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Incretin therapies have received much attention because of their tissue-protective effects, which extend beyond those associated with glycemic control. Cancer is a primary cause of death in patients who have diabetes mellitus. We previously reported antiprostate cancer effects of the glucagonlike peptide-1 (GLP-1) receptor (GLP-1R) agonist exendin-4 (Ex-4). Breast cancer is one of the most common cancers in female patients who have type 2 diabetes mellitus and obesity. Thus, we examined whether GLP-1 action could attenuate breast cancer. GLP-1R was expressed in human breast cancer tissue and MCF-7, MDA-MB-231, and KPL-1 cell lines. We found that 0.1 to 10 nM Ex-4 significantly decreased the number of breast cancer cells in a dose-dependent manner. Although Ex-4 did not induce apoptosis, it attenuated breast cancer cell proliferation significantly and dose-dependently. However, the dipeptidyl peptidase-4 inhibitor linagliptin did not affect breast cancer cell proliferation. When MCF-7 cells were transplanted into athymic mice, Ex-4 decreased MCF-7 tumor size in vivo. Ki67 immunohistochemistry revealed that breast cancer cell proliferation was significantly reduced in tumors extracted from Ex-4-treated mice. In MCF-7 cells, Ex-4 significantly inhibited nuclear factor κB (NF-κB ) nuclear translocation and target gene expression. Furthermore, Ex-4 decreased both Akt and IκB phosphorylation. These results suggest that GLP-1 could attenuate breast cancer cell proliferation via activation of GLP-1R and subsequent inhibition of NF-κB activation.

Recently, pleiotropic benefits of incretin therapy beyond glycemic control have been reported. Although cancer is one of the main causes of death in diabetic patients, few reports describe the anticancer effects of incretin. Here, we examined the effect of the incretin drug exendin (Ex)-4, a GLP-1 receptor (GLP-1R) agonist, on prostate cancer. In human prostate cancer tissue obtained from patients after they had undergone radical prostatectomy, GLP-1R expression colocalized with P504S, a marker of prostate cancer. In in vitro experiments, Ex-4 significantly decreased the proliferation of the prostate cancer cell lines LNCap, PC3, and DU145, but not that of ALVA-41. This antiproliferative effect depended on GLP-1R expression. In accordance with the abundant expression of GLP-1R in LNCap cells, a GLP-1R antagonist or GLP-1R knockdown with small interfering RNA abolished the inhibitory effect of Ex-4 on cell proliferation. Although Ex-4 had no effect on either androgen receptor activation or apoptosis, it decreased extracellular signal–regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) phosphorylation in LNCap cells. Importantly, Ex-4 attenuated in vivo prostate cancer growth induced by transplantation of LNCap cells into athymic mice and significantly reduced the tumor expression of P504S, Ki67, and phosphorylated ERK-MAPK. These data suggest that Ex-4 attenuates prostate cancer growth through the inhibition of ERK-MAPK activation.

The presence of the so-called Hodgkin and Reed-Sternberg (H-RS) like cells may occur in T-cell non-Hodgkin lymphoma. Reported herein is the autopsy case of Hodgkin-like peripheral T-cell lymphoma (PTCL) in a 77-year-old male with gradual submandibular lymph node enlargement. The first biopsy showed Hodgkin-like PTCL, initially misdiagnosed as classical Hodgkin lymphoma. Although he was treated with a regimen of ABVD, his disease recurred with cervical lymph node enlargement. A second biopsy showed angioimmunoblastic T-cell lymphoma (AITL) and H-RS like cells became obscure. Despite treatment with the CHOP regimen, he died. An autopsy confirmed that only Hodgkin-like lesions preserved while the AITL component had disappeared. This clinical course is very interesting in that only the Hodgkin-like lesions were systematically exacerbated and became the main cause of death. There are no reports of Hodgkin-like PTCL following AITL and finally preserved Hodgkin-like lesions in autopsy.

To evaluate the developmental changes of the nucleolar activity of neurons, we enumerated the number of argyrophilic nucleolar organizer regions (AgNOR) in neocortical neurons of embryonic and postnatal mouse brains. The number of AgNOR changed with time, peaking at late embryonic life and falling gradually through 12 weeks postnatally. Our observation gives indirect evidence that the number of AgNORs is a marker of ribosomal RNA transcriptional activity as well as of ribosomal protein synthesis activity in neurons but not of their proliferative activity, because they are post-mitotic. These findings indicate that the AgNOR staining technique could be a useful adjunct in assessing neuronal activity of the brain.

Background Although incretin therapy is clinically available in patients with type 2 diabetes undergoing hemodialysis, no study has yet examined whether incretin therapy is capable of maintaining glycemic control in this group of patients when switched from insulin therapy. In this study, we examined the efficacy of incretin therapy in patients with insulin-treated type 2 diabetes undergoing hemodialysis. Methods Ten type 2 diabetic patients undergoing hemodialysis received daily 0.3 mg liraglutide, 50 mg vildagliptin, and 6.25 mg alogliptin switched from insulin therapy on both the day of hemodialysis and the non-hemodialysis day. Blood glucose level was monitored by continuous glucose monitoring. After blood glucose control by insulin, patients were treated with three types of incretin therapy in a randomized crossover manner, with continuous glucose monitoring performed for each treatment. Results During treatment with incretin therapies, severe hyperglycemia and ketosis were not observed in any patients. Maximum blood glucose and mean blood glucose on the day of hemodialysis were significantly lower after treatment with liraglutide compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. The standard deviation value, a marker of glucose fluctuation, on the non-hemodialysis day was significantly lower after treatment with liraglutide compared with treatment with insulin and alogliptin (p < 0.05), but not with vildagliptin. Furthermore, the duration of hyperglycemia was significantly shorter after treatment with liraglutide on both the hemodialysis and non-hemodialysis days compared with treatment with alogliptin (p < 0.05), but not with vildagliptin. Conclusions The data presented here suggest that patients with type 2 diabetes undergoing hemodialysis and insulin therapy could be treated with incretin therapy in some cases.

Serum profiles of lipids and/or liver enzymes are established markers for the estimation of insulin resistance and diabetic risk in the non-diabetic middle-aged population. To identify prediabetic markers in young subjects, 110 young male subjects (20-29 years of age) with normal glucose tolerance (NGT) were divided into two groups by median body mass index (BMI),22.18 (n=55) and ≥22.18 (n=55) kg/m(2). Indices of insulin sensitivity including HOMA-IR and ISI composite, indices of β-cell function including HOMA-β, insulinogenic index (ΔI(30)/ΔG(30)) and ΔI(30)/ΔG(30)/ HOMA-IR were calculated. Statistical associations between these parameters and the serum lipid profiles and liver function were evaluated. Alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), total cholesterol (TC) and triglyceride (TG) levels were inversely correlated with the ISI composite among individuals with BMI ≥22.18 kg/m(2) but not those with BMI22.18 kg/m(2). Multivariate regression analysis revealed that, in Group N, the plasma glucose levels at 60 min (PG(60)) were inversely correlated with the ISI composite and the insulinogenic index, and were positively correlated with the GGT, TC and TG levels. On the other hand, in Group L, PG(60) was correlated with the insulinogenic index, TC and TG levels. In conclusion, elevated levels of GGT, TC and TG are good clinical markers to predict diabetic risks, even in young NGT males. Of these, GGT was the most strongly related factor among subjects with relatively high BMI.

We identified the Dexamethasone-induced RAS protein 1 (Dexras1) gene as a cycling gene in the suprachiasmatic nucleus (SCN). Investigation of the whole brain using in situ hybridization demonstrated the localization of the expression of the gene in the SCN, thalamus, piriform cortex and hippocampus. However, rhythmic expression of the gene was observed only in the SCN. The rhythmic change in gene expression during 1 day was approximately five-fold, and the maximum expression was observed during subjective night. Real-time PCR using the SCN, paraventricular nucleus and cortex confirmed these results. Next, we analyzed the expression of the Dexras1 gene in the SCN of cryptochrome (Cry) 1 and 2 double knockout mice. We found that the rhythmic expression disappeared. The results indicate that Dexras1 rhythmicity and levels are dependent upon CRYs. This is the first time that the G protein, which may be involved in the input pathway, has been isolated as a cycling gene in the SCN.

Background Incretin therapy is feasible in patients with type 2 diabetes mellitus undergoing hemodialysis (HD). However, few studies have examined the safety and efficacy of this therapeutic approach in patients with diabetes and renal impairment. Here, we examined glycemic control and the anti-oxidative-stress effects of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with type 2 diabetes undergoing HD. Methods Thirty-five patients with type 2 diabetes undergoing HD (including 13 insulin-treated patients) were switched from ongoing therapy to linagliptin (5 mg, once daily). Levels of fasting blood glucose, C-peptide immunoreactivity (CPR), glycated albumin, B-type natriuretic peptide, oxidized low-density lipoprotein (oxLDL), high-sensitivity C-reactive protein, 8-hydroxy-2′-deoxyguanosine (8OHdG), body mass index, blood pressure, and other biologic characteristics (liver function, renal function, lipid profile) were determined before and 3 months after linagliptin treatment. Patients were classified into insulin-treated and non-insulin groups. Results With the exception of levels of total bilirubin, aspartate aminotransferase, and CPR, none of the patients exhibited changes in glucose metabolism after switching to linagliptin treatment. However, oxLDL levels were decreased significantly by linagliptin therapy in the non-insulin-treated group despite the absence of changes in glycemic control. Conclusion Linagliptin can decrease serum levels of oxLDL in patients with type 2 diabetes undergoing HD independent of its glucose-lowering effect.