modifications. The baseline characteristics of the three groups are shown in Supplementary Table 5. Age, body mass index (BMI), GH_m, IGF-1 index, and HOMA-IR did not differ significantly among the three groups. HbA_1c was higher in the DM group than in the NGT and IGT groups, while HOMA-β was significantly lower in the DM group than in the other two groups.

No difference was found between females and males in age, BMI, HbA1c, GH_m, FPG, and BG₁₂₀. Females had significantly higher FPI, INS₁₂₀, HOME-β, INS₀/BG₀, and HOMA-IR, with lower IS_OGTT and lower IGF-1 index, than males had (Supplementary Table 6). Thus, females were prone to higher insulin resistance and higher β-cell function than males were.

3.2. Effect of SSA Treatment on BG and HbA_1c Levels

Compared to pretreatment, HbA_1c dropped significantly within the DM group (8.35 ± 2.47 versus 6.88 ± 1.00%, ) after SSA treatment. In the entire cohort, NGT, and IGT groups, HbA_1c showed no change from pretreatment to posttreatment (Table 1).

Compared to pretreatment, FPG increased significantly in the entire cohort, NGT, and IGT groups after SSA treatment. However, in the DM group, no changes were detected from pretreatment to posttreatment. From before to after SSA treatment, BG₁₂₀ increased in the NGT group and decreased in the DM group, while it was unaltered in the entire cohort and IGT group (Table 1).

3.3. Effect of SSA Treatment on Plasma Insulin Levels during OGTT

Compared to pretreatment, the posttreatment levels of fasting plasma insulin (FPI) declined in the group as a whole and in NGT and IGT groups. However, no change was detected within the DM group from pretreatment to posttreatment. Compared to pretreatment, after SSA treatment, INS₁₂₀ decreased in the group as a whole and in the IGT group, but remained unaltered in the NGT and DM groups (Table 1).

3.4. Effect of SSA Treatment on Insulin Resistance

After SSA treatment, HOMA-IR significantly decreased within the group as a whole, and in the NGT and IGT groups, but not in the DM group. Moreover, IS_OGTT significantly increased in the group as a whole, as well as in the NGT, IGT, and DM groups (Table 1). After SSA treatment, HOMA-IR significantly decreased, while IS_OGTT significantly increased, in both females and males (Supplemental Table 7).

3.5. Effect of SSA Treatment on Insulin Secretion

In the group as a whole and in the IGT group, there was a significant decline in β-cell function, including HOMA-β, INS₀/BG₀, IGI, IGI/IR, and AUC_INS/AUC_BG after SSA treatment. However, no significant change was observed in ISSI2. In the NGT group, all variables reflective of β-cell function declined. However, in the DM group, no change was observed in any variables reflective of insulin secretion (Table 1). In females, all variables reflective of β-cell function declined except AUC_INS/AUC_BG. In males, all variables reflective of β-cell function declined except ISSI2 (Supplementary Table 7).

3.6. Effects of SSA Treatment on Glucose Tolerance

At the baseline, 29.7% (19/64) of patients had NGT, 37.5% (24/64) had IGT, and 32.8% (21/64) had DM. After SSA treatment for 3 months, 26.6%, 42.2%, and 31.2% of the patients, respectively, were categorized as NGT, IGT, and DM (Figure 1). After SSA treatment, in the NGT group (), 31.5% maintained the status quo, while 63.2% developed IGT and 5.3% became diabetic. In the IGT group (), 45.8% of the patients became NGT, 33.4% remained unchanged, and 20.8% progressed to diabetes. In the DM group (), 66.7% continued to have diabetes mellitus while 33.3% improved to IGT. In summary, after SSA treatment, the distribution of glucose metabolism status was as follows: 43.8% (28/64) patients were stable, 28.1% (18/64) of the subjects improved, and 28.1% (18/64) of the subjects deteriorated (Figure 1).

After SSA therapy, subjects were classified into 3 groups according to the change of glucose tolerance category: Improved (, from IGT to NGT, from DM to IGT, or from DM to NGT), Stable (, from NGT to NGT, from IGT to IGT, or from DM to DM), and Deteriorated (, from NGT to IGT, from NGT to DM, or from IGT to DM). The baseline characteristics of these 3 groups are shown in Table 2. Patients in the Stable group were older than those in the other two groups (). The baseline BG₁₂₀ levels were significantly lower in the Deteriorated group than in the other two groups ().

The changes in glucose metabolism-related variables after SSA treatment are shown in Table 3. The reduction of GH_m was much less in the Deteriorated group than in the other two groups (). The reduction of HOMA-β was greater in the Deteriorated group than in the Stable group () and Improved group ().

Patients were further divided into biochemically controlled (, posttreatment GH ) group and uncontrolled (, posttreatment GH ) group based on posttreatment GH levels. As shown in Supplementary Table 8, We found a trend toward a decrease on HbA_1c (6.09 ± 1.32 versus 5.81 ± 0.64%), FPG (5.68 ± 1.75 versus 5.53 ± 0.45 mmol/l), and BG₁₂₀ (8.75 versus 7.85 mmol/l) in the controlled group. As for the change in insulin resistance and secretion, we found that after treatment, insulin resistance, represented by IS_OGTT, was significantly improved in both groups. And all variables reflective of insulin secretion except ISSI2 declined in both groups (Supplementary Table 8).

3.7. Correlation Studies

In the group as a whole, the reduction in HbA_1c positively correlated with the reduction in GH_m (, , Figure 2(a)) and negatively correlated with the reduction of ISSI2 (, , Figure 2(b)), IGI (, ), and IGI/IR (, ) after SSA treatment (Supplementary Table 9).

(a)

(b)

3.8. The Predictive Value of Baseline BG₁₂₀ for the Effect of SSA Treatment on Glucose Metabolism

ROC curve analysis was performed to further estimate the predictive value of BG₁₂₀ on the change of glucose tolerance status. The cutoff value of baseline BG₁₂₀ was 8.1 mmol/l which demonstrated the greatest sensitivity and specificity in predicting the stability and/or improvement of glycemic status after SSA treatment, with a PPV of 90.7% and a NPV of 66.7% (sensitivity 84.8%, specificity 77.8%, , , Figure 3).

Patients were categorized into two groups according to BG₁₂₀ at baseline: group A (BG₁₂₀ greater than 8.1 mmol/l) and group B (BG₁₂₀ less than 8.1 mmol/l). First, we compared these two groups at baseline. We found that IGI (), IGI/IR (), and ISSI2 () were higher in group B than in group A (Supplementary Table 10). Second, the changes in variables after SSA treatment were analyzed (Supplementary Table 11). We found that the reduction of GH_m was less in group B than in group A (), while the reduction of HOMA-β, IGI, IGI/IR, and ISSI2 was more in group B than in group A (, 0.002, 0.008, and 0.046, resp.).

4. Discussion

In the present study, we demonstrated that the change in glucose metabolic status after SSA therapy strongly correlated with the baseline status of glucose metabolism in patients with acromegaly. FPG rose in both NGT and IGT groups, but remained stable in the DM group. BG₁₂₀ increased in the NGT group, stabilized in the IGT group, and decreased in the DM group. Insulin resistance was improved in all 3 groups, while insulin secretion declined in the NGT and IGT groups and was unchanged in the DM group. The glucose tolerance status was improved in 28.1% patients, deteriorated in 28.1% patients, and stabilized in 43.8% patients. Deterioration was associated with lower baseline BG₁₂₀, less reduction in GH_m, and a greater reduction in insulin secretion after SSA therapy. The cutoff value of BG₁₂₀ (8.1 mmol/l) at baseline predicted the stabilization and/or improvement of glucose metabolism during SSA treatment.

The impact of SSA on glucose metabolism has been studied, but the results are conflicting [6–9]. Several studies have reported no change of glucose levels after SSA treatment [6, 25]. A meta-analysis also indicated that SSA might have an overall minor impact on glucose homeostasis in patients with acromegaly [26]. However, others found that SSA significantly aggravated glucose tolerance in patients with acromegaly [11, 27–29], thus mandating glucose monitoring during SSA therapy. Interestingly, Ho et al. even reported that SSA has beneficial effects on carbohydrate metabolism in patients with acromegaly and glucose intolerance [30]. In our study, the predominant pattern of change in glucose tolerance status was deterioration in the baseline NGT group, stabilization in the baseline IGT group, and amelioration in the baseline DM group. And the influence of SSA on glucose metabolism was not gender specific, although females were prone to have higher insulin resistance and higher β-cell function at baseline, which was highly consistent with the study of Ciresi et al. [31]. These data suggest that depending on the glucose tolerance status at baseline, SSA has distinct effects on the glucose metabolism in patients with acromegaly. This might partially explain the conflicting results from previous studies which had patients with different glucose tolerance status.

Recently, pasireotide was approved for acromegaly and showed more efficacy in controlling GH and IGF-1 levels [32]. As for the effects on glucose metabolism, a head-to-head study has reported that compared with octreotide LAR, hyperglycemia-related adverse events were more common with pasireotide [33].

The change in glucose metabolism correlated strongly with the change of insulin resistance and insulin secretion after SSA treatment [34]. Ronchi et al. found that HOMA-IR significantly declined during SSA treatment [9]. Baldelli et al. found that insulin resistance was improved but the insulin secretion was 30 minutes delayed after 6 months of SSA therapy [27]. However, Steffin et al. found that SSA decreased β-cell function without affecting insulin resistance [35]. In the present study, we used not only HOMA but also various derivatives of the OGTT to evaluate insulin sensitivity and β-cell function. For insulin sensitivity, HOMA-IR decreased in the NGT and IGT groups and remained unaltered in the DM group, while IS_OGTT, another major parameter reflecting insulin resistance, improved in all groups. Matsuda et al. first developed the IS_OGTT index and proved IS_OGTT to be a reasonable and better approximation of whole-body insulin sensitivity in patients with diabetes mellitus than HOMA [15]. This might be applicable to patients with acromegaly. Variables reflective of β-cell function, such as HOMA-β, INS₀/BG₀, IGI/IR, and IGI, declined in both NGT and IGT groups, but remained unchanged in the DM group. The above results showed SSA decreased insulin secretion in NGT and IGT groups, but had no effect in the DM group.

Excess GH levels led to insulin resistance in both NGT and DM patients, and SSA therapy could significantly reduce GH levels, resulting in the decrease of insulin resistance both in NGT and DM groups. Meanwhile, insulin secretion was decreased after SSA treatment in the NGT group, but was not compromised in the DM group. Thus, the glucose metabolic status was generally improved after SSA administration in the DM group due to the alleviated degree of insulin resistance without compromise of insulin secretion. But in the NGT group, the glucose metabolic status might even deteriorate if the reduction of insulin secretion overcomes the improvement of insulin resistance. This may be the potential underlying mechanism for the different effects of SSA on glucose metabolism in patients with NGT and patients with DM.

Several studies revealed factors associated with the SSA-induced changes in glucose tolerance status. Koop et al. stated that female patients and those with higher baseline insulin levels were more likely to develop DM during SSA therapy [11]. Ho et al. found that improvement in glucose tolerance status was dependent on pretreatment BG concentrations [30]. Colao et al. found that deterioration of glucose metabolism was correlated with increased BMI, uncontrolled acromegaly during SSA therapy, and abnormal glucose tolerance at baseline [28, 29]. In the present study, we showed that the deterioration of glucose tolerance was associated with less reduction of GH and greater reduction in insulin secretion after SSA therapy. In addition, the reduction of HbA_1c was positively correlated with the reduction of GH_m and negatively correlated with the reduction of insulin secretion. Interestingly, we found that SSA administration can significantly improve insulin resistance with a compromise in insulin secretion, in patients with both biochemically controlled (posttreatment GH ) and uncontrolled (posttreatment GH ) acromegaly, which was similar with Giordano et al. [36]. Some discrepancy (e.g., IGI) may be related to the different races and duration of SSA treatment (3 months in our study, ≥12 months in literature) between studies. When exploring potential baseline predictors, we found that the baseline BG₁₂₀ was significantly lower in patients whose glucose status deteriorated. Furthermore, for the first time, we generated ROC curves to obtain the most sensitive and specific cutoff values which predicted the change of glucose metabolism after SSA therapy. We showed that when the baseline BG₁₂₀ was higher than 8.1 mmol/l, there was a 90.7% chance of stabilized and/or improved glucose tolerance status. However, when the baseline BG₁₂₀ was lower than 8.1 mmol/l, there was a 66.7% chance of deterioration in glucose tolerance status.

To explore the potential mechanism, we examined the difference between patients with baseline BG₁₂₀ above 8.1 mmol/l and those with baseline BG₁₂₀ below 8.1 mmol/l. Interestingly, we found that patients with baseline BG₁₂₀ below 8.1 mmol/l had less of a reduction in GH_m and a greater reduction in β-cell function. Less reduction of GH_m led to less improvement in insulin resistance in patients with baseline BG₁₂₀ below 8.1 mmol/l. In addition to less improvement in insulin resistance, patients with baseline BG₁₂₀ below 8.1 mmol/l had a greater reduction in insulin secretion, which indicated that there was more chance of deteriorating glucose tolerance status after SSA treatment in these subjects. Thus, vice versa, baseline BG₁₂₀ higher than 8.1 mmol/l after OGTT may be considered as a beneficial predictive factor for glucose metabolism during SSA treatment. This seemed to be discordant with a previous study indicating that baseline glucose status was one of the major predictors of changing glucose status [29]. But actually, in our study, the percentage of improved glucose metabolism in the IGT group tended to be more than in the DM group [45.8% (11/24) versus 33.3% (7/21), ], which was consistent with the study of Colao et al.

The limitation of the current study is that this study is not a blinded study from a patient’s point of view and patients who are diagnosed with diabetes mellitus or impaired glucose tolerance at pretreatment assessment may have lifestyle/dietary modification, which may have had an impact on the glucose metabolism results in the follow-up assessment.

In conclusion, the impact of SSA on the change in glucose metabolic status, insulin resistance, and β-cell function depends on the pretreatment glucose metabolism status in patients with acromegaly. Deterioration is associated with lower baseline BG₁₂₀, the less of a reduction in GH_m, and a greater reduction in insulin secretion after SSA therapy. BG₁₂₀ during OGTT can predict the impact of SSA treatment on glucose metabolism.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed consent was obtained from all individual participants included in the study.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Authors’ Contributions

Ming Shen and Meng Wang contributed equally to this work.

Acknowledgments

The authors thank Dr. Karen Klahr Miller at Massachusetts General Hospital for helpful comments and edits with the manuscript. This work was supported by the following grants: from the National Natural Science Foundation of China (nos. 81370938, 81172391, 81370884, and 81602191), Shanghai Rising-Star Tracking Program (12QH1400400), and Shanghai Municipal Commission of Health and Family Planning (nos. XYQ2011002, XYQ2013120, XYQ20134280, and XYQ201640058).

Supplementary Materials

Supplementary Table 1: baseline characteristics of the 64 patients. Supplementary Table 2: patients’ data before and after SSA therapy. Supplementary Table 3: OGTT and glucose tolerance status before and after SSA therapy. Supplementary Table 4: insulin levels during OGTT before and after SSA therapy. Supplementary Table 5: comparison of pretreatment variables among NGT/IGT/DM groups. Supplementary Table 6: the baseline characteristics of the female group and male group. Supplementary Table 7: changes of variables in female and male groups from pretreatment to after SSA treatment. Supplementary Table 8: changes of variables in “controlled” and “uncontrolled” patients from pretreatment to after SSA treatment. Supplementary Table 9: correlation between the changes of HbA1c and glucose metabolism-related variables after SSA treatment. Supplementary Table 10: comparison of baseline characteristics between group A and B. Supplementary Table 11: comparison of the change in variables after SSA treatment between groups A and B. (Supplementary Materials)

References

O. M. Dekkers, N. R. Biermasz, A. M. Pereira, J. A. Romijn, and J. P. Vandenbroucke, “Mortality in acromegaly: a metaanalysis,” The Journal of Clinical Endocrinology & Metabolism, vol. 93, no. 1, pp. 61–67, 2008.
View at: Publisher Site | Google Scholar
A. Jadresic, L. M. Banks, D. F. Child et al., “The acromegaly syndrome. Relation between clinical features, growth hormone values and radiological characteristics of the pituitary tumours,” QJM: An International Journal of Medicine, vol. 51, no. 202, pp. 189–204, 1982.
View at: Google Scholar
A. Colao, D. Ferone, P. Marzullo, and G. Lombardi, “Systemic complications of acromegaly: epidemiology, pathogenesis, and management,” Endocrine Reviews, vol. 25, no. 1, pp. 102–152, 2004.
View at: Publisher Site | Google Scholar
D. R. Clemmons, “Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly,” Pituitary, vol. 5, no. 3, pp. 181–183, 2002.
View at: Publisher Site | Google Scholar
A. Giustina, P. Chanson, M. D. Bronstein et al., “A consensus on criteria for cure of acromegaly,” The Journal of Clinical Endocrinology & Metabolism, vol. 95, no. 7, pp. 3141–3148, 2010.
View at: Publisher Site | Google Scholar
L. B. Barnard, W. G. Grantham, P. Lamberton, T. M. O'Dorisio, and I. M. Jackson, “Treatment of resistant acromegaly with a long-acting somatostatin analogue (SMS 201-995),” Annals of Internal Medicine, vol. 105, no. 6, pp. 856–861, 1986.
View at: Publisher Site | Google Scholar
S. W. J. Lamberts, M. Zweens, L. Verschoor, and E. D. Pozo, “A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs,” The Journal of Clinical Endocrinology & Metabolism, vol. 63, no. 1, pp. 16–19, 1986.
View at: Publisher Site | Google Scholar
L. M. Sandler, J. M. Burrin, G. Williams, G. F. Joplin, D. H. Carr, and S. R. Bloom, “Effective long-term treatment of acromegaly with a long-acting somatostatin analogue (SMS 201-995),” Clinical Endocrinology, vol. 26, no. 1, pp. 85–95, 1987.
View at: Publisher Site | Google Scholar
C. Ronchi, P. Epaminonda, V. Cappiello, P. Beck-Peccoz, and M. Arosio, “Effects of two different somatostatin analogs on glucose tolerance in acromegaly,” Journal of Endocrinological Investigation, vol. 25, no. 6, pp. 502–507, 2002.
View at: Publisher Site | Google Scholar
M. Giusti, E. Ciccarelli, D. Dallabonzana et al., “Clinical results of long-term slow-release lanreotide treatment of acromegaly,” European Journal of Clinical Investigation, vol. 27, no. 4, pp. 277–284, 1997.
View at: Publisher Site | Google Scholar
B. L. Koop, A. G. Harris, and S. Ezzat, “Effect of octreotide on glucose tolerance in acromegaly,” European Journal of Endocrinology, vol. 130, no. 6, pp. 581–586, 1994.
View at: Publisher Site | Google Scholar
M. Wang, M. Shen, W. He et al., “The value of an acute octreotide suppression test in predicting short-term efficacy of somatostatin analogues in acromegaly,” Endocrine Journal, vol. 63, no. 9, pp. 819–834, 2016.
View at: Publisher Site | Google Scholar
M. I. Harris, W. C. Hadden, W. C. Knowler, and P. H. Bennett, “International criteria for the diagnosis of diabetes and impaired glucose tolerance,” Diabetes Care, vol. 8, no. 6, pp. 562–567, 1985.
View at: Publisher Site | Google Scholar
D. R. Matthews, J. P. Hosker, A. S. Rudenski, B. A. Naylor, D. F. Treacher, and R. C. Turner, “Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man,” Diabetologia, vol. 28, no. 7, pp. 412–419, 1985.
View at: Publisher Site | Google Scholar
M. Matsuda and R. A. DeFronzo, “Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp,” Diabetes Care, vol. 22, no. 9, pp. 1462–1470, 1999.
View at: Publisher Site | Google Scholar
Z. Kuloglu, M. Berberoglu, A. Kansu et al., “Effect of interferon therapy on glucose metabolism in children with chronic hepatitis B,” The Turkish Journal of Pediatrics, vol. 52, no. 6, pp. 594–601, 2010.
View at: Google Scholar
A. Mitrakou, D. Kelley, M. Mokan et al., “Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance,” The New England Journal of Medicine, vol. 326, no. 1, pp. 22–29, 1992.
View at: Publisher Site | Google Scholar
S. M. Haffner, H. Miettinen, S. P. Gaskill, and M. P. Stern, “Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans,” Diabetes, vol. 44, no. 12, pp. 1386–1391, 1995.
View at: Publisher Site | Google Scholar
F. Alford, H. Beck-Nielsen, G. M. Ward, and J. E. Henriksen, “Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients,” Diabetologia, vol. 40, no. 12, pp. 1439–1448, 1997.
View at: Publisher Site | Google Scholar
R. Retnakaran, S. Shen, A. J. Hanley, V. Vuksan, J. K. Hamilton, and B. Zinman, “Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test,” Obesity, vol. 16, no. 8, pp. 1901–1907, 2008.
View at: Publisher Site | Google Scholar
R. Retnakaran, Y. Qi, M. I. Goran, and J. K. Hamilton, “Evaluation of proposed oral disposition index measures in relation to the actual disposition index,” Diabetic Medicine, vol. 26, no. 12, pp. 1198–1203, 2009.
View at: Publisher Site | Google Scholar
A. Stancakova, M. Javorsky, T. Kuulasmaa, S. M. Haffner, J. Kuusisto, and M. Laakso, “Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6,414 Finnish men,” Diabetes, vol. 58, no. 5, pp. 1212–1221, 2009.
View at: Publisher Site | Google Scholar
M. M. Tai, “A mathematical model for the determination of total area under glucose tolerance and other metabolic curves,” Diabetes Care, vol. 17, no. 2, pp. 152–154, 1994.
View at: Publisher Site | Google Scholar
A. K. Annamalai, A. Webb, N. Kandasamy et al., “A comprehensive study of clinical, biochemical, radiological, vascular, cardiac, and sleep parameters in an unselected cohort of patients with acromegaly undergoing presurgical somatostatin receptor ligand therapy,” The Journal of Clinical Endocrinology & Metabolism, vol. 98, no. 3, pp. 1040–1050, 2013.
View at: Publisher Site | Google Scholar
I. Morange, F. De Boisvilliers, P. Chanson et al., “Slow release lanreotide treatment in acromegalic patients previously normalized by octreotide,” The Journal of Clinical Endocrinology & Metabolism, vol. 79, no. 1, pp. 145–151, 1994.
View at: Publisher Site | Google Scholar
G. Mazziotti, I. Floriani, S. Bonadonna, V. Torri, P. Chanson, and A. Giustina, “Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies,” The Journal of Clinical Endocrinology & Metabolism, vol. 94, no. 5, pp. 1500–1508, 2009.
View at: Publisher Site | Google Scholar
R. Baldelli, C. Battista, F. Leonetti et al., “Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment,” Clinical Endocrinology, vol. 59, no. 4, pp. 492–499, 2003.
View at: Publisher Site | Google Scholar
A. Colao, R. S. Auriemma, M. Galdiero et al., “Impact of somatostatin analogs versus surgery on glucose metabolism in acromegaly: results of a 5-year observational, open, prospective study,” The Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 2, pp. 528–537, 2009.
View at: Publisher Site | Google Scholar
A. Colao, R. S. Auriemma, S. Savastano et al., “Glucose tolerance and somatostatin analog treatment in acromegaly: a 12-month study,” The Journal of Clinical Endocrinology & Metabolism, vol. 94, no. 8, pp. 2907–2914, 2009.
View at: Publisher Site | Google Scholar
K. K. Y. Ho, A. B. Jenkins, S. M. Furler, M. Borkman, and D. J. Chisholm, “Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly,” Clinical Endocrinology, vol. 36, no. 3, pp. 271–279, 1992.
View at: Publisher Site | Google Scholar
A. Ciresi, M. C. Amato, R. Pivonello et al., “The metabolic profile in active acromegaly is gender-specific,” The Journal of Clinical Endocrinology & Metabolism, vol. 98, no. 1, pp. E51–E59, 2013.
View at: Publisher Site | Google Scholar
K. McKeage, “Pasireotide in acromegaly: a review,” Drugs, vol. 75, no. 9, pp. 1039–1048, 2015.
View at: Publisher Site | Google Scholar
A. Colao, M. D. Bronstein, P. Freda et al., “Pasireotide versus octreotide in acromegaly: a head-to-head superiority study,” The Journal of Clinical Endocrinology & Metabolism, vol. 99, no. 3, pp. 791–799, 2014.
View at: Publisher Site | Google Scholar
C. Urbani, C. Sardella, A. Calevro et al., “Effects of medical therapies for acromegaly on glucose metabolism,” European Journal of Endocrinology, vol. 169, no. 1, pp. 99–108, 2013.
View at: Publisher Site | Google Scholar
B. Steffin, B. Gutt, M. Bidlingmaier, C. Dieterle, F. Oltmann, and J. Schopohl, “Effects of the long-acting somatostatin analogue Lanreotide Autogel on glucose tolerance and insulin resistance in acromegaly,” European Journal of Endocrinology, vol. 155, no. 1, pp. 73–78, 2006.
View at: Publisher Site | Google Scholar
C. Giordano, A. Ciresi, M. C. Amato et al., “Clinical and metabolic effects of first-line treatment with somatostatin analogues or surgery in acromegaly: a retrospective and comparative study,” Pituitary, vol. 15, no. 4, pp. 539–551, 2012.
View at: Publisher Site | Google Scholar

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Copyright © 2018 Ming Shen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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International Journal of Endocrinology

Impact of Long-Acting Somatostatin Analogues on Glucose Metabolism in Acromegaly: A Hospital-Based Study

Abstract

1. Introduction

2. Subjects and Methods

2.1. Patients

2.2. Evaluation of Insulin Resistance and β-Cell Function

2.3. Abbreviated Variables and Formulas

2.4. Biochemical Measurements

2.5. Statistics Analysis

3. Results

3.1. Baseline Characteristics among NGT/IGT/DM Groups

3.2. Effect of SSA Treatment on BG and HbA1c Levels

3.3. Effect of SSA Treatment on Plasma Insulin Levels during OGTT

3.4. Effect of SSA Treatment on Insulin Resistance

3.5. Effect of SSA Treatment on Insulin Secretion

3.6. Effects of SSA Treatment on Glucose Tolerance

3.7. Correlation Studies

3.8. The Predictive Value of Baseline BG120 for the Effect of SSA Treatment on Glucose Metabolism

4. Discussion

Ethical Approval

Consent

Conflicts of Interest

Authors’ Contributions

Acknowledgments

Supplementary Materials

References

Copyright

3.2. Effect of SSA Treatment on BG and HbA_1c Levels

3.8. The Predictive Value of Baseline BG₁₂₀ for the Effect of SSA Treatment on Glucose Metabolism