Insulinoma Research Articles

Pomegranate peel, chokeberry leaves and Ironwort extract as novel natural inhibitors of amylin aggregation and cellular toxicity in pancreatic β cells

Impeding or reducing human amylin aggregation and/or its toxicity can be key to preventing pancreatic islet amyloidosis and β-cell loss in patients with Type 2 Diabetes Mellitus (T2DM). Here, Punica granatum (pomegranate) peel, Sideritis raeseri (ironwort) and Aronia melanocarpa (chokeberry) leaf extracts, were tested for their novel anti-aggregative and antitoxic properties in human amylin (hIAPP) treated rat pancreatic insulinoma (INS) cells. The protein aggregation (Th-T) assay revealed an inhibitory trend of all three plant extracts against amylin aggregates. In agreement with this finding, pomegranate peel and ironwort extracts effectively prevented the transition of hIAPP from disordered, random coil structures into aggregation prone β-sheet enriched molecular assemblies, revealed by CD spectroscopy. Consistent with their anti-aggregative action, all three extracts prevented, to various degrees, reactive oxygen species (ROS) accumulation, mitochondrial stress, and, ultimately, apoptosis of INS cells. Collectively, the results from this study demonstrate effectiveness of natural products to halt hIAPP aggregation, redox stress, and toxicity, which could be exploited as novel therapeutics against amylin-derived islet amyloidosis and β-cell stress in T2DM.

Retrospective study of 20 cats surgically treated for insulinoma.

To report the clinical signs, histopathology results, and prognostic factors for outcomes following excision for feline insulinoma (INS). Retrospective study. Twenty client-owned cats. Medical records from 2006 to 2020 were reviewed by Veterinary Society of Surgical Oncology members for cats with hypoglycemia resulting from INS, with surgical excision and follow up. Clinical signs and histopathology results were summarized. Factors potentially related to disease-free interval (DFI), disease-related death (DRD), and overall survival time (OST) were analyzed with a Cox proportional hazards regression analysis. All cats were hypoglycemic on presentation with neurologic signs in 18 out of 20 and inappropriate insulin levels in 12/13. Excision of insulinomas resulted in immediate euglycemia or hyperglycemia in 18 cats. Eighteen cats survived to hospital discharge. The median time to death or last postoperative follow up was 664 days (range: 2-1205 days). Prognostic factors included age at presentation (for DFI); time to postoperative euglycemia (for DRD); preoperative and postoperative serum blood glucose concentrations; metastasis at the time of surgery (DFI and DRD), and histopathologic tumor invasion (for OST). The median OST for all cats was 863 days. The 1-, 2- and 3-year survival rates were 75%, 51%, and 10%, respectively. Excision of insulinoma resulted in euglycemia or hyperglycemia in most cats. Negative prognostic factors included young age, low serum glucose concentrations, metastasis at time of surgery, tumor invasion, and shorter time to euglycemia. Surgical excision resulted in survival times comparable to those of canine INS.

Transcriptomic analysis by RNA sequencing characterises malignant progression of canine insulinoma from normal tissue to metastatic disease

Insulinomas (INS) are the most common human and canine functioning pancreatic neuroendocrine tumours. The long-term prognosis for malignant INS is poor, because micrometastases are frequently missed during surgery. As human and canine malignant INS share clinical and histopathological features, dogs have been proposed as models for INS research. Using RNA-sequencing, we conducted a pilot study to better understand the underlying molecular mechanisms of canine INS. Normal canine pancreas and lymph node control tissues were compared with primary INS and INS-metastatic lymph nodes, revealing more than 3,000 genes differentially expressed in normal pancreas compared to primary INS. Only 164 genes were differentially expressed between primary INS and INS-metastatic lymph nodes. Hierarchical clustering analysis demonstrated similar genetic profiles in normal pancreas and early clinical stage primary INS, whereas late clinical stage primary INS resembled the genetic profile of INS-metastatic lymph nodes. These findings suggest that markers of malignant behaviour could be identified at the primary site of the disease. Finally, using the REACTOME pathways database, we revealed that an active collagen metabolism, extracellular matrix remodelling, beta-cell differentiation and non-beta-cell trans-differentiation might cause disease progression and hyperinsulinism in INS, identifying major pathways worthy of future research in this currently poorly controlled disease.

MON-640 Endogenous Insulin and C-Peptide Suppression Test Using a Rapid-Acting Insulin Analog in the Diagnosis of Insulinoma

C-peptide suppression test (CPS) was shown to diagnose the cause of hyperinsulinemic hypoglycemia, i.e. insulinoma, as effectively as supervised 72-hour fast test with less time consuming and cost. In the conventional CPS, regular insulin (RI) is used to induce hypoglycemia that subsequently suppresses endogenous insulin secretion. As RI is measurable in plasma insulin (PI) assay, plasma C-peptide (PCP) but not PI response is therefore used for assessment of endogenous insulin secretion in CPS using RI. As rapid acting insulin analogs (RA) are not measurable in a selected PI assay, both PCP and PI levels can be used to assess endogenous insulin secretion if an RA is used instead of RI in CPS. There is no study on PI and PCP responses to RA in insulinoma. This study aimed to examine efficacy of modified CPS, so-called insulin and C-peptide suppression test (ICPS) by using an RA (insulin aspart) in the diagnosis of insulinoma. Ten patients, 7 with histopathological proven insulinoma (IN) and 3 with non-insulinoma (non-IN), underwent ICPS. Blood samples were collected for measurement of plasma glucose (PG), PCP, and PI using a Roche Cobas 8000 module e602 which does not measure insulin aspart at before and every 10-20 minutes during intravenous infusion of insulin aspart at the rate of 0.05-0.075 unit/kg/hr. The test was terminated if the patients had a PG level of <40 mg/dL. There was no difference in baseline biochemical data between two groups. At the end of the test, IN had significantly higher PCP level (range: 0.60-10.20 vs. 0.31-0.48 ng/mL and median: 4.67 vs. 0.47 ng/mL; p = 0.017), lower percentage of PCP suppression (range: 2.10-53.10% vs. 63.08-91.24% and mean: 24.78 ± 19.4% vs. 73.17 ± 15.7%; p = 0.005), higher PI level (range: 1.13-113.70 vs. 0.22-0.73 µIU/mL and median: 21.29 vs. 0.49 µIU/mL; p = 0.017) and lower percentage of PI suppression (range: -14.63-81.32% vs. 88.14-96.10% and mean: 28.45 ± 36.2% vs. 93.31 ± 4.5%; p = 0.003) than did the non-IN. No overlapping of these parameters was observed between IN and non-IN. Using the same cut-off levels as the supervised 72-hour fast test, the insulin criterion (≥3 µIU/mL) in ICPS had a sensitivity of 86% and a specificity of 100% and the C-peptide criterion (≥0.6 ng/mL) in ICPS had a sensitivity of 100% and a specificity of 100%. There was a high correlation of 89% between using PCP and PI responses. In conclusion, ICPS using an RA is effective in the diagnosis of insulinoma.

An Unusual Presentation of Insulinoma: Confusion With Psychiatric Symptoms

Insulinoma is a rare but common functional neuroendocrine tumor that secretes an excess amount of insulin resulting in mostly fasting hypoglycemia but can also cause postprandial hypoglycemia. It usually presents with neuroglycopenic and autonomic sympathetic symptoms that resolve following the administration of dextrose. The patients may remain symptomatic from 1 week to as long as several decades before diagnosis. Insulinoma presenting with psychiatric symptoms has been documented in case/case series reports. Laboratory findings of elevated insulin and C-peptide level in the presence of hypoglycemia and absence of plasma sulfonylurea are suggestive of the diagnosis. Localization of the tumor is essential preoperatively. Surgery usually cures most of the patients, but a minority will have a recurrence especially with malignant insulinoma. The manuscript presents a case of insulinoma presenting with psychiatric symptoms without sympathetic symptoms that led to the delay of the diagnosis for 3 months as initially thought to be related to psychiatric problems. Pancreatic insulinoma was localized by computed tomography (CT) scan and confirmed with endoscopic ultrasound (EUS). The patient underwent successful resection of the tumor, and her symptoms were completely resolved. J Med Cases. 2020;11(5):142-144 doi: https://doi.org/10.14740/jmc3477

Correction to: A Man With Whipple’s Triad Secondary to a Malignant Insulinoma

Correction to: A Man With Whipple’s Triad Secondary to a Malignant Insulinoma

Инсулинома - сложности диагностики

Инсулинома - сложности диагностики

Сложности диагностики инсулиномы

Сложности диагностики инсулиномы

Melatonin influences the expression and oligomerization of amylin in rat INS-1E cells.

The present study investigated whether melatonin influences the expression/oligomerization of amylin with endoplasmic reticulum (ER) stress in rat insulinoma INS-1E cells. No change in cell survival after exposure to thapsigargin- and tunicamycin-combined melatonin treatment or melatonin-only treatment was observed when compared with the normal control cells. With thapsigargin-only or combined tunicamycin-melatonin treatments, phosphorylation of extracellular signal-regulated kinase (ERK) was significantly increased compared with control and melatonin-only treatments. A significant increase was observed in the levels of ER stress markers, namely, phosphorylated inositol-requiring protein 1α (p-IRE1α), CCAAT enhancer binding proteins (C/EBP)-homologous protein, p-eukaryotic translation initiation factor 2α and cleaved caspase-12, in the thapsigargin-combined melatonin-treated cells as compared with the tunicamycin-combined or only melatonin treatment. The melatonin-only treatment resulted in increased levels of amylin expression/oligomerization in 15-25 kDa and insulin proteins, compared with the thapsigargin- and tunicamycin-combined melatonin treatments. Treatment with ER stress inhibitor 4-phenylbutyric acid (4-PBA) did not suppress amylin expression/oligomerization or insulin production with thapsigargin or tunicamycin treatment. Levels of cleaved caspase-12 were significantly decreased in the thapsigargin- or tunicamycin-4-PBA combination treatments. Therefore, whether melatonin regulates the amylin expression/oligomerization in thapsigargin- or tunicamycin-combined with Bafilomycin A1 (autophagy inhibitor) or MG132 (proteasome inhibitor) treatments were investigated. Amylin expression/oligomerization with melatonin treatment was significantly decreased in the thapsigargin- or tunicamycin-combined Bafilomycin A1 or MG132 treatments. Since these outcomes are involved in cell viability, they indicate that increased cell death leads to decreased amylin expression/oligomerization, however, the effects of melatonin treatment on amylin expression/oligomerization induce proliferation of pancreatic β cells and improve the cellular functions of pancreatic β cells.

Application value of augmented reality technology in pancreatoduodenectomy

Objective To investigate the application value of augmented reality (AR) technology in pancreatoduodenectomy (PD). Methods The retrospective and descriptive study was conducted. The clinicopathological data of 3 male patients who underwent PD in Tsinghua University Affiliated Beijing Tsinghua Changgung Hospital from June 2018 to February 2019 were collected. The 3 patients were aged from 52 to 63 years, with a median age of 57 years. Digital imaging and communication standard format data of enhanced computed tomography (CT) scan were collected, the three-dimensional (3D) images of abdominal arteries, portal vein, descending duodenum, pancreatic body and tail, pancreatic head, common bile duct, and pancreatic duct were reconstructed. The results were imported into the AR software. Optical tracking based on two-dimensional codes and manual interactive rigid registration were adopted for intraoperative navigation. Observation indicators: (1) surgical and postoperative conditions; (2) postoperative pathological examination; (3) follow-up. Follow-up using outpatient examination or telephone interview was conducted to detect survival of patients and tumor metastasis and recurrence up to June 2019. The measurement data with skewed distribution were expressed as M (range). Count data were expressed as absolute numbers. Results (1) Surgical and postoperative conditions: all the 3 patients underwent PD with AR technology as intraoperative navigation successfully. The operation time, volume of intraoperative blood loss, and duration of postoperative hospital stay were 6 hours (range, 5-8 hours), 700 mL (range, 300-900 mL), 11 days (range, 9-12 days). There was no perioperative death or complication occured. After surgery, the patients who underwent PD combined with superior mesenteric vein (SMV) resection and reconstruction had patent SMV on the enhanced computed tomography examination. (2) Postoperative pathological examination: results of pathological examination showed 1 case of intraductal papillary mucinous neoplasm (IPMN) of the pancreas with invasive adenocarcinoma (neoplasm invading SMV), 1 case of insulinoma, and 1 case of periampullary neuroendocrine carcinoma, respectively. (3) Follow-up: 3 patients were followed up for 4-12 months, with a median follow-up time of 6 months. During the follow-up, the patient with IPMN of the pancreas and invasive adenocarcinoma had liver metastasis at 3 months after surgery, and received chemotherapy at other hospital. After 4 cycles of chemotherapy, the metastatic nodule shrank, and the patient was still in follow-up up to deadline of follow-up. Other 2 patients had no recurrence or metastasis. Conclusion AR technique assisted PD is safe and feasible, which is helpful to indentify vascular branches and tracks. Key words: Pancreatic neoplasms; Augmented reality technology; Three-dimensional reconstruction; Pancreatoduodenectomy; Surgical navigation

Relationship between the changes of plasma levels of leptin and obesity in patients with insulinoma

Objective To analyze the relationship between the changes of fasting plasma level of leptin and obesity in patients with insulinoma before operation. Methods From January 2003 to May 2008, 40 patients with insulinoma diagnosed at Peking Union Medical College Hospital were selected. Preoperative fasting plasma samples of them were collected. From January 2003 to May 2008, the plasma samples of 28 volunteers matched with age, gender and body weight matched with the patients were collected as the controls. All the subjects were divided into overweight-obesity group and normal weight group according to their body mass index (BMI). Plasma levels of leptin of all the subjects were measured by enzyme linked immunosorbent assay(ELISA). The Mann-Whitney U test and the correlation coefficient test were used for statistical analysis. Results The plasma leptin level of patients with insulinoma was 0.35 ng/mL (0.25 ng/mL to 1.13 ng/mL), which was higher than that of the control group (0.29 ng/mL, 0.25 ng/mL to 1.15 ng/mL), and the difference was statistically significant (U=324.50, P=0.003). In the normal-weight group, the plasma leptin level of the patients with insulinoma was 0.35 ng/mL (0.27 ng/mL to 0.62 ng/mL), which was higher than that of the control group (0.28 ng/mL, 0.25 ng/mL to 0.37 ng/mL), and the difference was statistically significant (U=28.000, P=0.001). While in the overweight-obesity group, the plasma leptin levels of the patients with insulinoma and the controls were 0.35 ng/mL (0.25 ng/mL to 1.13 ng/mL) and 0.34 ng/mL (0.26 ng/mL to 1.15 ng/mL), respectively, and the difference was not statistically significant (U=153.500, P=0.525). Plasma leptin levels in both the patients with insulinoma and the controls, were correlated with BMI (r=0.355, P=0.025; r=0.571, P=0.001, respectively). Conclusion Preoperative fasting plasma level of leptin increase in patients with insulinoma which is correlated with BMI. Key words: Insulinoma; Obesity; Leptin; Insulin; Body mass index; Pancreatic neuroendocrine tumor

A case of 'Camouflaged Insulinoma &amp; Diazoxide quandary'

A case of 'Camouflaged Insulinoma &amp; Diazoxide quandary'

Automated radiolabeling and in vivo evaluation of 18F-FDOPA

Objective To synthesize 18F-fluoro-L-3, 4-dihydroxyphenylalanine (18F-FDOPA) and evaluate its biodistribution and kinetics in mice, in order to explore its feasibility for insulinoma detection. Methods 18F-FDOPA was synthesized by a three-step nucleophilic reaction. Radiolabeling yield, radiochemical purity and stability in vitro were analyzed. Normal mice were scarified at 2, 5, 15, 30, 60 and 120 min postinjection to measure radioactive counts in main organs. Biodistribution and kinetics were evaluated by dynamic microPET in normal mice. The insulinoma tumor (INS-1) model was established and dynamic microPET was performed immediately after intravenous injection and stopped at 60 min. Region of interest (ROI) was drawn to access time-activity curve (TAC) in main organs and insulinoma. Results 18F-FDOPA was prepared with radiochemical yield of (11.0±0.4)%, radiochemical purity of (99.3±0.2)%. The radiochemical purity was still >99% after being stored for 120 min at room temperature. Predominant uptake of 18F-FDOPA was in the kidneys, and was cleared rapidly in blood. Pancreas showed stable uptake from 20 to 50 min, which was (5.98±0.71) percentage activity of injection dose per gram of tissue (%ID/g) at 20 min and (4.62±0.47) %ID/g at 50 min postinjection, respectively. 18F-FDOPA showed high affinity to tumor tissue of insulinoma ((11.42±0.70) %ID/g) at 2 min. Conclusions 18F-FDOPA could be easily synthesized in short total reaction time with high radiochemical purity and stability. Early phase imaging of 18F-FDOPA may be helpful for insulinoma detection. Key words: Levodopa; Isotope labeling; Fluorine radioisotopes; Insulinoma; Positron-emission tomography; Mice

The pathological types of pancreatic carcinoma: an analysis based on US SEER database

Objective To study the component ratios of pancreatic carcinoma, and prognosis of patients with the different pathological types. Methods The data of 92 011 pancreatic carcinoma patients who were diagnosed by the definite pathological method from 2004 to 2014 were extracted from the US SEER database. The life table was used to calculate the 1-, 3- and 5-year survival rates. The Kaplan-Meier was used to construct the survival curves of the patients. The Cox univariate analysis was applied to evaluate the HR of the different pathological types, and the χ2 test and independent sample t-test were used to evaluate the baseline data. Results The overall 5-year survival of 92 011 pancreatic carcinoma patients was 7.6%. The median survival time was 8.8 months and the component ratios of the pancreatic ductal adenocarcinoma (PDAC), pancreatic epithelium cancer bedside the PDAC, neuroendocrine tumors, undifferentiated carcinoma, mesenchymal carcinoma and rare cancer unclassified were 85.78%, 6.40%, 6.67%, 0.97%, 0.10% and 0.08%, respectively. The differences were statistically significant between the baseline data such as age, gender, race and position (P<0.05). The overall 5-year survivals of the PDAC, pancreatic epithelium cancer beside the PDAC, neuroendocrine tumors, undifferentiated carcinoma, mesenchymal carcinoma and rare cancer unclassified were 4.2%, 13.4%, 49.2%, 5.0%, 29.2% and 24.5%, respectively, and the median survival times were 5 months, 7 months, 58 months, 2 months, 26 months and 7 months respectively. The distant metastasis rate of neuroendocrine carcinoma was the lowest (35.0%). The undifferentiated carcinoma was the most prone to distant metastases (65.2%). Basically, half of the other types of pancreatic cancer had metastasis at the time of diagnosis. In pancreatic epithelium cancer beside the PDAC, the high to low 5-year survival rates were solid pseudopapillary carcinoma (87.3%), cystadenocarcinoma (36.8%), intraductal papillary mucinous neoplasm (36.5%), acinar cell carcinoma (20.0%), and pancreatic adenocarcinoma mixed with other subtypes (19.7%). The incidence of the other types of pancreatic carcinoma was less than 8%, such as mucinous carcinoma, squamous cell carcinoma, adenosquamous carcinoma and signet ring cell carcinoma. In neuroendocrine tumor, the 5-year survival rate of insulinoma (77.1%) was higher than those of neuroendocrine tumor (malignant) (NET, 62.0%) and neuroendocrine carcinoma (NEC, 46.5%). Conclusion The prognosis of pancreatic carcinoma was poor, and the pathological types had a significant impact on the prognosis of the patients. Key words: Pancreatic carcinoma; Prognosis; Pathological types; Surveillance, epidemiology, and end results (SEER)

Insulinoma - a cause of recurrent hypoglycaemias

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A study on etiological spectrum of hypoglycemia in nondiabetic patients in a rural medical teaching institution

INTRODUCTION: Awareness regarding etiological distribution of nondiabetic hypoglycemia is poor among physicians. No study of etiological spectrum of hypoglycemia is found in rural West Bengal. We conducted this study to identify different causes of hypoglycemia in nondiabetics in a rural area of the western part of West Bengal. METHODS: Nondiabetic patients admitted in general medical ward with clinical or laboratory features of hypoglycemia with blood sugar level RESULTS: A total of 55 patients were included in this study. The most common cause of hypoglycemia was alcoholism (27.27%). Next common cause was steroid withdrawal (18.18%), especially in rheumatic patients. The third common cause was sepsis (12.73%), followed by panhypopituitarism (10.91%). Sheehan syndrome was seen in three cases. Hypoglycemia was detected in one chronic kidney disease (CKD) patient after hemodialysis (HD) and two CKD patients without HD. Hypoglycemia developed in one case of fulminant hepatitis, two cases of decompensated cirrhosis (hepatitis B and alcoholic), and two cases of congestive cardiac failure. Hypoglycemia developed in two cases of primary adrenocortical insufficiency due to tuberculosis and histoplasmosis of bilateral adrenal glands. All patients had fasting hypoglycemia except one case of dumping syndrome due to Billroth II gastrojejunostomy surgery. Other rare causes were insulinoma, malnutrition, and malignancy. CONCLUSION: Knowledge regarding different causes of hypoglycemia will increase the alertness and suspicion of possible hypoglycemia in appropriate situations. It will also help to identify underlying disorders in cases of hypoglycemia.

Intractable hypoglycemia in an elderly lady with breast cancer

Paraneoplastic hypoglycemia is one of the rare causes of noninsulin-mediated hypoglycemia, which has been encountered mostly with solid tumors or mesenchymal in origin; however, it can also occur in patients with diverse kinds of tumor origin. Hypoglycemia related to tumors can be induced by different hormones produced by different tumors – for example, excessive secretion of insulin by islet cell tumors (insulinoma and neuroendocrine tumors); insulin-like growth factor 2 (IGF2) from mesenchymal and epithelial tumors; and rarely by secretion of IGF1, cytokines, and catecholamines or increased tumor metabolism of glucose. Herein, we report the case of an 89-year-old female, known to have type 2 diabetes mellitus with frequent hospital admission due to recurrent episodes of severe hypoglycemia, which was initially attributed to the insulin therapy she was taking; the patient continued to have episodes of hypoglycemia even after cessation of insulin. During her previous admission, she was found to have a swelling over the left breast. Ultrasound-guided biopsy was done and histopathology was suggestive of an invasive ductal cell breast carcinoma. We eventually found that these episodes of severe hypoglycemia were secondary to the paraneoplastic effect of invasive ductal cell carcinoma of the breast.

Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells.

Insulinomas (INS) are the most common neuroendocrine pancreatic tumours in humans and dogs. The long-term prognosis for malignant INS is still poor due to a low success rate of the current treatment modalities, particularly chemotherapy. A better understanding of the molecular processes underlying the development and progression of INS is required to develop novel targeted therapies. Cancer stem cells (CSCs) are thought to be critical for the engraftment and chemoresistance of many tumours, including INS. This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies. Highly invasive and tumourigenic human and canine INS CSC-like cells were successfully isolated. These cells expressed stem cell markers (OCT4, SOX9, SOX2, CD133 and CD34), exhibited greater resistance to 5-fluorouracil (5-FU) and demonstrated a more invasive and tumourigenic phenotype in vivo compared to bulk INS cells. Here, we demonstrated that Notch-signalling-related genes (NOTCH2 and HES1) were overexpressed in INS CSC-like cells. Protein analysis showed an active NOTCH2-HES1 signalling in INS cell lines, especially in cells resistant to 5-FU. Inhibition of the Notch pathway, using a gamma secretase inhibitor (GSI), enhanced the sensitivity of INS CSC-like cells to 5-FU. When used in combination GSI and 5-FU, the clonogenicity in vitro and the tumourigenicity in vivo of INS CSC-like cells were significantly reduced. These findings suggested that the combined strategy of Notch signalling inhibition and 5-FU synergistically attenuated enriched INS CSC populations, providing a rationale for future therapeutic exploitation.

Triple tumors in a patient with insulinoma

Triple tumors in a patient with insulinoma

Abstract #741: Singnificance of an Elevated VIP in a Men 1 Patient with Insulinoma

Abstract #741: Singnificance of an Elevated VIP in a Men 1 Patient with Insulinoma