Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; = 0.020; 80% vs 50% at 10 years; = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Lavine JA, Kibbe CR, Baan M, Sirinvaravong S, Umhoefer HM, Engler KA, Meske LM, Sacotte KA, Erhardt DP, Davis DB. Cholecystokinin expression in the ␤-cell leads to increased ␤-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. Am J Physiol Endocrinol Metab 309: E819 -E828, 2015. First published September 22, 2015; doi:10.1152/ajpendo.00159.2015.-Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic ␤-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced ␤-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from ␤-cell apoptosis. To determine the specific role of ␤-cell-derived CCK in ␤-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the ␤-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain ␤-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased ␤-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced ␤-cell apoptosis. Directed CCK overexpression in cultured ␤-cells also protects from cytokineinduced apoptosis. We have identified an important new paracrine/ autocrine effect of CCK in protection of ␤-cells from apoptotic stress. Understanding the role of ␤-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect ␤-cells from apoptosis.cholecystokinin; islet; ␤-cell; apoptosis; aging; streptozotocin TYPE 1 AND TYPE 2 DIABETES MELLITUS are both diseases of reduced ␤-cell mass. In type 1 diabetes, autoimmune destruction of ␤-cells results in an absolute ␤-cell mass deficit. In type 2 diabetes, obesity increases insulin resistance, resulting in a relative insulin deficiency. In patients with type 2 diabetes, ␤-cell mass is lost via increased ␤-cell apoptosis (7, 16). Therefore, there has been wide interest in the development of diabetes therapeutics that preserve ␤-cell mass and prevent ␤-cell apoptosis.Cholecystokinin (CCK) is a gastrointestinal peptide produced by duodenal I cells and secreted in response to fat and protein (31). CCK signals through two G protein-coupled receptors, the CCK1(A) receptor [CCK1(A)R] and the CCK2(B) receptor [CCK2(B)R]. In healthy and diabetic patients, CCK infusion increases insulin secretion and decreases glucose excursion after a meal, suggesting that CCK is a potential diabetes therapeutic (1, 2). CCK also increases satiety by ...

ObjectivePostprandial hypoglycemia is an infrequent but disabling complication of Roux-en-Y gastric bypass (RYGB) surgery. Controversy still exists as to whether the postprandial hyperinsulinemia observed is due to inherent changes in pancreatic β-cell mass or function or to reversible alterations caused by RYGB anatomy. We aimed to determine if gastric feeding or reversal of RYGB would normalize postprandial glucose and hormone excursions in patients with symptomatic hypoglycemia.MethodsWe completed a prospective study of six patients with severe symptomatic RYGB hypoglycemia who underwent RYGB reversal. An additional subject without hypoglycemia who underwent RYGB reversal was also studied prospectively. Mixed meal tolerance testing (MTT) was done orally (RYGB anatomy), via gastrostomy tube in the excluded stomach in the setting of RYGB, and several months after RYGB reversal.ResultsAll subjects reported symptomatic improvement of hypoglycemia after reversal of RYGB. Weight gain after reversal was moderate and variable. Postprandial glucose, insulin, and GLP-1 excursions were significantly diminished with gastric feeding and after reversal. Insulin secretion changed proportional to glucose levels and insulin clearance increased after reversal. Glucagon/insulin ratios were similar throughout study. We further compared the impact of modified sleeve gastrectomy reversal surgery to those with restoration of complete stomach and found no significant differences in weight regain or in postprandial glucose or hormone levels.ConclusionsReversal of RYGB is an effective treatment option for severe postprandial hypoglycemia. The pathophysiology of this disorder is primarily due to RYGB anatomy resulting in altered glucose, gut, and pancreatic hormone levels and decreased insulin clearance, rather than inherent β-cell hyperplasia or hyperfunction.

Data on the rate of adrenal insufficiency (AI) in patients receiving short-course and high-dose corticosteroids are limited. In this study, we aimed to determine the incidence of AI in newly diagnosed, diffuse large B cell lymphoma (DLBCL) patients after receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [or prednisolone] (R-CHOP/CHOP) regimen. We enrolled newly diagnosed DLBCL patients who were scheduled to receive 6–8 cycles of R-CHOP/CHOP regimen. One-microgram adrenocorticotropic hormone (ACTH) stimulation tests were performed at the study entry and 3 weeks after each cycle of chemotherapy (CMT). AI was defined by a peak-stimulated serum cortisol of less than 18 μg/dL. For patients who had AI after completing a course of CMT, 1-μg ACTH stimulation tests were carried out at 60 and 90 days after the last CMT cycle to assess the duration of hypothalamic-pituitary-adrenal (HPA) axis recovery. Ten DLBCL patients were included in this study, with a total of 84 1-μg ACTH stimulation tests. Their mean age was 52 years. AI occurred in 3 out of the 10 patients (30%). The first occurrence of AI was after the third CMT cycle, and the incidence was highest after the fifth cycle. Adrenal function recovered completely 3 to 5 weeks after completing the course of CMT, except for 1 patient, whose HPA axis suppression persisted 90 days after the last CMT cycle. Receiver operating characteristic (ROC) analysis revealed that a basal cortisol level of < 8.7 μg/dL was predictive of AI, with a sensitivity and specificity of 80% and 72.2%, respectively. Transient HPA axis suppression can occur in DLBCL patients receiving R-CHOP/CHOP regimen. We strongly encourage careful observation and examination for potential adrenal insufficiency in such patients, particularly after the fifth cycle of chemotherapy.