Kinin B1 receptor deficiency protects mice fed by cafeteria diet from abnormal glucose homeostasis.

The kallikrein-kinin system has been implicated in body weight and glucose homeostasis. Their major effectors act by binding to the kinin B2 and B1 receptors. It was assessed the role of the kinin B1 receptor in weight and glucose homeostasis in B1 receptor knockout mice (B1RKO) subjected to a cafeteria diet (CAF). Wild-type (WT) and B1RKO male mice (C57BL/6 background; 8 weeks old) were fed a standard diet (SD) or CAF for 14 weeks, ad libitum, and four groups were formed: WT-SD; B1RKO-SD; WT-CAF; B1RKO-CAF. Body weight and food intake were assessed weekly. It was performed glucose tolerance (GTT) and insulin tolerance tests (ITT), and HOMA-IR, HOMA-ß and HOMA-ß* 1/HOMA-IR were calculated. Islets from WT and B1RKO were isolated in order to measure the insulin secretion. Western blot was used to assess the hepatic AKT phosphorylation and qPCR to assess gene expression. CAF induced a higher body mass gain in B1RKO compared to WT mice. CAF diet increased epididymal fat depot mass, hepatic fat infiltration and hepatic AKT phosphorylation in both genotypes. However, B1RKO mice presented lower glycemic response during GTT when fed with CAF, and a lower glucose decrease in the ITT. This higher resistance was overcomed with higher insulin secretion when stimulated by high glucose, resulting in higher glucose uptake in the GTT when submitted to CAF, despite lower insulin sensitivity. Islets from B1RKO delivered 4 times more insulin in 3-month-old mice than islets from WT. The higher insulin disposition index and high insulin delivery of B1RKO can explain the decreased glucose excursion during GTT. In conclusion, CAF increased the ß-cell function in B1RKO mice, compensated by the diet-induced insulin resistance and resulting in a healthier glycemic response despite the higher weight gain.

Mucin expression, p53 overexpression, and peritumoral lymphocytic infiltration of advanced colorectal carcinoma with mucus component: is mucinous carcinoma a distinct histological entity?

Mucinous carcinoma of the colorectum is conventionally defined as carcinoma with an interstitial mucus component (MC) that occupies more than 50% of the tumor tissue. To examine the validity of this definition, we quantified the ratio between the area of MC and the total area of carcinoma (MC ratio) in 152 advanced colorectal carcinomas, and investigated whether MUC1, MUC2 and MUC5AC mucin expression, frequency of p53 overexpression, and peritumoral lymphocytic infiltration (PLI) of tumors differ in the MC ratio. Samples were classified into MC ratios of >50% (n=30), 10-50% (n=24), <10% (n=22), and 0% (n=76). Carcinomas with MC commonly possessed the MUC2+ phenotype (90.9-100%), and 76.6-83.3% possessed either the MUC2+/MUC5AC+/MUC1+ or the MUC2+/MUC5AC-/MUC1+ phenotype. Carcinoma without MC (MC ratio of 0%) was typically the MUC2- phenotype (89.5%). Frequencies of p53 overexpression of carcinomas with MC were significantly lower compared to those without MC (21-27% vs. 55%). PLI was observed in 0-4% of carcinomas with MC, but was observed in 17% of carcinomas without MC. These results indicate that colorectal carcinomas with MC can be grouped together as goblet cell type (MUC2+) carcinoma. These data also suggest that such carcinomas may have a common genetic background and alteration of immune responsiveness. Therefore, separately classifying carcinomas with an MC ratio of more than 50% as an independent histological type may be invalid, and re-evaluation of the histological classification of colorectal carcinoma may be required.

Bidirectional gastric differentiation in cellular mucin phenotype (foveolar and pyloric) in serrated adenoma and hyperplastic polyp of the colorectum.

This study examined whether gastric pyloric gland-type mucin is expressed in serrated adenoma (SA) and in hyperplastic polyp (HP) of the colorectum, and whether cellular position-based gastric differentiation is observed in these lesions as previously hypothesized. Immunostaining was performed for MUC6 and alpha-linked GlcNAc residue (pyloric gland-type mucin markers), human gastric mucin (HGM; foveolar-type mucin marker) and Ki-67 (proliferating cell marker) for 31 SA, 22 HP, 21 traditional tubular adenoma (TA) and 20 hyperplastic nodule (HN). MUC6 showed varying expression in SA, 22/31 (71.0%); HP, 15/22 (68.2%); TA, 2/21 (9.5%); and HN, 0/20 (0%) with significantly higher frequencies in SA and HP compared to those in TA and HN. The alpha-linked GlcNAc residue was found only in SA (3/31, 9.7%) and in HP (2/22, 9.1%). In SA and HP, HGM was typically expressed in the entire crypt length, but some reduction in expression was shown in the basal crypt portion below the proliferative zone. MUC6 and alpha-linked GlcNAc residues were expressed in the basal crypt portion below or below and including proliferative zone. These data demonstrate that SA and HP show bidirectional gastric (foveolar and pyloric gland) differentiation with respect to mucin cellular phenotype and the potential for cellular position-based differentiation, which mimics the gastric antral mucosa.