Insulinoma in a Young Female Patient With Systemic Lupus Erythematosus: A Case Report

ObjectiveFasting hypoglycemia may occur in subjects with systemic lupus erythematosus (SLE) when accompanied with insulin-binding antibodies or insulin-receptor antibodies. However, insulinoma has not been reported in SLE subjects with hypoglycemia.MethodsWe present a case report and review the relevant literature.ResultsA 26-year-old female with underlying SLE experienced several episodes of neuropsychiatric symptoms in a fasting state. The steroid dosage was titrated up, but in vain. Timely imaging studies showed a pancreatic tumor, and insulinoma was proven by pathology. Hypoglycemia did not recur after surgery.ConclusionPhysicians should distinguish insulinoma from autoimmunity-mediated hypoglycemia in SLE patients with fasting hypoglycemia. (Endocr Pract. 2014; 20:e256-e259)     

Insulinoma in a Patient with Normal Results from Prolonged Fast and Glucagon-Induced Hypoglycemia

ObjectiveTo describe a man with a functioning insulinoma and normal results from two 72-hour fasts who developed hypoglycemia secondary to exaggerated insulin response following glucagon stimulation.MethodsWe report the patient’s clinical findings, laboratory findings, and clinical course. We also review the literature for previously reported cases and possible mechanisms.ResultsA 49-year-old man presented with hypoglycemic symptoms initially occurring after jogging and well-documented symptomatic hypoglycemia occurring during an evening meal. A 72-hour fast was associated with a serum glucose concentration of 50 mg/dL, suppressed insulin and C-peptide levels, and mildly elevated β-hydroxybutyrate. Another documented episode of hypoglycemia occurring 3 hours postprandially was associated with elevated insulin and C-peptide and suppressed β-hydroxybutyrate. A second 72-hour fast provoked asymptomatic hypoglycemia (glucose concentration at 60 hours: 32 mg/dL) with suppressed insulin and measurable β-hydroxybutyrate. After 72 hours of fasting, glucagon administration led to a decrease in glucose from 50 to 18 mg/dL, elevations in insulin and C-peptide, and suppression of β-hydroxybutyrate. Computed tomography revealed a mass lesion in the pancreatic tail. Distal pancreatectomy was performed, and the resected specimen demonstrated immunostaining for insulin. Hypoglycemic symptoms resolved postoperatively.ConclusionsNormal results from a prolonged fast do not preclude an insulinoma and may demonstrate exaggerated insulin secretion from the insulinoma following glucagon administration. In addition to examining the glucose response to glucagon as a surrogate for insulinoma diagnosis, measurement of serum insulin levels following glucagon administration may provide a further clue to the diagnosis of insulinoma. (Endocr Pract. 2010;16:838-841)     

Use of A Continuous Glucose Monitor in the Management of Inoperable Meta Static Insulinoma: A Case Report

ObjectiveTo describe the successful use of a continuous glucose monitor in the management of a patient with inoperable metastatic insulinoma.MethodsWe present a case of inoperable recurrent metastatic insulinoma in which medical therapy failed to relieve symptoms of dangerous hypoglycemia. We describe how the use of a continuous glucose monitor has assisted in avoiding hypoglycemia and improving her quality of life.ResultsA 70-year-old woman with a history of recurrent surgically treated insulinoma presented with recurrent hypoglycemia secondary to multiple metastases in the liver. Diazoxide therapy decreased the frequency of symptoms, but she continued to have hypoglycemic episodes resulting in frequent visits to the emergency department. Since starting to use a continuous glucose monitor, she has been able to avoid hypoglycemia with associated neuroglycopenic symptoms. While the accuracy of the device was poor when compared with conventional fingerstick monitors, the sensor tended to read higher than the meter in the hypoglycemic range. Although this led to more frequent false-positive hypoglycemic alarms, true episodes of severe hypoglycemia were rare.ConclusionsMalignant insulinomas are rare tumors. Many affected patients have disease that is unresectable, and medical therapy is limited in its ability to prevent hypoglycemic episodes. We have demonstrated that a continuous glucose monitor can be a useful adjunct to therapy to reduce hypoglycemic episodes by alerting the patient to low glucose concentrations before the development of neuroglycopenic symptoms. (Endocr Pract. 2008;14:880-883)     

Everolimu Resolving Hypoglycemia,Producing Hyperglycemia,and Necessitating Insulin Use in A Patient With Di Etes and Nonresectable Malignant Insulinoma

ObjectiveTo present a case of management of refractory hypoglycemia due to malignant insulinoma with use of everolimusresulting in recurrent insulin-requiring diabetes.MethodsThis report describes a case of a nonresectable malignant insulinoma in a 78-year-old patient with long-standing type 2 diabetes mellitus. Endogenous hyperinsulinism was confirmed by a fasting test, which revealed a glucose level of 35 mg/dL and an insulin value of 23.7 μIU/mL. Endoscopic ultrasonography, magnetic resonance imaging, and computed tomography identified a pancreatic mass, infiltration of the superior mesenteric vein, and metastatic lesions in the liver.ResultsAfter chemoembolization of the metastatic lesions, hypoglycemia recurred, despite combined treatment with somatostatin analogues, dexamethasone, and diazoxide. Everolimus, an orally administered mammalian target of rapamycin, was used at a daily dose of 5 mg. After 6 months, the hypoglycemia was controlled, and the patient presented with a C-peptide level of 0.2 ng/mL and secondary hyperglycemia that necessitated insulin treatment.ConclusionThe orally administered drug everolimus controlled hypoglycemia due to a malignant insulinoma in a patient with prior insulinrequiring diabetes. Secondary hyperglycemia was an acceptable drug effect (to the patient and managing physicians), in light of the complex and often poorly tolerated treatments available for this rare condition. (Endocr Pract. 2011;17:e17-e20)     

Insulinoma diagnosed in the postpartum: clinical and immunohistochemical features

Insulinomas are rare pancreatic β-cell tumors with an estimated incidence of 1:250.000 persons/year. We present a novel case of insulinoma manifesting immediately after childbirth. Eight days after delivery, a 21-year-old, previously healthy woman presented paresthesia in hands, upper and lower limbs muscle weakness with difficult walking, which worsened during breastfeeding sessions. Laboratory tests showed blood glucose levels between 37 and 55 mg/dL with inappropriately normal insulin levels (7.78 μUI/mL; normal range: 5-29). An abdominal computed tomography showed a nodular lesion measuring 2 cm at the head of the pancreas. Tumor enucleation resulted in complete resolution of hypoglycemia. Histopathological and immunohistochemical analysis were consistent with an insulinoma. About 27 cases of insulinoma associated with pregnancy have been reported to date, mostly diagnosed before the 16th week. The beginning of symptoms soon after delivery is less common. Understanding the interactions between pancreatic β-cell function and all the physiological metabolic and hormonal adaptations associated with gestation is essential for the adequate management of hypoglycemic disorders in pregnant women.     

Qualitative abnormality of insulin secretion in a case with insulinoma.

We have presented here a case of atypical insulinoma. Despite the recurrent episodes of hypoglycemic symptoms, the plasma level of insulin has never been excessive at fasting or by regular provocative tests. Detailed examination had demonstrated qualitative abnormality of insulin secretion. Hyposuppressibility of insulin secretion by hypoglycemia, borderline diabetic curve of glucose tolerance test, blunted response ot insulin to glucagon and leucine were the principle characteristics of these abnormalities. After removal of adenoma, insulin response to glucose, glucagon and leucine was improved. Only secretion provoked a high level of insulin and this abnormal elevation was no longer seen after the removal of adenoma. A removed elevation was no longer seen after the removal of adenoma. A removed insulinoma contained 25 U of immunoreactive insulin per gram tissue, but was negative for aldehyde-fuchsin staining. On electromicroscopy only atypical beta-cell granules were seen.     

Complete clinical remission and disappearance of liver metastases after treatment with somatostatin analogue in a 40-year-old woman with a malignant insulinoma positive for somatostatin receptors type 2

Insulinoma is the most common pancreatic endocrine tumor, accounting for 40% of all pancreatic functional neoplasm, and is characterized by hypersecretion of insulin and hypoglycemia. Elective treatment for insulinomas is surgical enucleation. Medical therapy with diazoxide, followed by somatostatin analogues in some cases, may be necessary to treat the hypoglycemic symptoms. We report a case of a patient affected by metastatic insulinoma with severe hypoglycemia. After surgery, histopathology confirmed the presence of a malignant insulinoma with multiple metastases in the liver. Due to the persistence of hypoglycemia, the patient was started on octreotide LAR treatment, which determined a complete clinical remission with regression of the metastatic lesions in the liver after one year. Repeated CT scans 2 and 3 years after surgery confirmed the remission. To our knowledge, the complete regression of the disease in insulinomas treated with long-standing somatostatin analogue therapy has never been reported. Immunohistochemical analysis in tissue specimens showed a strong membrane immunoreactivity for somatostatin receptors type 2 (SSTR2) in both the primary nodule and the metastases. The capacity of somatostatin analogues to negatively regulate cell proliferation through indirect and direct mechanisms has been experimentally demonstrated. Furthermore, SSTR2 activation may exert pro-apoptotic effects in neoplastic cells. Thus, both mechanisms may have been responsible of the remission of the disease in this patient. This case underlies the potential impact of the treatment of pancreatic insulinomas with somatostatin analogues, and, if confirmed, the usefulness of SSTR determination in these neoplastic specimens.     

Insulinoma--diagnosis and treatment

Insulinomas are the most common functioning endocrine tumors of pancreas. Approximately 10% are multiple, less than 10% can be malignant and 5-10% associated with the MEN-1 syndrome. Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. The aim of this lecture is to present the up-to-date information concerning the prevalence, diagnosis and treatment of insulinoma.     

Evaluation,Medical Therapy,and Course of Adult Persistent Hyperinsulinemic Hypoglycemia After Roux-En-Y Gastric Bypass Surgery: A Case Series

ObjectiveTo describe the evaluation and treatment of hyperinsulinemic hypoglycemia in adults who had undergone gastric bypass surgery. A small number of patients who undergo Roux-en-Y bypass surgery develop postprandial hypoglycemia in the absence of dumping. In some cases, such patients have been treated with pancreatectomy.MethodsWe report the demographics, diagnostic results, response to medical therapy, and subsequent course of 6 referral patients with post–Roux-en-Y gastric bypass hypoglycemia.ResultsCharacteristic clinical and metabolic parameters consistent with hyperinsulinemic hypoglycemia were identified. Parameters were similar for both spontaneous and glucose-challenge-induced hypoglycemia. In the context of exclusively postprandial symptoms, simultaneous glucose ≤ 55 mg/dL, insulin ≥ 17 μU/mL, C peptide ≥ 3.0 ng/mL, and insulin to glucose ratio > 0.3 were associated with Roux-en-Y gastric bypass hyperinsulinemic hypoglycemia. Five of 6 patients improved on therapy consisting of dietary modification plus either calcium channel blockade, acarbose, or both. Two patients have remained on therapy for 12 to 15 months. The nonresponder was atypical and had had hypoglycemic events for several decades. Three treated patients were subsequently observed to have undergone partial or complete remission from hypoglycemic episodes after 2 to 37 months of therapy. None of the 6 have undergone pancreatectomy, and none have evidence of insulinoma. Invasive diagnostic procedures were of limited utility.ConclusionIn a subset of patients with post–Roux-en-Y gastric bypass hyperinsulinemic hypoglycemia, medical management can be efficacious and an alternative to partial pancreatectomy. In some cases, the disorder remits spontaneously. (Endocr Pract. 2015;21:237-246)     

Clinical Presentation and Diagnostic Approach to Hypoglycemia in Adults Without Diabetes Mellitus

ObjectiveTo review the clinical presentation, causes, and diagnostic approach to spontaneous hypoglycemia in adults without diabetes mellitus.MethodsA literature review was performed using the PubMed and Google Scholar databases.ResultsHypoglycemia is uncommon in people who are not on glucose-lowering medications. Under normal physiologic conditions, multiple neural and hormonal counterregulatory mechanisms prevent the development of abnormally low levels of plasma glucose. If spontaneous hypoglycemia is suspected, the Whipple triad should be used to confirm hypoglycemia before pursuing further diagnostic workup. The Whipple criteria include the following: (1) low levels of plasma glucose, (2) signs or symptoms that would be expected with low levels of plasma glucose, and (3) improvement in those signs or symptoms when the level of plasma glucose increases. Spontaneous hypoglycemia can be caused by conditions that cause endogenous hyperinsulinism, including insulinoma, postbariatric hypoglycemia, and noninsulinoma pancreatogenous hypoglycemia. Spontaneous hypoglycemia can also be seen with critical illness, hepatic or renal dysfunction, hormonal deficiency, non–diabetes-related medications, and non–islet cell tumors. The initial diagnostic approach should begin by obtaining a detailed history of the nature and timing of the patient’s symptoms, medications, underlying comorbid conditions, and any acute illness. A laboratory evaluation should be conducted at the time of the spontaneous symptomatic episode. Supervised tests such as a 72-hour fast or mixed-meal test may be needed to recreate the situation under which the patient is likely to experience symptoms.ConclusionWe provide an overview of the physiology of counterregulatory response to hypoglycemia, its causes, and diagnostic approaches to spontaneous hypoglycemia in adults.     

The CM cell line derived from liver metastasis of malignant human insulinoma is not a valid beta cell model for in vitro studies

The CM cell line is derived from the ascitic fluid of a patient with liver metastasis of a malignant insulinoma. Insulin levels potentially derived from the insulinoma were detected only once in vivo in the subject with the malignant pancreatic tumor and hypoglycemia. After multiple unsuccessful attempts to detect insulin in the culture medium, insulin levels were again detected only once in vitro. In our repeated experiments, we extensively exposed early-passages of the CM cell line to 0.91 mM glucose and acutely to increasingly higher glucose concentrations (2.75, 5.5, 11, and 22 mM) and did not detect any insulin secretion as well as any significant insulin cell content. The electronic microscopic examinations of several vials containing early-passages of the CM cell lines showed a polyclonal nature of the cells mostly resembling fibroblasts. The karyotype detected severe and consistent chromosomal aberrations of the CM cell line, including the chromosome 11 tetraploidy and the genetic material translocation in three out of four chromosomes 11 at the insulin gene locus 11p15.1. These data, unfortunately, exclude the possibility of considering the CM cell line as a valid beta cell model in vitro.     

A case of malignant insulinoma responsive to somatostatin analogs treatment

Background

Insulinoma is a rare tumour representing 1–2% of all pancreatic neoplasms and it is malignant in only 10% of cases. Locoregional invasion or metastases define malignancy, whereas the dimension (>?2?cm), CK19 status, the tumor staging and grading (Ki67?>?2%), and the age of onset (>?50?years) can be considered elements of suspect.

Case presentation

We describe the case of a 68-year-old man presenting symptoms compatible with hypoglycemia. The symptoms regressed with food intake. These episodes initially occurred during physical activity, later also during fasting. The fasting test was performed and the laboratory results showed endogenous hyperinsulinemia compatible with insulinoma. The patient appeared responsive to somatostatin analogs and so he was treated with short acting octreotide, obtaining a good control of glycemia. Imaging investigations showed the presence of a lesion of the uncinate pancreatic process of about 4?cm with a high sst2 receptor density. The patient underwent exploratory laparotomy and duodenocephalopancreasectomy after one month.The definitive histological examination revealed an insulinoma (T3N1MO, AGCC VII G1) with a low replicative index (Ki67: 2%).

Conclusions

This report describes a case of malignant insulinoma responsive to octreotide analogs administered pre-operatively in order to try to prevent hypoglycemia. The response to octreotide analogs is not predictable and should be initially assessed under strict clinical surveillance.

     

Endocrine symptoms as the initial manifestation of Wilson's disease

Wilson's disease is a rare genetic disorder of copper metabolism. The difference in copper tissue accumulation is responsible for the various clinical manifestations of this disorder. If left untreated, Wilson's disease progresses to hepatic failure, severe neurological disability, and even death. Due to the complex clinical picture of Wilson's disease, its diagnosis relies on a high index of suspicion. In our paper, we present endocrine symptoms suggesting the presence of insulinoma and hyperprolactinemia as the initial clinical manifestation of Wilson's disease in a young female. Zinc acetate treatment resulted in the disappearance of hypoglycemia, galactorrhea, and menstrual abnormalities.     

Inhibition of insulin receptor function by a human,allosteric monoclonal antibody

Novel therapies are needed for the treatment of hypoglycemia resulting from both endogenous and exogenous hyperinsulinema. To provide a potential new treatment option, we identified XMetD, an allosteric monoclonal antibody to the insulin receptor (INSR) that was isolated from a human antibody phage display library. To selectively obtain antibodies directed at allosteric sites, panning of the phage display library was conducted using the insulin-INSR complex. Studies indicated that XMetD bound to the INSR with nanomolar affinity. Addition of insulin reduced the affinity of XMetD to the INSR by 3-fold, and XMetD reduced the affinity of the INSR for insulin 3-fold. In addition to inhibiting INSR binding, XMetD also inhibited insulin-induced INSR signaling by 20- to 100-fold. These signaling functions included INSR autophosphorylation, Akt activation and glucose transport. These data indicated that XMetD was an allosteric antagonist of the INSR because, in addition to inhibiting the INSR via modulation of binding affinity, it also inhibited the INSR via modulation of signaling efficacy. Intraperitoneal injection of XMetD at 10 mg/kg twice weekly into normal mice induced insulin resistance. When sustained-release insulin implants were placed into normal mice, they developed fasting hypoglycemia in the range of 50 mg/dl. This hypoglycemia was reversed by XMetD treatment. These studies demonstrate that allosteric monoclonal antibodies, such as XMetD, can antagonize INSR signaling both in vitro and in vivo. They also suggest that this class of allosteric monoclonal antibodies has the potential to treat hyperinsulinemic hypoglycemia resulting from conditions such as insulinoma, congenital hyperinsulinism and insulin overdose.     

Inhibition of insulin receptor function by a human,allosteric monoclonal antibody: A potential new approach for the treatment of hyperinsulinemic hypoglycemia

Novel therapies are needed for the treatment of hypoglycemia resulting from both endogenous and exogenous hyperinsulinema. To provide a potential new treatment option, we identified XMetD, an allosteric monoclonal antibody to the insulin receptor (INSR) that was isolated from a human antibody phage display library. To selectively obtain antibodies directed at allosteric sites, panning of the phage display library was conducted using the insulin-INSR complex. Studies indicated that XMetD bound to the INSR with nanomolar affinity. Addition of insulin reduced the affinity of XMetD to the INSR by 3-fold, and XMetD reduced the affinity of the INSR for insulin 3-fold. In addition to inhibiting INSR binding, XMetD also inhibited insulin-induced INSR signaling by 20- to 100-fold. These signaling functions included INSR autophosphorylation, Akt activation and glucose transport. These data indicated that XMetD was an allosteric antagonist of the INSR because, in addition to inhibiting the INSR via modulation of binding affinity, it also inhibited the INSR via modulation of signaling efficacy. Intraperitoneal injection of XMetD at 10 mg/kg twice weekly into normal mice induced insulin resistance. When sustained-release insulin implants were placed into normal mice, they developed fasting hypoglycemia in the range of 50 mg/dl. This hypoglycemia was reversed by XMetD treatment. These studies demonstrate that allosteric monoclonal antibodies, such as XMetD, can antagonize INSR signaling both in vitro and in vivo. They also suggest that this class of allosteric monoclonal antibodies has the potential to treat hyperinsulinemic hypoglycemia resulting from conditions such as insulinoma, congenital hyperinsulinism and insulin overdose.     

Giant Pancreatic Tumor With Clinical Characteristics of Insulinoma But Without Common Pathologic Features

ObjectiveTo report a case of a large pancreatic tumor that had clinical characteristics of an insulinoma without classic pathologic features.MethodsWe describe a 58-year-old woman who presented with a 3-month history of symptomatic hypoglycemic episodes, which were characterized by confusion. The laboratory, imaging, and pathologic findings are summarized, the current literature on giant insulinomas is reviewed, and the distinction between clinical and pathologic diagnosis of neuroendocrine tumors is discussed.ResultsThe biochemical diagnosis of insulinoma was established with concomitant low fasting blood glucose concentrations and inappropriately high insulin levels. An abdominal computed tomographic scan revealed a mass (10 by 11.7 by 9.7 cm) in the head and body of the pancreas, which was resected. Pathologic examination revealed a massive neuroendocrine tumor (13.5 by 11 by 8 cm) without immunohistochemical evidence of insulin expression. Nevertheless, tumor resection resulted in decreased blood insulin levels and resolution of the patient’s hypoglycemia.ConclusionAlthough more than 95% of insulinomas are smaller than 3 cm, this case is unique in that the extremely large pancreatic tumor had clinical characteristics of an insulinoma but did not have the classic pathologic findings. Because of the extensive pancreatic resection, the patient is dependent on both insulin and orally administered pancreatic enzymes but remained free of symptoms and disease recurrence at 1-year follow-up. (Endocr Pract. 2011;17:e12-e16)     

Sulfonylurea-induced factitious hypoglycemia in a nondiabetic nurse.

A case of sulfonylureainduced factitious hypoglycemia occurring in a nondiabetic medical nurse is reported. The patient presented with symptoms of hypoglycemia, consistently low fasting plasma glucose values and a reversal of symptoms with glucose administration. An intravenous tolbutamide provocative test on two occasions showed little increase in plasma glucose values. The case is presented to illustrate that sulfonylureainduced hypoglycemia should be considered in the differential diagnosis of fasting adult hypoglycemia, especially in paramedical personnel, and particularly in those with a poor response to the intravenous tolbutamide test.