LEAP2 changes with body mass and food intake in humans and mice

Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during starvation-like conditions but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state-dependence of ghrelin’s metabolic actions. Here, we hypothesized that LEAP2 (liver enriched antimicrobial peptide-2), a recently-characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and post-prandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increase with body mass and blood glucose, and decrease with fasting, RYGB, and in post-prandial states following VSG. These changes were mostly opposite to those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2:acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose

Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment

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