OBJECTIVE-Mammalian target of rapamycin (mTOR) and its downstream target S6 kinase 1 (S6K1) mediate nutrient-induced insulin resistance by downregulating insulin receptor substrate proteins with subsequent reduced Akt phosphorylation. Therefore, mTOR/S6K1 inhibition could become a therapeutic strategy in insulin-resistant states, including type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of nutrition-dependent type 2 diabetes, using the mTOR inhibitor rapamycin.RESEARCH DESIGN AND METHODS-Normoglycemic and diabetic P. obesus were treated with 0.2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 i.p. rapamycin or vehicle, and the effects on insulin signaling in muscle, liver and islets, and on different metabolic parameters were analyzed.RESULTS-Unexpectedly, rapamycin worsened hyperglycemia in diabetic P. obesus without affecting glycemia in normoglycemic controls. There was a 10-fold increase of serum insulin in diabetic P. obesus compared with controls; rapamycin completely abolished this increase. This was accompanied by weight loss and a robust increase of serum lipids and ketone bodies. Rapamycin decreased muscle insulin sensitivity paralleled by increased glycogen synthase kinase 3␤ activity. In diabetic animals, rapamycin reduced ␤-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive c-Jun NH 2 -terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and ␤-cell apoptosis. Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin.CONCLUSIONS-Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing ␤-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating ␤-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes. Diabetes 57:945-957, 2008

Based on the current medical literature, the worldwide incidence of neuroendocrine tumours (NETs) seems to have increased; however, a systematic literature overview is lacking. This study aimed to collect all available data on the incidence of gastroenteropancreatic (GEP)-NETs and characteristics of population to establish their epidemiology. A sensitive MEDLINE search was carried out. The papers were selected via a cascade process that restricted the initial pool of 7991 articles to 33, using predefined inclusion and exclusion criteria. Original articles evaluating the incidence of sporadic GEP-NETs in regional, institutional and national registries were considered. The majority of data originated from the US National Cancer Institute Surveillance, Epidemiology and End Results database and from national cancer registries in Western Europe. Generally, because of the retrospective nature of existing databases the outcomes of studies might be biased, which hinders the drawing of firm conclusions. The age-adjusted incidence of GEP-NETs has increased steadily over the past four decades , increasing 3.65-fold in the USA and 3.8-to 4.8-fold in the UK. Incidence has changed variably from one anatomical site to another. The greatest increase in incidence occurred for gastric and rectal NETs, while the smallest increase occurred for small intestine NETs. There were gender and racial differences, which differed site by site and, in some cases, changed over time. The incidence rates (IRs) of GEP-NETs have increased significantly in the last 40 years. Data are only available from North America, Western Europe and Japan. A siteby-site analysis revealed that the IRs of some NETs increased more than those of others.

The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Gastroenteropancreatic neuroendocrine tumours are a heterogeneous group of tumours arising from diffuse endocrine cells, causing unique clinical syndromes. These tumours, formerly named carcinoid, can involve any part of the gastrointestinal tract and the endocrine pancreas and have a wide range of malignant potential: from benign to poorly differentiated tumours. In this review we will summarize the data available on the epidemiology of gastroenteropancreatic tumours as it is reported from around the world. This includes annual incidence rates at the various anatomic sites, and trends in incidence rates with time. In addition age and stage at presentation, gender and racial differences and finally prognosis and survival were collected when reported.

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.