Insulin Secretion and Insulin Sensitivity Before and After Surgical Treatment of Pheochromocytoma or Paraganglioma

Abstract

Context

Pheochromocytoma and paraganglioma are catecholamine-producing tumors that often impair glucose tolerance. The effects of these tumors on insulin sensitivity and insulin secretion in patients have remained unclear, however.

Objective

To characterize the influence of pheochromocytoma or paraganglioma on glucose tolerance, we comprehensively analyzed various parameters related to insulin secretion or insulin sensitivity in patients with these tumors.

Design

Hyperglycemic and hyperinsulinemic-euglycemic clamps, as well as an oral glucose tolerance test (OGTT), were performed in patients before and after tumor excision.

Setting

Patients underwent metabolic analyses on admission to Kobe University Hospital.

Patients

Eleven patients with pheochromocytoma and two with paraganglioma were examined.

Intervention

None.

Main Outcome Measures

We evaluated various parameters related to insulin secretion or insulin sensitivity as determined by an OGTT and by hyperglycemic and hyperinsulinemic-euglycemic clamp analyses.

Results

Surgical treatment of the tumor reduced urinary catecholamine excretion and improved glucose tolerance. The insulinogenic index, but not total insulin secretion, measured during the OGTT as well as the first phase, but not the second phase, of insulin secretion during the hyperglycemic clamp were improved after surgery. The insulin sensitivity index determined during the hyperinsulinemic-euglycemic clamp remained unchanged after surgery.

Conclusion

These results suggest pheochromocytoma and paraganglioma impair glucose tolerance primarily through impairment of insulin secretion—in particular, that of the early phase of the insulin secretory response. A prospective study with more patients is warranted to further confirm these results.

Pheochromocytoma and paraganglioma are catecholamine-producing tumors that elicit a deterioration in glucose tolerance in ∼20% to 40% of affected individuals (1–3). Insulin secretion and insulin sensitivity are both key determinants of glucose tolerance, and previous studies have suggested that insulin secretion is impaired in patients with pheochromocytoma or paraganglioma (4–8), likely as a result of the inhibitory effect of catecholamines on this process mediated by the activation of α-adrenergic receptors in pancreatic β cells (9–11). These studies examined few patients, however. Catecholamines also antagonize insulin action in target organs (12, 13) and might, thereby, trigger insulin resistance. Information on insulin sensitivity in patients with pheochromocytoma or paraganglioma is also limited, however, with studies of five and 10 patients, respectively, with pheochromocytoma showing that the tumor impaired insulin sensitivity as assessed by euglycemic-hyperinsulinemic clamp analysis (14, 15).

To provide further insight into the influence of pheochromocytoma or paraganglioma on glucose tolerance, we performed a comprehensive analysis of insulin secretion and insulin sensitivity in 13 patients with these tumors both before and after surgical treatment. We thus measured various parameters during hyperglycemic and hyperinsulinemic-euglycemic clamps as well as during an oral glucose tolerance test (OGTT), and we found that insulin secretion—in particular, the early phase of the secretory response—was markedly impaired in these individuals before surgery.

Materials and Methods

Patients

The study conformed to the provisions of the 1995 Declaration of Helsinki, was approved by the ethics committee of Kobe University Graduate School of Medicine, and was registered with the University Hospital Medical Information Network (UMIN000002359). All patients provided written informed consent to analyze and publish their data for scientific purposes. Patients were recruited at the Division of Diabetes and Endocrinology of Kobe University Hospital from January 2009 to August 2013. Thirteen Japanese individuals (six men, seven women) were diagnosed with pheochromocytoma (n = 11) or paraganglioma (n = 2), received successful surgical treatment of the tumor and underwent glucose clamp analyses and a 75-g OGTT both before and after surgery during this period. Patients with diabetes mellitus (DM) underwent the glucose clamp analyses and OGTT after they had achieved a target control level for fasting plasma glucose (FPG) of <130 mg/dL in response to treatment with oral hypoglycemic agents or insulin. At the presurgical metabolic analyses, four, three, two, one, and no patients were administered α-blockers, calcium blockers, angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors, diuretics and β blockers, respectively.

OGTT and glucose clamp analyses

A75-g OGTT and consecutive hyperglycemic and hyperinsulinemic-euglycemic clamp analyses were performed on admission within a period of 10 days. For the OGTT, blood samples were collected before and at 30, 60, 90, and 120 minutes after ingestion of glucose for measurement of plasma glucose and serum insulin concentrations. Categories of glucose tolerance, which are normal glucose tolerance (NGT; FPG level of <110 mg/dL and 120-minutes plasma glucose level of <140 mg/dL), impaired glucose tolerance (IGT) (120-minute plasma glucose level of ≥140 mg/dL and <200 mg/dL), and DM (FPG level of ≥126 mg/dL or 120-minute plasma glucose level of ≥200 mg/dL), were determined by the results of the OGTT. Consecutive hyperglycemic and hyperinsulinemic-euglycemic clamp analyses were performed with the use of an artificial endocrine pancreas (STG-22 and STG-55; Nikkiso, Shizuoka, Japan), as previously described (16). In brief, we first performed a hyperglycemic clamp by intravenous infusion of a bolus of glucose (9622 mg/m²) followed by a variable dose of glucose to maintain the plasma glucose level at 200 mg/dL for 90 minutes. Blood samples were collected before and at 5, 10, 15, 60, 75, and 90 minutes after the onset of glucose infusion for measurement of plasma glucose and serum insulin levels. After the hyperglycemic clamp, a 120-minute euglycemic clamp was performed. First- and second-phase insulin secretion during the hyperglycemic clamp were defined as the incremental area under the insulin concentration curve (mg/dL·min) from 0 to 10 minutes [area under the curve (AUC)_ins10] and from 10 to 90 minutes (AUC_ins10–90), respectively. An index of insulin sensitivity derived from the hyperinsulinemic-euglycemic clamp was calculated by dividing the mean glucose infusion rate during the final 30 minutes of the clamp (mg/kg/min) by both the plasma glucose (mg/dL) and serum insulin (μU/mL) levels at the end of the clamp, and then multiplying the resulting value by 100. A clamp-based analog of the disposition index (DI), termed the clamp DI, was calculated as the product of first-phase insulin secretion and insulin sensitivity index (ISI), as described previously (16). An OGTT-based analog of DI, which we termed the oral DI, was calculated as the product of the composite index (17) and the ratio of the area under the insulin curve to the area under the glucose curve from 0 to 120 minutes of the OGTT (AUC_ins/glu120), as described previously (18, 19). The insulinogenic index was calculated as the change in serum insulin concentration divided by change in plasma glucose concentration from 0 to 30 minutes during the OGTT.

Subgroup analysis

Wet divided 13 study patients into two groups by the median values of the time between the pre- or postsurgical clamp analyses and the surgery. The mean ± standard deviation (SD) time between the presurgical clamp analyses and the surgery of the shorter time group (n = 7) and the longer time group (n = 6) was 69.6 ± 55.4 days and 362.0 ± 171.8 days, respectively, and the mean ± SD time between the surgery and the postsurgical clamp analyses of the shorter time group (n = 7) and the longer time group (n = 6) was 22.3 ± 6.6 days and 94.2 ± 45.4 days, respectively. We analyzed the difference in the rate of improvement by the surgery [(presurgical values minus postsurgical values) divided by presurgical values] of parameters for insulin sensitivity and insulin secretion between the two groups.

Statistical analysis

Data are presented as means ± SD. Data normally distributed and nonnormally distributed were analyzed with the paired Student t test and the Wilcoxon signed-rank test, respectively, with the use of SPSS version 11.0 for Windows (IBM, Armonk, NY). P < 0.05 was considered statistically significant.

Results

Clinical and laboratory parameters for the study patients before and after surgical treatment are shown in Table 1. The time between the presurgical metabolic analyses and surgery ranged from 5 to 646 days (205 ± 192 days) and that between surgery and the postsurgical analyses ranged from 14 to 169 days (55 ± 48 days). Body mass index, FPG, and the serum level of aspartate aminotransferase were significantly reduced after surgery compared with before. Catecholamine levels in 24-hour urine samples were also reduced after surgery (Table 2).

Before surgery, five, four, and four patients were categorized as having NGT, IGT, or DM, respectively, on the basis of the results of the OGTT (Fig 1). After surgery, 11 and two patients were categorized as having NGT or IGT, respectively. The glucose tolerance category remained unaltered in six patients after surgery (five with NGT and one with IGT), whereas that of seven patients improved (from IGT to NGT in three, from DM to NGT in three, and from DM to IGT in one). Plasma glucose and serum insulin concentrations during the OGTT performed before and after surgery are shown in Fig 2. Plasma glucose concentrations at all time points (Fig 2) as well as the area under the glucose curve from 0 to 120 minutes (AUC_glu120; Table 3) of the OGTT were reduced after surgery. Oral DI and clamp DI, both of which are directly related to whole-body glucose disposal (16, 18, 20), were significantly increased after surgery.

Although homeostatic model assessment of β-cell function and AUC_ins/glu120, both of which reflect the capacity for insulin secretion, were increased after surgery, these changes were not statistically significant. The insulinogenic index, a measure of the early phase of the insulin secretory response, was significantly increased after surgery. Serum insulin concentrations during the hyperglycemic clamp analysis are shown in Figure 3. The insulin concentration measured 5 min after initiation of the clamp was markedly increased after the surgery compared with before (Figure 3). First-phase insulin secretion (AUC_ins10) during the hyperglycemic clamp was significantly improved after surgery, whereas second-phase insulin secretion (AUC_ins10–90) remained unchanged (Table 3).

Homeostatic model assessment of insulin resistance (HOMA-IR) and the composite index were significantly reduced and increased, respectively, after surgery. The hyperinsulinemic-euglycemic clamp, a gold standard for the evaluation of insulin sensitivity, revealed that ISI was not significantly altered after surgery.

The subgroup analysis based on the time length between the metabolic analyses and the surgery revealed that the rates of improvement by the surgery of all the parameters for insulin secretion and insulin sensitivity were not significantly different between the shorter and the longer time groups (data not shown).

Discussion

Although pheochromocytoma and paraganglioma are well known to be associated with glucose intolerance, information on the effects of these tumors on insulin secretion and insulin sensitivity has been limited. Arginine-induced insulin secretion was previously found to be improved after tumor resection in seven patients with pheochromocytoma (5). There have also been several studies showing that the insulin secretory response during an OGTT or intravenous glucose tolerance test was enhanced after surgical treatment of pheochromocytoma or paraganglioma in a single case or small number of cases (4, 6–8). We have now analyzed various parameters during hyperglycemic and hyperinsulinemic-euglycemic clamps as well as during an OGTT in patients with pheochromocytoma and paraganglioma, and confirmed the previous findings that the tumors impair the insulin secretory response. We also have demonstrated that the first phase of insulin secretion, but not the second phase, during a hyperglycemic clamp was selectively attenuated in patients with pheochromocytoma or paraganglioma. In addition, an OGTT revealed that the insulinogenic index, but not AUC_ins/glu120, was improved significantly after tumor resection. Together, these results indicate that the early phase of the insulin secretory response was impaired by the tumors.

Our finding that pheochromocytoma and paraganglioma impair the early phase of insulin secretion is consistent with the previous observation that administration of epinephrine in healthy volunteers results in inhibition of the acute insulin secretory response to pulsatile intravenous glucose infusion (21). Overexpression of the α2-adrenergic receptor in mice or the presence of a variant of the receptor gene in humans has also been shown to result in suppression of the acute insulin secretory response (10). The mechanism by which the adrenergic stimulus selectively attenuates the early phase of insulin secretion is not fully understood. The Epac2A-Rap1 pathway, which is activated by cyclic adenosine monophosphate–dependent signaling, has been shown to play an important role in the acute insulin secretory response (22). It is possible that an alternation in this signaling pathway contributes to the pathological effects of the adrenergic stimulus on insulin secretion in pancreatic β cells.

Surgical treatment of pheochromocytoma has been shown to improve insulin sensitivity as evaluated by hyperinsulinemic-euglycemic clamp analysis (14, 15). However, we did not detect a change in ISI between before and after surgery in our study patients. Differences in ethnicity or body composition might contribute to this difference in results; the patients of the current study were nonobese Japanese individuals, whereas the ethnicity and body composition of those in the previous studies were not described. We found that the composite index and HOMA-IR were improved after surgery, suggesting that pheochromocytoma and paraganglioma may also impair glucose tolerance through alteration of insulin sensitivity. The apparent inconsistency between ISI on the one hand and the composite index and HOMA-IR on the other might be explained by the notion that each parameter reflects insulin sensitivity of different organs (skeletal muscle or liver) under different conditions (fasting or postprandial). The influence of pheochromocytoma and paraganglioma on insulin sensitivity thus warrants further detailed analysis.

At the presurgical metabolic analyses, four patients had been administered α-blockers, which have been shown to ameliorate insulin resistance of patients with pheochromocytoma (14). However, the rates of improvement of the parameters for insulin secretion and insulin sensitivity were not significantly different between patients who took α-blockers and who did not (data not shown), suggesting that the administration of α-blockers did not exert a great influence on the current investigation.

One limitation of our study is the relatively long time between performance of the metabolic analyses and surgery in some patients, with the potential consequence that insulin sensitivity and insulin secretion might have been affected by factors other than tumor removal (e.g., a change in daily life style) during this time. Although the subgroup analysis revealed the rates of improvement of parameters for insulin secretion and insulin sensitivity were not significantly different between the shorter and the longer time groups, these results do not completely exclude the possibility that long time exerted some influence. Body mass index was slightly but significantly reduced after surgery, whereas the resection of pheochromocytoma or paraganglioma can lead to an increase in body mass through amelioration of the hypermetabolic condition (23–25). Furthermore, although the number of patients in our study is larger than that in any previous similar study, to our knowledge, it is still relatively small.

In summary, our present results suggest that pheochromocytoma and paraganglioma impair glucose tolerance primarily via impairment of insulin secretion—in particular, that of the early phase of the secretory response, which has been shown to determine the capacity for glucose disposal in the living body under a variety of physiological and pathological conditions (26–28).

Abbreviations:

 
• AUC

  area under the curve

 
• DI

  disposition index

 
• DM

  diabetes mellitus

 
• FPG

  fasting plasma glucose

 
• HOMA-IR

  homeostatic model assessment of insulin resistance

 
• IGT

  impaired glucose tolerance

 
• ISI

  insulin sensitivity index

 
• NGT

  normal glucose tolerance

 
• OGTT

  oral glucose tolerance test

 
• SD

  standard deviation.

Acknowledgments

We thank Drs. Yoshifumi Inoue, Naoko Hashimoto, Tomokazu Matsuda, Tomoko Nishiumi, Michinori Takabe, Shinsuke Nakajima, Yuki Nishimoto, and Sachi Nishida for assistance with data collection.

This work was supported by a Grant-in-Aid for Young Scientists (B) awarded to Y.H. by the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

This study has been registered with the University Hospital Medical Information Network (UMIN000002359).

Disclosure Summary: The authors have nothing to disclose.

References