Early Postoperative Fasting Serum Glucose Levels are Useful in Depicting Future Diabetes Mellitus in Patients with Curative Insulinoma Surgery.

BACKGROUND: Hyperglycemia has been reported in some patients after curative insulinoma resection but no systematic investigation of glucose metabolism has been shown in a larger cohort of these patients. Therefore, it is still unknown, whether long lasting hyperinsulinism in insulinoma patients induces insulin resistance, which may jeopardize the postoperative health status of these patients. METHODS: Early postoperative fasting serum glucose levels were measured in all insulinoma patients after curative tumor resection during the first 48 h, being operated between 2011 and 2018, retrospectively. RESULTS: Of 77 (100%) patients with benign, spontaneous occuring insulinoma 51 (66.2%) patients were operated on by tumor enucleation. In 15 (19.5%) patients a left pancreatic resection was performed and in 11 (14.3%) patients the pancreatic head or the middle console of pancreatic corpus were excised. In 32 (41.6%) cases the highest fasting postoperative glucose levels were measured between 140-200 mg/dl. In 16 (20.8%) patients the glucose serum levels reached values above 200 mg/dl and in 4 (5.2%) patients short term substitution with insulin was indicated. Only one (1.3%) of these patients developed diabetes mellitus with the need of ongoing insulin treatment. Major postoperative complications were registered in 31 of all 77 patients (40.3%) and in 9 of 16 patients (56.3%) with postoperative glucose levels above 200 mg/dl. This difference was not statistically significant. CONCLUSIONS: Early postoperative (first 48 h) fasting serum glucose levels in insulinoma patients showed significant hyperglycemia above 200 mg/dl in only few patients (20.8%) and chronic postoperative Diabetes mellitus developed in only one of 77 patients (<2%). Therefore, recovery of glucose metabolism after insulinoma resection is fast and medical intervention is not mandatory in most of these patients.

The IGF pathway is activated in insulinomas but downregulated in metastatic disease.

Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n=48) and immunohistochemistry (n=86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2-4 folds higher than in islets. High protein expression of IGF2, IGF1R and INSR (in 51-92% of the tumors) and low to moderate expression of mTORC1 pathway proteins p-PS6k and p-4EBP1 (7-28% of the tumors) were observed. Correlations were found between 1) ERK1 mRNA expression and that of numerous IGF pathway genes, 2) p-ERK and IGF1R protein expression and 3) decrease of IGF pathway components and both metastatic disease and shorter 10 years disease free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.

Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas.

The long-term prognosis after surgical resection of malignant insulinoma (INS) is poor. Novel adjuvant therapies, specifically targeting cancer stem cells (CSCs), are warranted. Therefore, the goal of this study was to characterize and target putative INS CSCs. Using fluorescence-activated cell sorting, human INS cell line CM and pancreatic carcinoid cell line BON1 were screened for the presence of stem cell-associated markers. CD90, CD166, and GD2 were identified as potential CSC markers. Only CD90(+) INS cells had an increased tumor-initiating potential in athymic nude mice. Anti-CD90 monoclonal antibodies decreased the viability and metastatic potential of injected cells in a zebrafish embryo INS xenograft model. Primary INS stained positive for CD90 by immunohistochemistry, however also intratumoral fibroblasts and vascular endothelium showed positive staining. The results of this study suggest that anti-CD90 monoclonals form a potential novel adjuvant therapeutic modality by targeting either INS cells directly, or by targeting the INS microenvironment.

Differentiation of insulin secretion patterns in insulinoma.

BACKGROUND: In patients with insulinoma, biochemical proof of inappropriately elevated insulin secretion during hypoglycemia is required prior to surgery. Because circulating insulin levels usually vary widely, we have used the combined OGTT-fasting test to define new normative criteria for a retrospective systematic analysis. METHODS: We retrospectively analyzed insulin concentrations from OGTT-fasting tests of 64 patients with surgically removed insulinomas. In addition, the response to intravenous somatostatin infusions was estimated. Normative criteria were defined to obtain comparable estimates of insulin concentrations: basal, glucose-stimulated maximum, postglucose plateau, and secretory bursts. RESULTS: Three types of insulin secretion patterns were identified: (1) the autonomous secretion pattern (type 1, N=17) with basal and post-OGTT plateau insulin concentrations of approximately 50 mU/L, suppression after OGTT by 41%, virtual absence of distinctive secretory bursts, and resistance to somatostatin-mediated suppression (25 %); (2) the inadequate suppression pattern (type 2, N=28) with moderately elevated basal and post-OGTT insulin concentrations of approximately 20 mU/L, suppression after OGTT by 73%, absence of secretory bursts, and incomplete somatostatin-induced suppression (56 %); (3) the late-burst secretion pattern (type 3, N=19) with similar basal and post-OGTT insulin concentrations of 17 mU/L, suppression after OGTT by 76%, true insulin bursts of Delta 13+/-11 mU/L (184%), and nearly complete somatostatin-induced suppression by 64%. CONCLUSIONS: By means of a new normative analysis of the combined OGTT-fasting test, three different patterns of insulin secretion can be described in patients with insulinoma: the autonomous secretion type, the inadequate suppression type, and the late-burst secretion type.

Islet hyperplasia in adults: challenge to preoperatively diagnose non-insulinoma pancreatogenic hypoglycemia syndrome.

BACKGROUND: Pancreatic hyperfunctional islet hyperplasia in adults has been more and more frequently described in the literature. Postprandial neuroglycopenia, a negative normal fasting test, negative pancreatic imaging results, and positive intra-arterial calcium stimulation of serum insulin are characteristic. In affected patients the term non-insulinoma pancreatogenic hypoglycemia syndrome (NIPHS) was proposed. MATERIALS AND METHODS/PATIENTS: We also encountered fasting hypoglycemia in such patients and therefore evaluated clinical and biochemical data in patients with NIPHS (n = 11), patients with insulinoma (n = 70), and patients in whom hypoglycemia was ruled out (n = 70). RESULTS: Patients with NIPHS were younger (median age: 41 years; range: 18-66) and mostly non-obese (median body mass index/BMI: 22.2 kg/m2; range: 19-39) compared with patients with an insulinoma (median age: 50 years; median: BMI 26.1 kg/m2). During an oral glucose tolerance test (OGTT) followed by a standard fasting test, neuroglycopenia was observed postprandially with a mean minimal blood glucose level of 36 +/- 9 mg/dl in 7 out of 11 patients. Spontaneous hypoglycemia during the fast was 38 +/- 5 mg/dl in 8 out of 11 patients. The corresponding insulin levels were 9.2 +/- 9.8 mU/l (OGTT) and 6.8 +/- 5.4 mU/l (fasting), significantly lower than in patients with insulinoma (P < 0.001), but not different from patients without hypoglycemia (P = 0.05). After pancreatic resection 8 patients (73%) were cured with enduring euglycemia. Pathohistological islet abnormalities with hyperplasia, hypertrophy, and microadenomatosis were confirmed in all patients. CONCLUSION: In patients with postprandial and/or fasting neuroglycopenia NIPHS may be suspected when insulin levels are low but inadequately suppressed and localization studies failed to show a distinct pancreatic tumor.

Malignant metastatic insulinoma-postoperative treatment and follow-up.

The rarity of malignant insulinoma limits reports on therapeutic strategies and outcome. The treatment and follow-up of 10 patients, all presenting an insulinoma with metastatic disease of the liver and newly diagnosed between 1992 and 2002, is reported. Pancreatic surgery with successful removal of the primary tumor preferentially located in the tail was performed in 7 women and 3 men, median age 55 years (range 36-82 years). If appropriate, 5 patients underwent additional hepatic surgery and lymph node resections. Liver metastases as the major cause of postoperatively persistent hypoglycemia were subsequently treated by repeated transarterial hepatic chemoembolization and chemoperfusion protocols using high-dose transhepatic streptozocin perfusions (3-4 g per session). The current median survival time for all 10 patients is 2.6 years (range: 1.6-9.7 years). Six patients are currently alive with a median survival of 3.7 years (1.7-9.7 years), five of them with stable disease and free of hypoglycemia. Four patients died after a median survival of 1.8 years (range: 1.6-7.5 years) from complications of unmanageable hypoglycemia. It is concluded that the necessity to treat debiliating and life-threatening hypoglycemia in metastatic malignant insulinoma warrants the option of radical endocrine surgery in combination with extended and repeated postoperative chemoembolization of liver metastases.

A new classification plot for the C-peptide suppression test.

CONTEXT AND OBJECTIVE: To evaluate the C-peptide suppression test as a screening test in patients with symptoms of hypoglycemia as compared to the standard fasting test. DESIGN: Retrospective discriminant analysis of data from C-peptide suppression tests. SETTING: Clinical study. PATIENTS: Patients with insulinomas and patients without insulinomas but having symptoms compatible with hypoglycemia. INTERVENTIONS: The results from C-peptide suppression tests of 26 patients with insulinomas and 100 patients without insulinomas were compared. MAIN OUTCOME MEASURES: A classification plot which introduces two discriminant parameters for the C-peptide suppression test: the ratio of [blood glucose]/[C-peptide] at the lowest C-peptide concentration and mean glycemia during insulin infusion. RESULTS: In patients with insulinomas, minimal serum C-peptide levels were higher (1.81+/- 0.87 ng/mL; median 1.83 ng/mL; maximal suppression 37 +/- 24% of basal C-peptide levels) as compared to patients without insulinoma (0.40 +/- 0.15 ng/mL; median 0.30 ng/mL; maximal suppression of 75 +/- 9%; P<0.001). Mean glycemia during the test was lower in patients with insulinomas (30.8 +/- 3.3 vs. 47.5 +/- 8.3 mg/dL; P<0.001) as was the [blood glucose]/[C-peptide] ratio (21.9 +/- 14.6 vs. 139.2 +/- 43.8; P<0.001). Discriminant analysis revealed a specificity of 96% to rule out the diagnosis of 'insulinoma' at a 1% probability threshold with a sensitivity of 100%. CONCLUSIONS: We developed a new classification plot for the C-peptide suppression test in order to accurately identify those patients whose symptoms of hypoglycemia are not due to endogenous hyperinsulinemia/insulinomas. Thus, the need for fasting tests and hospitalization costs can be reduced.