Incidence and management of postoperative hyperglycemia in patients undergoing insulinoma resection

Abstract

Purpose

It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring.

Methods

A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l).

Results

Twelve patients (36%) developed hyperglycemia within 24 h (range 1–16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97–325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents.

Conclusions

Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

Introduction

Insulinomas are the most common functional pancreatic neuroendocrine tumor, with a reported incidence of 0.1–0.3 cases per 100,000 individuals per year [1, 2]. Approximately 90% of insulinomas are sporadic, while the remaining 10% of patients have an inherited predisposition. Most insulinomas are solitary lesions and benign tumors [2, 3]. The median age of presentation in patients with sporadic insulinoma is 50 years, and insulinoma has a slightly higher female preponderance. Patients with multiple endocrine neoplasia (MEN) type 1 syndrome have a predisposition to developing insulinoma, which typically manifests in them at an earlier age and is more likely to be multifocal [3]. Hyperinsulinemic hypoglycemia and the resultant autonomic overactivity are the predominant clinical manifestations, often presenting with the features of Whipple’s triad, namely hypoglycemic symptoms, low blood glucose, and relief of symptoms after glucose administration [4]. The diagnosis is established by an inappropriately elevated level of insulin and proinsulin, along with hypoglycemia [less than 50 mg/dL (2.77 mmol/l)], during a 48-h supervised fast [5, 6].

Postoperative rebound hyperglycemia has long been known to manifest after insulinoma resection and has been attributed to the atrophy of the remaining pancreatic islet cells, as well as the hormonal effects of the glucagon, growth hormone, and glucocorticoids that prevail during the immediate postoperative period [7, 8]. Some investigators have reported that elevations in blood glucose eventually occur, to some extent, in all patients after surgery [9–11], and it has been proposed that postoperative hyperglycemia can be used as a marker of complete resection or even as an intraoperative guide for appropriate resection [12]. However, others have questioned its clinical utility, noting that a significant proportion of patients display delayed elevations in blood glucose, thus limiting its use as an intraoperative guide for complete resection [11, 13–15]. Blood glucose levels may also be influenced by multiple other factors, such as anesthetic agents and intraoperative fluid management, and, hence, some patients may not display hyperglycemia in the postoperative period [16].

The duration and significance of postoperative hyperglycemia in patients who have insulinoma resection is unknown. Most studies suggest hyperglycemia is transient, taking anywhere from 3 to 4 days [7] to more than 9 days to resolve [11]. In addition, there are reports of previously unknown diabetes mellitus that manifested after insulinoma resection, leading to persistent postoperative hyperglycemia and requiring permanent treatment [17, 18]. Currently, there is no high-quality data on the rate of hyperglycemia (defined as plasma glucose ≥ 180 mg/dL (10 mmol/L)) and the need for intense glucose monitoring and treatment after insulinoma resection.

In this study, we determined the rate of hyperglycemia after insulinoma resection, potential clinical and intraoperative factors associated with it, and the natural history of hyperglycemia in a prospective cohort observational study of patients undergoing intense glucose monitoring.

Materials and methods

Patients with suspected or confirmed insulinoma were enrolled in a prospective clinical protocol at the National Institutes of Health (NIH) Clinical Center after giving written informed consent (NCT00001276, NCT01005654). The studies were approved by the institutional review boards of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute.

The biochemical diagnosis of an insulinoma was made based on a patient’s glucose, insulin, proinsulin, and C-peptide levels during a 48-h supervised fast, as previously described [19]. Patients underwent multimodal imaging, including pancreatic protocol contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), selective arterial calcium stimulation testing, endoscopic ultrasound, ¹¹¹In-pentetreotide single-photon emission computed tomography (SPECT)/CT, and ⁶⁸Ga-DOTATATE positron emission tomography/computed tomography (PET/CT).

Preoperative insulin levels were obtained via peripheral venous or arterial puncture prior to the start of the operation and postoperative insulin levels were obtained twenty minutes after the resection of insulinoma. The specimens were analyzed with Roche cobas^® e601 blood analyzer (Pleasanton, CA).

Postoperative monitoring included routine measurement of blood glucose at a minimum of once every hour for the first six hours and every four hours for the first 24 h after surgery. Hyperglycemia was defined as plasma glucose ≥ 180 mg/dL (10 mmol/l) [20]. Serum glucose was collected with a finger stick and processed with a StatStrip GLU Meter glucometer (Nova Biomedical UK, Runcorn, Cheshire, UK). All patients with resolution of hypoglycemic symptoms and normalization of glucose levels on postoperative evaluation were included in the study. Routinely, patients had the dextrose infusion stopped at the time of the operation when a neuroendocrine tumor was diagnosed on frozen section and intraoperative glucose was normal (within 20 min of insulinoma resection). Only two patients received fluids containing 10% dextrose solution during the first 24 h after the operation.

The statistical analysis of patient demographics, clinical characteristics, and laboratory data was performed using t-test, Mann Whitney test and Fisher’s Exact tests, where appropriate. A p value < 0.05 was considered statistically significant. IBM SPSS Statistics Data Editor (New York, NY) and Microsoft Excel (Redmond, WA) were used for statistical analyses.

Results

The clinical and laboratory characteristics are summarized in Table 1. Twenty-eight patients had sporadic insulinoma, and five patients had MEN1-associated insulinoma. Nineteen patients underwent tumor enucleation (57.6%), 13 underwent distal pancreatectomy (41.9%), and one underwent a Whipple procedure (3.2%). In 13 patients, an open resection was performed, while 20 patients underwent a laparoscopic resection, ten of whom had a hand-assisted laparoscopic procedure performed.

Table 1.

Demographic characteristics of patients based on postoperative hyperglycemia

	Postoperative hyperglycemia (n = 12) [mean ± SD]	No postoperative hyperglycemia (n = 21) [mean ± SD]	P value
Age (years)	56.8 ± 15.1	50.5 ± 14.5	0.24
BMI (kg/m2)	33.7 ± 8.3	30.3 ± 8	0.26
Size (cm)	1.42 ± 0.49	1.56 ± 0.76	0.57
Hospital stay (days)	11.2 ± 8.2	7.5 ± 3.6	0.16
Pre-op Insulin (mcU/mL)	40.9 ± 31.6	39.2 ± 38.1	0.90
C-peptide (ng/mL)	5.6 ± 4.2	5.4 ± 3.4	0.89
Proinsulin (pmol/L)	257 ± 262	242 ± 335	0.90
Duration of fast (h)	14.7 ± 9.0	12.6 ± 9.2	0.53
Duration of operation (min)	275 ± 83.3	233.3 ± 82.7	0.18
Intraoperative insulin drop (%)	66 ± 17.8 (n = 4)	53.7 ± 44.4 (n = 8)	0.61
Gender (female)	8/12	13/21	1
Family history of diabetes mellitus	3/12	9/21	0.70
Sporadic vs. MEN1	Sporadic 9	Sporadic 19	0.30
	MEN1 3	MEN1 2
Extent of resection	Enucleation 5	Enucleation 14	0.33
	Distal Pancreatectomy 6	Distal Pancreatectomy 7
	Whipple 1	Whipple 0
Type of operation	Open 8	Open 7	0.27
	Laparoscopic 1	Laparoscopic 7	0.30
	Laparoscopic/hand-assisted 3	Laparoscopic/hand-assisted 7

SD standard deviation, BMI body mass index, MEN1 multiple endocrine neoplasia type 1 syndrome

Postoperative hyperglycemia

Twelve of 33 patients (36.3%) had postoperative hyperglycemia (glucose level ≥ 180 mg/dL [>10 mmol/l]) in the first 24 h after insulinoma resection (range 1–16 h), and two patients remained hyperglycemic after 24 h (Fig. 1). Two other patients manifested hyperglycemia more than 24 h after surgery. Eight out of 12 patients developed hyperglycemia in the first 4 h, while four patients developed it in the first 8 h. The median peak blood glucose level during the first 24 h for all patients was 171 mg/dL (9.5 mmol/l, range 126–325 mg/dL [7–18 mmol/l]). Sixteen of 33 patients (48.48%) reached the peak of their post-excision blood glucose levels on postoperative day zero, and most patients (17/33, 51.5%) reached their peak levels by the end of the first postoperative day (Table 2). One patient had a history of insulin resistance, and 11 patients (35.5%) had a family history of diabetes mellitus. None of the other patients had a personal history of diabetes mellitus or glucose intolerance. Among patients with no postoperative hyperglycemia we did not find a time dependent trend in plasma glucose levels.

Fig. 1.

Postoperative glucose levels after insulinoma resection. a Average glucose levels by hour (error bars: standard deviation). b Minimum and maximum glucose levels after insulinoma resection

Table 2.

Postoperative day when maximum plasma glucose levels were reached

Postoperative day	Patients who had maximal plasma glucose levels n (%)
0	16 (48.5)
1	3 (9.7)
2	4 (12.9)
3	4 (12.9)
4	2 (6.5)
5	2 (6.5)
7	2 (6.5)

No patient required insulin intraoperatively. Four patients received insulin within 24 h of surgery for blood glucose levels greater than 180 mg/dL (10 mmol/l), and two of those patients received insulin for blood glucose levels greater than 200 mg/dL (11.1 mmol/l). None of the two patients who received 10% Dextrose solution in their postoperative fluid developed hyperglycemia. The average postoperative length of hospital stay was 9 days and prior to discharge, every patient’s hyperglycemia resolved, and none of the patients were discharged on anti-hyperglycemic medications.

The patients’ characteristics, such as BMI, age, gender, biochemical profile, duration of the supervised fast, and presence of predisposing germline mutations, did not have any statistically significant association with the development of post-resection hyperglycemia. Furthermore, hyperglycemia was not associated with the tumor’s location in the pancreas, the operative approach, or the duration of the operation.

Intraoperative insulin level

Insulin levels before and after excision were measured in 14 patients. The mean pre-excision insulin was 36.06 ± 39.9 mIU/L, while the mean post-excision levels were 9.35 ± 7.20 mIU/L, with a mean percent drop of 59.3% ± 34.6. Ten of 14 (71%) patients had a drop in insulin levels greater than 50% twenty minutes after tumor excision (Table 3). The percentage post-excision insulin drop was not significantly different between patients who developed hyperglycemia in the first 24 h and those who did not (P = 0.61).

Table 3.

Insulin levels pre and post-resection of insulinoma

Pre-resection insulin level (mIU/L)	Post-resection insulin level (mIU/L)	Percent change (%)
34.30	10.80	−68.51
31.40	6.70	−78.66
12.70	18.50	45.67
6.40	3.30	−48.44
23.90	10.80	−54.81
35.80	4.80	−86.59
57.60	8.70	−84.90
3.80	2.70	−28.95
5.60	1.50	−73.21
36.00	9.40	−73.89
71.20	8.80	−87.64
151.00	29.00	−80.79
10.00	4.40	−56.00

Discussion

Hyperglycemia has long been known to manifest postoperatively in patients after resection of insulinoma, but the incidence of hyperglycemia and the resultant requirements in insulin therapy have not been comprehensively evaluated to determine if close glucose monitoring is justified. Our results demonstrate that there were no predictive factors associated with hyperglycemia and that, within 24 h of insulinoma resection, 36.3% of patients were found to have glucose levels greater than 180 mg/dL (10 mmol/l). A short-term insulin treatment was administered in four patients with hyperglycemia.

A glucose level of 180 mg/dL (10 mmol/l) or greater was used to define hyperglycemia based on the 2009 recommendations by Finfer and colleagues [20]. The authors showed improvement in mortality with a less stringent glucose control in critically ill patients [20]. Whether this threshold is appropriate in patients undergoing insulinoma resection is unclear, but we believe the clinical scenario is applicable to patients undergoing pancreatectomy.

Postoperative elevations in blood glucose both in humans and animals after resection of insulin-hypersecreting tissue have been reported [9–11]. However, cases where patients did not develop hyperglycemia after insulinoma resection have also been reported [16]. The clinical utility of blood glucose elevations is not a reliable marker of a curative resection of insulinoma due to both false positive and false negative results [11, 13–16]. Postoperative hyperglycemia is a significant, clinically important issue that may result in patients requiring short-term insulin treatment. In our study, 12 of 33 patients developed hyperglycemia in the first 24 h following resection, but only four patients required short-term insulin therapy. The hyperglycemia eventually resolved in all cases, and none of the patients required glucose-lowering medications upon discharge. Chang et al. reported that, out of a cohort of 10 patients, two were diagnosed with diabetes after insulinoma resection; however, both patients had impaired oral glucose tolerance tests prior to the operation [10]. Given these data, we believe close blood glucose monitoring is important, as one-third of patients develop hyperglycemia and require transient administration of insulin.

Postoperative elevations in blood glucose levels have been attributed to the suppression, atrophy, and degranulation of the remaining beta pancreatic cells [8], as well as the hyperglycemic hormonal effects of glucagon, glucocorticoids, and growth hormone in the immediate postoperative period [7]. Additional factors that may contribute toward blood glucose elevations include large pancreatic resections and the coexistence of diabetes mellitus or insulin resistance [21]. Our study did not identify any clinical factors associated with postoperative hyperglycemia, including increasing age and BMI, which could be related to insulin resistance, tumor size, and intraoperative insulin drop after resection. We also found no association between the extent of pancreatic resection and postoperative hyperglycemia. These data suggest that there is no reliable, usable predictor of hyperglycemia and that patients should have routine blood glucose monitoring postoperatively. The absence of plasma glucose level trend among patients with no postoperative hyperglycemia, may be explained by the short half-life time of insulin in the blood [22].

One patient had a history of insulin resistance and developed postoperative hyperglycemia. Given the scarcity of patients with diabetes mellitus or insulin resistance in our cohort we cannot confidently conclude that it is not a risk factor for hyperglycemia after insulinoma resection, however, this should be taken into consideration based on previous reports [23].

Based on our data, in patients after insulinoma resection, with a normal plasma glucose levels post operatively, we would suggest to monitor plasma glucose levels for hyperglycemia hourly in the first 4 h after surgery, every 2–3h in the next 8 h, and every 6–12 h until the end of postoperative day 4. This suggestion should be validated in an independent cohort before implemented in clinical practice.

This study has several limitations. The sample size is small, so a type II error cannot be excluded, and intraoperative insulin levels were not measured in all cases. However, insulinomas are rare and a small difference or association with hyperglycemia likely would not result in a clinically meaningful change in management. We are a referral center, but that did not appear to considerably influence our cohort since MEN1-associated insulinoma accounted for 16.1% of the cases, similar to the reported incidence [3]. One of the patients showed an increase in the intraoperative insulin level. Pathologic diagnosis confirmed that pancreatic lesion was insulinoma, and the patient remained euglycemic postoperatively, and did not require dextrose supplementation. Given the retrospective nature of this study it is difficult to explain the mechanism behind this result and lab error cannot be excluded.

In conclusion, patients require close glucose monitoring after insulinoma resection during the first 24 h. Hyperglycemia may require short-term insulin management, but it is self-limiting in patients without a prior history of impaired glucose tolerance.