Islet Cell Hyperplasia Research Articles

Non-diabetic hypoglycemia

Glucose is the main substrate utilized by the brain, and therefore numerous counterregulatory mechanisms exist to maintain plasma glucose concentration. This makes it rare for hypoglycemia to develop in people who are not taking hypoglycemic drugs, such as insulin or sulfonylureas, for diabetes. The symptoms of hypoglycemia are nonspecific. The presence of Whipple’s triad is necessary for diagnosis. When symptoms occur spontaneously, the patient can be evaluated for hypoglycemia. If this is not possible, then a 72-hour fasting test or a mixed meal tolerance test can be performed to create conditions for symptoms to occur. Non-diabetic hypoglycemia is mainly divided into two main groups: insulin-mediated (hyperinsulinism) and insulin-independent. The main causes of hypoglycemia due to endogenous hyperinsulinism are insulinoma and islet cell hyperplasia (nesidioblastosis), post-bariatric surgery, and autoimmune hypoglycemia with the presence of anti-insulin antibodies. Other important causes of hypoglycemia include hypoglycemic drugs, non-islet cell tumors, hormonal deficiencies (primary adrenal insufficiency, anterior pituitary insufficiency), and critical illnesses (liver/kidney failure). In this article, we provide an overview of the pathogenesis and treatment of hypoglycemia.

109 Effects of Fat-Rich Nutrients in the Pancreas of an Experimental Burn Model

Abstract Introduction Oversupply of nutrients overstimulates beta cells in standard conditions, and severe burn injuries increase the metabolic needs. In this study, we investigated the effects of fat-rich nutrients on the endocrine pancreas during the acute phase of severe burns. Methods Twenty-one Wistar albino rats were randomly divided into 3 groups. Two groups were fed with standard commercial rat chow (1 with sham procedure and 1 with burn procedure), and the third group (also with burn procedure) was fed a fat-rich diet (60% kcal fat). The burn procedure involved a 25% total body surface area fullthickness burn. Blood samples were taken at 36 hours and 7 days after burn injury or sham procedure. On postburn day 7, skin biopsies were taken and a pancreatectomy was performed. Pancreatic tissues were examined under light microscopy; islets size and cellularity were calculated and investigated immunohistochemically. Results Plasma glucose, C-Peptide, and insulin levels were similar in all the study groups 36 hours and 7 days after burn induction or sham procedure. There was a significant increase in the number of cells per one islet in the burn group given a fat-rich diet compared with the other groups (P = .05). Caspase-3 was strongly expressed in both groups with burn injuries. Conclusions Overconsumption of certain fats can lead to a compensatory response by beta cells that eventually can progress to beta-cell dysfunction during the acute phase of burns. Severe burns induce pancreatic islet cell hyperplasia. Providing excessive fat nutrients during the acute postburn period attenuates this response. Despite the morphophysiological changes observed in the pancreas, all animals in our study achieved similar glycemic homeostasis. Applicability of Research to Practice The delivery of nutritional support is a vital element of burn care, and the main goal is simply to avoid nutritional complications. Lipotoxicity contributes to multisystem organ failure and worse clinical outcomes in obese patients and mice with pancreatitis. Neutralization of IL-1β produces beneficial effects on postburn glycemic control and improves survival. apoptosis in the pancreas of patients with severe burns may be linked to a series of events that can induce Caspase-1 activation and IL-1β release, and these pathways may be influenced by the nutritional status, especially in the early postburn phase. Effective nutritional assessment and management can optimize wound healing and decrease complications and mortality.

A rare cause of hypoglycemia in adults

The aim of the study was to describe a clinical case of noninsulinoma pancreatogenous hypoglycemia (NIPH).Materials and methods. Patient R. 42 years old, woman, was admitted with complaints on spastic abdominal pain, heartburn, flatulence, bloating. The patient had a history of cramping pains in the upper abdomen, episodes of hypoglycemia up to once a day, periodically diarrhea with undigested food up to 3 times a day, and frequent weakness during last 9 years. In 2013, she was diagnosed with a neuroendocrine tumor of the pancreas, and therefore distal pancreatectomy was performed that year. According to histological and immuno-histochemical studies, foci of islet-cell hyperplasia (nesidioblastosis) were noted in the tail of the pancreas against the background of tissue fibrosis. Non-insulinoma pancreatogenous hypoglycemia of adults (NIPH) was diagnosed, enzyme replacement therapy and Octreotide-depo were prescribed. Relapses were noted twice. Two weeks before admission, the patient noted episodes of hypoglycemia. Upon admission, the patient had state of moderate severity, irregular stools up to 3–4 times a day. Antibacterial treatment was carried out, enzyme replacement therapy, octreotide was continued.Results. On the 7th day of hospitalization, the patient was stabilized: the level of glycemia was 4.5–4.9 mmol / l, the frequency and consistency of stool normalized. No data for decompensation of the disease has been received. The patient was discharged in a satisfactory condition.Conclusion. This clinical case demonstrates the influence of NIPH on the patient’s quality of life and the need for constant vigilance against the recurrence of hypoglycemic episodes, despite the treatment. This case can improve the awareness about this rare but important disease.

Multifocal insulinoma secondary to insulinomatosis: persistent hypoglycaemia despite total pancreatectomy.

SummaryInsulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure.Learning points:Insulinomas are usually benign and managed surgically.Insulinomatosis is characterised by multifocal benign insulinomas with a tendency to recur early. It is rare.Multifocal or recurrent insulinomas should raise suspicion of MEN-1 syndrome, or insulinomatosis.Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumour staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones.The ideal treatment strategy is unknown. Total pancreatectomy may not offer cure.

Morphologic changes associated with neoadjuvant-treated pancreatic ductal adenocarcinoma and comparison of two tumor regression grading systems

Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with an overall five-year survival rate of 9%, and few patients are candidates for pancreatectomy at presentation. The role of neoadjuvant therapy (NAT) is evolving, especially for high-risk potentially resectable tumors. Owing to the increasing number of NAT resection specimens, we aim to characterize the histologic changes associated with NAT and to compare two tumor regression grading schemes. One hundred eighteen resections for PDAC were selected from the cases between 2011 and 2018, 59 not treated and 59 treated with NAT. All H&E stained tumor slides were reviewed for histologic changes and graded using the four-tier modified Ryan score (recommended by College of American Pathologists) and the three-tier MD Anderson (MDA) score. The histologic changes evaluated included blue/grey fibrosis, islet cell hyperplasia, dystrophic calcification, amyloid deposition, cholesterol clefts, nerve hypertrophy, elastotic stromal/vascular change, abscess formation, and eosinophilic tumor cell changes. There were statistically significant differences for dystrophic calcification, eosinophilic tumor cell changes, elastotic stromal/vascular change, islet cell hyperplasia, and nerve hypertrophy between the two groups, with these features seen more frequently in NAT cases. Blue/grey stromal fibrosis was present in all cases regardless of NAT, except few complete regression cases and one treated case with intraneural invasion only. Blue/grey fibrosis is a useful histologic visual clue to suggest the possibility of adjacent tumor in the majority of PDAC cases regardless of NAT. By Kaplan-Meier analysis, neither grading scheme correlated with overall survival in our cohort. However, the MDA score was significantly correlated with both time to primary tumor recurrence (p=0.002) and time to distant recurrence (p=0.04), whereas the modified Ryan score was not.

S2754 Noninsulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS) and Severe Portein-Calorie Malnutrition; Unexpected Outcomes After Gastric Bypass Surgery

INTRODUCTION: Bariatric surgery is the most effective way to achieve a clinically significant weight loss in severely obese patients but rarely it can cause Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) and severe protein-calorie malnutrition which happened in our case. CASE DESCRIPTION/METHODS: 49 years old female with a history of Roux-en-Y gastric bypass (2005) admitted for altered mental status secondary to hypoglycemia ( FS 25) and multiple electrolyte abnormalities ( Na 158, K 2.5, BUN 50, Cr 2.5). She was acutely managed resulting in improvement in mental status. She endorsed continued weight loss for the last 6 months along with anorexia. Upper endoscopy and Colonoscopy did not reveal any cause. Her hospital course was complicated by recurrent episodes of hypoglycemia. Further workup raised the possibility of Noninsulinoma pancreatogenous hypoglycemia syndrome(NIPHS) for which diazoxide was started. A feeding tube was placed in the remnant stomach because of continued weight loss. The patient was followed after 2 months by the bariatric surgery team and underwent reversal of RYGB with uneventful post-op recovery. DISCUSSION: Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) and severe protein-calorie malnutrition are extremely rare complications after bariatric surgery. NIPHS is characterized by endogenous hyperinsulinemic hypoglycemia that is not caused by an insulinoma. Histopathology specimens have revealed islet cell hypertrophy and sometimes islet cell hyperplasia. The predominant clinical feature is postprandial hypoglycemia. Biochemical findings are similar to insulinoma which include elevated plasma insulin, C-peptide, and proinsulin concentrations. Definitive diagnosis is made by EUS guided pancreatic biopsy which might be difficult to do in RYGB patients. In case reports, octreotide, verapamil, diazoxide, and acarbose have reportedly improved hypoglycemic symptoms. In severe cases, partial or subtotal pancreatectomy is performed. Severe protein-calorie malnutrition can cause continued weight loss years after bariatric surgery. It can be managed successfully with nutritional support in most of the cases. Patients may also require a psychological evaluation and/or counseling to determine the degree to which a psychosocial etiology is involved. It is important to rule out and treat all possible underlying mechanical and behavioral causes before considering a surgical revision such as the lengthening of the common channel or surgical reversal.

Prolonged bisphenol-A exposure decreases endocrine pancreatic proliferation in response to obesogenic diet in ovariectomized mice

Research on the deleterious actions of bisphenol (BP)-A have focused on its effects on insulin secretion during pre/perinatal periods or adulthood. Estrogens also modulate endocrine pancreas physiology in females during aging; however, the effects of BPA on islet morphophysiology after menopause have not been investigated. We evaluated the effects of BPA exposure on glucose homeostasis and islet morphofunction in ovariectomized (OVX) mice fed on a high-fat diet (HFD). Adult Swiss female mice were underwent to bilateral ovariectomy, and with the confirmation of the establishment of surgical menopause, the females were then submitted, or not,to a normolipidic diet or HFD [control (CTL) and HFD groups, respectively] without or with 1 μg/mL BPA in their drinking water (CBPA and HBPA groups) for 90 days. HFD females displayed obesity, hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance. BPA did not modulate HFD-induced obesity or body glucose impairments in HBPA females, and islets isolated from both the HFD and HBPA groups exhibited insulin hypersecretion. The HBPA islets, however, displayed enlarged islet cells and reduced proliferation, in association with the downregulation of mRNAs encoding PDX-1, NGN3 and CCND2 and upregulation of mRNAs encoding ER-β, GPR30, TNF-α and IL-1β in HBPA islets. BPA consumption in OVX mice impaired the islet-cell hyperplasia response to the HFD, partly mediated by increased expression of ER-β and GPR30, which impaired the expression of major genes involved in islet-cell survival and functionality. Together with higher pro-inflammatory cytokines expression in the islet milieu, these alterations may accelerate β-cell failure in postmenopause.

SUN-901 A Case of Coexisting Insulinoma and Islet Cell Hyperplasia

IntroductionInsulinoma is the most common neuroendocrine tumour of the pancreas and cause of endogenous hyperinsulinemia hypoglycaemia. Islet cell hyperplasia is a rare cause of hypoglycaemia in adults.Clinical CaseA 42-year-old lady presented with hyperphagia, giddiness, decreased concentration and weight gain of 10 kg over one year. Her symptoms occurred both during fasting and postprandial. She did not have any medical conditions and did not take alcohol.A 72-hour fast confirmed the presence of endogenous hyperinsulinemia; serum glucose of 2.4 mmol/L paired with insulin 8.14 mU/L and C -peptide 0.71 nmol/L occurring after 16 hours of fasting. Screening for sulphonylureas and meglitinides was negative. Serum beta-hydroxybutyrate was 0.1 mmol/L with a 1.6 mmol/L rise in serum glucose post 1 mg glucagon administration. Computed tomography (CT) of the abdomen showed a 13 X 11 X 15 mm exophytic lesion at the superior aspect of the pancreatic body and another exophytic projection measuring 9 X 8 X 6 mm arising from the tail. In view of possible multifocal insulinoma, a 68Ga-DOTATATE scan was performed and it showed an intensely DOTATATE-avid exophytic nodule arising from the pancreatic body and a second indeterminate DOTATATE-avid nodule close to the pancreatic tail. In addition, there was diffuse DOTATATE uptake in the tail of pancreas.She underwent enucleation of pancreatic body nodule and spleen-saving distal pancreatectomy as the pancreatic tail nodule was not seen intra-operatively. Histology showed an insulinoma; a well-differentiated neuroendocrine tumour (Grade 1, pT1 N0 Mx) that was positively stained for synaptophysin, CD56, insulin, SSTR2 and SSTR5. The pancreatic tail nodule and distal pancreatectomy specimen showed islet cell hyperplasia; the pancreatic parenchyma showed multiple foci of well-circumscribed nests of bland islet cells with similar morphology to those seen in the insulinoma. She did not have further hypoglycaemia episodes post-operatively.Concomitant presence of fasting and postprandial hypoglycaemia may suggest underlying dual pathology. Clinical and biochemical differentiation between insulinoma and islet cell hyperplasia is difficult. Therefore, imaging for diagnosis and precise preoperative localisation is important for successful resection of suspected lesions. 68Ga-DOTATATE scan can be as useful as 68Ga-DOTANOC and 68Ga-DOTATOC scan and is better than CT scan in localising not only insulinoma but also islet cell hyperplasia. In this case, islet cell hyperplasia-induced hyperinsulinemic hypoglycaemia may have persisted if distal pancreatectomy was not performed.ConclusionAdult-onset endogenous hyperinsulinemia hypoglycaemia can be caused by concurrent insulinoma and islet cell hyperplasia. 68Ga-DOTATATE scan may be a useful, non-invasive investigation, especially in cases where CT imaging suggests multifocal disease.

68Ga-DOTATATE: Significance of Uptake in the Tail of the Pancreas in Patients Without Lesions.

To measure the SUVs in the tail of the pancreas compared with normal liver parenchyma and somatostatin receptor-positive lesions. Ga-DOTATATE PET/low mAs CT of 35 patients were reviewed. There was no significant difference (P = 0.59) between the SUVaverage of normal liver and the SUVpeak of normal tail. Five patients had uptake in the tail slightly above that of normal liver that were interpreted equivocally. In one of these patients with Ga-DOTATATE uptake in a peripancreatic lymph node, proven neuroendocrine tumor underwent a distal pancreatectomy and pathologic examination revealed islet cell hyperplasia. Ga-DOTATATE uptake in the tail of the pancreas above that of normal liver indicates a somatostatin receptor-avid lesion. Uptake in the tail of the pancreas equal to the liver can be normal. Patients with uptake equivalent to the liver should undergo further anatomical imaging before procedural intervention.

Pancreatitis Is an Important Feature of Broilers Suffering from Inclusion Body Hepatitis Leading to Dysmetabolic Conditions with Consequences for Zootechnical Performance.

The aim of the present study was to further unravel the pathophysiologic mechanisms of inclusion body hepatitis (IBH). In a first trial, the susceptibility of specific-pathogen-free (SPF) broilers to fowl aviadenovirus (FAdV) infections was investigated. Regardless of viral dose, route of infection, and susceptibility to disease on day 1, the 3-week-old SPF broilers showed resistance to IBH, with no mortality being recorded throughout the experiment. In a second trial, SPF broilers were orally infected at 3 weeks of age with a FAdV-E strain, and their digestive and metabolic processes were monitored. The birds' performance decreased from 7 days postinfection (dpi) onward, and hepato- and pancreatomegaly were found at necropsy at 4, 7, and 10 dpi and at 7 dpi, respectively. Clinical chemistry revealed transient hyperlipasemia at 4 dpi and hyperglycemia from 4 dpi onwards, with 25% of infected birds showing glycemia levels suggestive of diabetes mellitus. Histopathology findings included typical adenoviral hepatitis in the liver, while in the pancreas, inflammation characterized by multifocal infiltrations of lymphocytes, together with shrinkage of acinar cells, loss of acinar arrangement, and hyperplasia of islet cells, was noticed. Additionally, the pancreatic tissue had tendentiously lower levels of enzyme activity, and in the ileum, the digestibility of fat was significantly impaired. Hence, our data reinforce the concept of age-related resistance to experimentally induced IBH. Additionally, we demonstrated that FAdV-induced pancreatitis in broilers interferes with the digestive process and evolves into a dysmetabolic condition that resembles diabetes, affecting the health and zootechnical performance of birds, and therefore providing an important component of IBH pathogenesis.

Application of dynamic glucose monitoring in the diagnosis and differential diagnosis of hypoglycemia

Objective To analyze the characteristics of dynamic blood glucose in hypoglycemia patients with different causes and explore the application value of dynamic glucose monitoring system (DGMS) in the diagnosis and differential diagnosis of hypoglycemia. Methods We used DGMS to monitor the blood glucose levels of 20 hypoglycemia patients for 3-6 days, including 6 cases of insulinoma, 7 cases of reactive hypoglycemia, 2 cases of autoimmune hypoglycemia, 3 cases of islet cell hyperplasia, 1 case of drug-induced hypoglycemia, 1 case of congenital hyperinsulinism. The blood glucose profiles of hypoglycemia patients with different causes were compared. Results The average monitoring duration was (88.9±10.8)hours. 38-936 points of hypoglycemia were detected in these patients with hypoglycemia. The average blood glucose of patients of each cause, in the order from low to high, were: congenital hyperinsulinism [(2.97±0.59)mmol/L], islet cell hyperplasia [(4.83±1.32)mmol/L], insulinoma [(4.87±1.37)mmol/L], drug-induced hypoglycemia [(5.98±0.8)mmol/L], reactive hypoglycemia [(6.38±1.99)mmol/L], and autoimmune hypoglycemia [(7.63±2.67)mmol/L]. The constituent ratio of hypoglycemia from low to high were: autoimmune hypoglycemia and drug-induced hypoglycemia (0%), reactive hypoglycemia [0.5% (0.0%, 1.6%), insulinoma [9.0% (5.2%, 16.3%), islet cell hyperplasia [9.5% (1.1%, 14.2%), congenital hyperinsulinism (58.5%). In terms of the blood glucose profiles in day and night, the night blood glucose levels were lower than those in daytime in insulinoma [(5.16±1.37)mmol/L vs. (4.44±1.24)mmol/L], reactive hypoglycemia [(6.93±2.19)mmol/L vs. (5.57±1.25)mmol/L], autoimmune hypoglycemia [(8.08±2.79)mmol/L vs. (6.95±2.31)mmol/L], islet cell hyperplasia [(5.23±1.31)mmol/L vs. (4.11±1.00)mmol/L] and congenital hyperinsulinism [(3.06±0.57)mmol/L vs. (2.83±0.59)mmol/L] (all P<0.05); while the daytime blood glucose level was lower than that at night in drug-induced hypoglycemia [(5.90±0.81)mmol/L vs. (6.11±0.77)mmol/L, P<0.05]. 62.2% and 78.9% of the hypoglycemia episodes happened at night in patients with insulinoma and islet cell hyperplasia, and 43.2% at night in patients with congenital hyperinsulinism. The highest standard deviation of blood glucose (2.67 mmol/L), largest amplitude of glycemic excursions (9.2 mmol/L)and coefficient of variation (35%) were found in patients with autoimmune hypoglycemia. The largest range of blood glucose (20.4 mmol/L) was found in patients with reactive hypoglycemia. The day-night differences in coefficient of variation (31.6% vs. 22.4%) and range of blood glucose (20.4 mmol/L vs. 6.8 mmol/L) were most prominent in patients with reactive hypoglycemia. Conclusion The dynamic monitoring of blood glucose and the analysis of the parameters such as average blood glucose, blood glucose profiles and variability of blood glucose may be helpful for the diagnosis of hypoglycemia and differential diagnosis of causes of hypoglycemia. Key words: Hypoglycemia; Insulinoma; Dynamic glucose monitoring system; Continuous glucose monitoring system; Reactive hypoglycemia; Differential diagnosis

Impact of proton pump inhibitor treatment on pancreatic beta-cell area and beta-cell proliferation in humans.

Gastrin has been shown to promote beta-cell proliferation in rodents, but its effects in adult humans are largely unclear. Proton pump inhibitors (PPIs) lead to endogenous hypergastrinaemia, and improved glucose control during PPI therapy has been reported in patients with diabetes. Therefore, we addressed whether PPI treatment is associated with improved glucose homoeostasis, islet cell hyperplasia or increased new beta-cell formation in humans. Pancreatic tissue specimens from 60 patients with and 33 patients without previous PPI therapy were examined. The group was subdivided into patients without diabetes (n = 27), pre-diabetic patients (n = 31) and patients with diabetes (n = 35). Fasting glucose and HbA1c levels were not different between patients with and without PPI therapy (P = 0.34 and P = 0.30 respectively). Beta-cell area was higher in patients without diabetes than in patients with pre-diabetes or diabetes (1.33 ± 0.12%, 1.05 ± 0.09% and 0.66 ± 0.07% respectively; P < 0.0001). There was no difference in beta-cell area between patients with and without PPI treatment (1.05 ± 0.08% vs 0.87 ± 0.08%, respectively; P = 0.16). Beta-cell replication was rare and not different between patients with and without PPI therapy (P = 0.20). PPI treatment was not associated with increased duct-cell replication (P = 0.18), insulin expression in ducts (P = 0.28) or beta-cell size (P = 0.63). These results suggest that in adult humans, chronic PPI treatment does not enhance beta-cell mass or beta-cell function to a relevant extent.

Localization of benign insulinomas using glucagon-like peptide-1 receptor (GLP1-R) SPECT/CT and PET/CT in a prospective clinical study

358 Objectives The aim of our study is to compare the detection rate of GLP-1R PET/CT and GLP-1R SPECT/CT in patients with a biochemically proven endogenous hyperinsulinemic hypoglycemia highly suspicious for an insulinoma. Preliminary results of an ongoing study are reported. Methods Thirty-three patients (25 females, 8 males, age range 18-80 years, mean 49 years) with neuroglycopenic symptoms due to endogenous hyperinsulinemic hypoglycemia were enrolled (ClinicalTrials.gov, NCT02127541). The patients received a SPECT/CT 72 hours after injection of 111In-DOTA-exendin-4 and PET/CT 2.5 hours after injection of 68Ga-DOTA-exendin-4 in a randomized fashion within a week. Histological diagnosis after surgery was used as reference standard. Two expert readers reviewed PET/CT and SPECT/CT data in a standardized, randomized and blinded fashion. Results Previously performed cross-sectional imaging (CT/MRI) was negative or not conclusive in 25/33 (76%) of patients. So far 22 patients have been operated. In this collective, the histological diagnosis of a benign insulinoma was confirmed in 19 patients, 1 patient had adult islet cell hyperplasia. In 1 patient both intraoperative palpation as well as the histological diagnosis did not confirm an insulinoma. In 1 patient symptoms of endogenous hypoglycemia ceased postoperative but histological diagnosis did not confirm the diagnosis of a benign insulinoma or nesidioblastosis. Only this patient was excluded from evaluation as the final diagnosis remained unclear. Two patients refused surgery. Five patients are awaiting surgery. In 4 patients PET/CT, SPECT/CT as well as the previous performed conventional imaging did not find any suspicious lesion and were thus not operated up to date. In this interim analysis PET/CT showed an overall pooled sensitivity of 93 % SPECT/CT at 72 hours showed an overall pooled sensitivity of 75 % PET/CT was the only modality which correctly identified the area of islet cell hyperplasia (adult nesidioblastosis) within the pancreas. Conclusions Our interims analysis suggests that GLP-1R PET/CT performs better than GLP-1R SPECT/CT at a lower radiation dose and shorter examination time. GLP-1R PET/CT will be a useful diagnostic tool in patients where cross sectional imaging (CT/MRI) fails to localize the insulinoma.

Beneficial effects of a red wine polyphenol extract on high-fat diet-induced metabolic syndrome in rats.

Individuals with metabolic syndrome (MS) show several metabolic abnormalities including insulin resistance, dyslipidaemia, and oxidative stress (OS). Diet is one of the factors influencing the development of MS, and current nutritional advice emphasises the benefits of fruit and vegetable consumption. Here, we assessed the effects of naturally occurring antioxidants, red wine polyphenols (RWPs), on MS and OS. Wistar rats (n=20) weighing 200-220g received a high-fat diet (HFD) for 2months before they were divided into two groups that received either HFD only or HFD plus 50mg/kg RWPs in their drinking water for an additional 2months. A control group (n=10) received a normal diet (ND) for 4months. Rats receiving HFD increased body weight over 20% throughout the duration of the study. They also showed increased blood levels of C-peptide, glucose, lipid peroxides, and oxidised proteins. In addition, the HFD increased OS in hepatic, pancreatic, and vascular tissues, as well as induced pancreatic islet cell hyperplasia and hepatic steatosis. Addition of RWPs to the HFD attenuated these effects on plasma and tissue OS and on islet cell hyperplasia. However, RWPs had no effect on blood glucose levels or hepatic steatosis. RWPs showed an antioxidant mechanism of action against MS. This result will inform future animal studies exploring the metabolic effects of RWPs in more detail. In addition, these findings support the use of antioxidants as adjunctive nutritional treatments for patients with diabetes.

Molecular alterations in sporadic pancreatic neuroendocrine microadenomas.

Pancreatic neuroendocrine microadenomas (pNEMAs) are neuroendocrine tumors measuring <5mm in diameter. They are considered the precursor of pancreatic neuroendocrine tumors (pNETs). The aim of this study was to investigate the immunohistochemical differences between pNEMA, pNET, and hyperplasia of pancreatic islet cells (HPIL) in patients with non-familial syndromes. We evaluated 21 pNEMAs, 19 HPILs, and 21 non-functional pNETs (10 G1 and 11 G2 cases) in patients with non-familial syndromes. Immunohistochemistry for tumor-associated markers death domain-associated protein (DAXX), alpha thalassemia/mental retardation X-linked (ATRX), cytokeratin 19 (CK19), bcl-2, and CD99 was performed. DAXX was expressed in 95%, 71%, and 71% of HPIL, pNEMA, and pNET samples, respectively; the differences were not significant. ATRX expression in pNEMA and pNET was significantly lower than that in HPIL, whereas there was no significant difference between pNEMA and pNET (HPIL: 95%, pNEMA: 43%, and pNET: 52%). All HPIL and pNEMA cases were negative for bcl-2 and positive for CD99, whereas 29% of pNETs were positive for bcl-2 and 24% were negative for CD99. CK19 expression in HPIL was significantly lower than in pNEMA and pNET, although no significant difference was observed between pNEMA and pNET (HPIL: 5%, pNEMA: 57%, and pNET: 43%). Among G1 and G2 pNETs, CD99 was expressed in 50% of G1 pNETs but not in any G2 pNET cases. Non-familial HPIL, pNEMA, and pNET patients exhibit distinct ATRX, CD99, CK19, and bcl-2 molecular profiles.

A novel mutation ofABCC8gene in a patient with diazoxide-unresponsive congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is a rare condition that can cause irreversible brain damage during the neonatal period owing to the associated hypoglycemia. Hypoglycemia in CHI occurs secondary to the dysregulation of insulin secretion. CHI has been established as a genetic disorder of islet-cell hyperplasia, associated with a mutation of the ABCC8 or KCNJ11 genes, which encode the sulfonylurea receptor 1 and the inward rectifying potassium channel (Kir6.2) subunit of the ATP-sensitive potassium channel, respectively. We report the case of a female newborn infant who presented with repetitive seizures and episodes of apnea after birth, because of hypoglycemia. Investigations revealed hypoglycemia with hyperinsulinemia, but no ketone bodies, and a low level of free fatty acids. High dose glucose infusion, enteral feeding, and medications could not maintain the patient's serum glucose level. Genetic testing revealed a new variation of ABCC8 mutation. Therefore, we report this case of CHI caused by a novel mutation of ABCC8 in a half-Korean newborn infant with diazoxide-unresponsive hyperinsulinemic hypoglycemia.

Lesson of the month 2: An unusual presentation of hyperinsulinaemic hypoglycaemia with possible underlying diagnosis of glucose-sensitive insulinoma or islet cell hyperplasia

Postprandial hypoglycaemia can occur in islet cell hyperplasia and in reactive hypoglycaemia. Less commonly, it can occur with insulinoma. A case is described where the differential diagnosis was glucose-sensitive insulinoma or islet cell hyperplasia. Typical provocation was prolonged exertion or fasting followed by ingestion of sugary snacks resulting in hypoglycaemic seizures and collapse. Biochemistry and computerised tomography imaging were consistent with an insulinoma in the pancreatic tail, but this was not confirmed on endoscopic ultrasound. Selective intra-arterial calcium stimulation with hepatic venous sampling results suggested a diagnosis of islet cell hyperplasia. Ten years later, repeat imaging was consistent with a neuroendocrine tumour. Surgical resection has resulted in remission of symptoms. The patient will be monitored long term to ensure no recurrence.

Spontaneous lesions in endocrine glands of experimental Wistar rats and beagle dogs

A retrospective analysis was undertaken at Zydus Research Centre to understand the incidences of spontaneous lesions in endocrine glands of Wistar rats and beagle dogs. The data from a total of 841 Wistar rats (418 males and 423 females) and 144 beagle dogs (72 males and 72 females) was used from placebo/vehicle treated control group of different non-clinical toxicity studies. The lesions in various endocrine glands were classified according to the species and age of the animals at termination of study. Among the endocrine glands, the highest numbers (types) of spontaneous lesions were observed in adrenal glands followed in descending order by pituitary, thyroid, endocrine pancreas and parathyroid glands in Wistar rats. In beagle dogs, highest numbers (types) of spontaneous lesions were seen in adrenals followed by thyroid, endocrine pancreas, pituitary and parathyroid gland. In adrenal glands of Wistar rats, the incidences of cortical cell vacuolation, hemorrhages and hemangiectasis/peliosis were increased with age. Incidence of peliosis at ∼110 weeks of age was higher in female rats. Among the proliferative lesions in rats, higher incidences of cortical cell hyperplasia was observed followed by medullary hyperplasia, complex pheochromocytoma, cortical cell adenoma and cortical adenocarcinoma. In beagle dogs, the incidences of hemangiectasis and cortical cell vacuolation in adrenal glands were higher in 18–21 months aged dogs in both the sexes as compared to 10–12 months of age. In pituitary gland, the incidences of cystic changes were higher in older rats and dogs and the incidences were more in beagles as compared to rats. In thyroid glands, C-cell (parafollicular cells) hyperplasia/complex was observed more frequently in both the species. Few incidences of cystic changes were observed in parathyroid of 18–21 months aged beagle dogs. In endocrine pancreas, few incidences of islet-cell vacuolation, atrophy and hyperplasia were observed in both the species. The Islet cell hyperplasia was found to be more frequent in male rats at ∼110 weeks of age.

Musa sapientum with exercises attenuates hyperglycemia and pancreatic islet cells degeneration in alloxan-diabetic rats.

Aim:We tested the hypothesis that administrations of methanolic extracts of Musa sapientum sucker (MEMS) with exercises attenuated hyperglycemia in alloxan-diabetic rats.Materials and Methods:A total of 40 adult male rats were divided into equal eight groups. Normoglycemic Group A was Control. Alloxan (180 mg/kg, i.p.) was administered to rats in Groups B - H to induce diabetes. Group B (diabetic control) received physiological saline. Groups C - H received MEMS (5 mg/kg), MEMS (10 mg/kg), Glibenclamide (5 mg/kg), MEMS (5 mg/kg) + exercises, MEMS (10 mg/kg) + exercises and Exercises only, respectively. Changes in body weight, blood glucose levels (BGL) and pancreatic histology were evaluated during or at the end of experiment. Body weights and BGL of rats were expressed as mean ± standard deviation and analyzed using the statistical software program SPSS 15. Statistical comparisons were done using the Student’s t-test for unpaired samples. Differences between groups were determined as significant at P ≤ 0.05.Results:Significantly (P < 0.05) decreased bodyweight was observed in B and H compared to A and C - G. Treatment with MEMS significantly (P < 0.05) decreased elevated BGL in C and D. Hypoglycemic effect of MEMS appeared enhanced with exercises in F and G. Exercises regimen alone (H) resulted in percentage reduction in BGL lower than those of C - G. Histopathological examinations revealed normal pancreas (A), atrophied islet cells (B), hyperplasia with adequate population of islet cells (C - G), and reduced hyperplasia of islet cells (H).Conclusion:MEMS with exercises attenuated hyperglycemia in alloxan-diabetic rats.

Small cell carcinoma arising in a pancreatic neuroendocrine tumour (PNET) in a patient with family history of multiple endocrine neoplasia type 1 (MEN1): a case report

Case presentation A 47-year-old woman with family history of MEN1 underwent an abdominal CT scan to reveal a 20mm cystic mass in the distal pancreas and an enlarged coeliac lymph node. FNA of lymph node showed features of a neuroendocrine tumour (NET). Distal pancreato-splenectomy and regional lymphadenectomy was performed and histology showed pancreatic neuroendocrine tumour with progression into small cell carcinoma in an involved lymph node. There were also two separate pancreatic microadenomas and background islet cell hyperplasia favouring underlying MEN1. Discussion and conclusion Poorly differentiated PNETs are rare. Neoplastic progression of well differentiated NETs has been proposed as the origin of some poorly differentiated pancreatic neuroendocrine carcinomas. 1,2 Although the frequency with which pancreatic well differentiated (WHO grade 1 and 2) NETs may transform to true poorly differentiated neuroendocrine carcinomas is unknown, most observation to date suggest this is an uncommon pathway. 1 This is the first report of PNET with progression into small cell carcinoma in MEN1 patient.