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The role of long noncoding RNAs (lncRNAs) in the epithelial‐mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) is unclear. Some lncRNAs can be transferred by extracellular vesicles (EVs) and have potential as biomarkers. Here, we identify an lncRNA that could serve as a biomarker for PDAC and show the functional roles of the lncRNA. Expression profiling of lncRNAs revealed that highly upregulated in liver cancer (HULC) was highly expressed, and induced, by transforming growth factor‐β in PDAC cells and their EVs. Knockdown of HULC decreased PDAC cell invasion and migration by inhibiting the EMT. Thus, HULC could be transferred by EVs, and promote EMT, invasion, and migration in recipient PDAC cells. To assess the roles of HULC, PDAC cell xenografts in nude mice were established. Knockdown of HULC in PDAC cells implanted in mice inhibited tumor growth. Moreover, microRNA‐133b suppressed PDAC cell invasion and migration by inhibiting the EMT through targeting HULC. Furthermore, serum samples were obtained from 20 PDAC and 22 intraductal papillary mucinous neoplasm (IPMN) patients, as well as 21 healthy individuals. Analysis of serum EV HULC expression by digital PCR showed that HULC expression was significantly increased in PDAC patients compared to healthy individuals or IPMN patients. Additionally, HULC showed good predictive performance for discriminating PDAC, suggesting that the analysis of EV‐encapsulated HULC would contribute to the diagnosis for human PDAC. Extracellular vesicle‐transported HULC promotes cell invasion and migration by inducing the EMT, and microRNA‐133b suppresses the EMT by targeting HULC. Extracellular vesicle‐encapsulated HULC could be a potential circulating biomarker for human PDAC., Extracellular vesicle HULC can regulate cell invasion and migration through induction of epithelial‐mesenchymal transition. Extracellular vesicle HULC could compare favorably with CA19‐9 as a novel biomarker in liquid biopsy for human pancreatic ductal adenocarcinoma.

Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (

Aims This double‐blind, randomized, placebo‐controlled trial (http://clinicaltrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add‐on to linagliptin (Lina) 5 mg (fixed‐dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients. Methods The trial (40 sites; May 2015‐March 2017) involved screening 433 adults (≥20 years) who were treatment‐naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%‐10.0% after ≥16 weeks of using Lina (pre‐enrolment or during a 16‐week, open‐label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once‐daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up‐titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks. Results Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, −0.93% vs 0.21%; adjusted mean difference, −1.14%) and Week 52 (−1.16% vs 0.06%; adjusted mean difference, −1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin‐associated events (eg, increased urination, increased blood ketones). There were no adjudication‐confirmed diabetic ketoacidosis events or lower limb amputations. Conclusions These results support the notion that empagliflozin‐linagliptin in fixed‐dose combination is a therapeutic option for Japanese patients with type 2 diabetes.

The principal causes of death among 45,708 patients with diabetes (29,801 men and 15,907 women) who died in 241 hospitals throughout Japan during 2001–2010 were determined based on a survey of the hospital records. Autopsy had been conducted in 978 of the 45,708 cases. The most frequent cause of death was malignant neoplasia (38.3%), followed by, in order of descending frequency: infections (17.0%); and then vascular diseases (14.9%), including renal failure (3.5%), ischemic heart diseases (4.8%) and cerebrovascular diseases (6.6%). Diabetic coma associated with hyperglycemia with or without ketoacidosis accounted for only 0.6% of the deaths. In regard to the relationship between the age and cause of death in patients with diabetes, the incidence of death due to vascular diseases was higher in patients over the age of 30 or 40 years, and the 97.0% of the total death due to vascular diseases was observed in patients over the age of 50 years. The incidence of death due to infectious diseases, especially pneumonia, increased in an age‐dependent fashion, and the 80.7% of the total death due to pneumonia was observed in patients over the age of 70 years. ’Poorer’ glycemic control was associated with the reduced lifespan of patients with diabetes, especially of those with nephropathy. The average age at death in the survey population was 72.6 years. The lifespan was 1.6 years shorter in patients with ‘poorer’ glycemic control than in those with ‘better’ glycemic control. In patients with diabetes of less than 10 years’ duration, the incidence of death due to macroangiopathy was higher than that due to nephropathy. Of the 45,708 patients with diabetes, 33.9% were on oral medication, 41.9% received insulin therapy and 18.8% were treated by diet alone. Among the patients in whom the cause of death was diabetic nephropathy, a high percentage, 53.7%, was on insulin therapy. The average age at death of the 45,708 patients with diabetes was 71.4 years in men and 75.1 years in women. However, the report of the Ministry of Health and Welfare of Japan in 2010 set the average lifespan of the Japanese at 79.6 years for men and 86.3 years for women. Thus, the average lifespan of patients with diabetes still appears to be shorter than that of the general population in Japan. However, the differences in lifespan between patients with diabetes and the general population were shorter than those in the former surveys.

Introduction Two studies were carried out to investigate the efficacy and safety of luseogliflozin added to existing oral antidiabetic drugs (OADs) in Japanese type 2 diabetic patients inadequately controlled with OAD monotherapy. Materials and Methods In the trial involving add-on to sulfonylureas (study 03-1), patients were randomly assigned to receive luseogliflozin 2.5 mg or a placebo for a 24-week double-blind period, followed by a 28-week open-label period. In the open-label trial involving add-on to other OADs; that is, biguanides, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, glinides and α-glucosidase inhibitors (study 03-2), patients received luseogliflozin for 52 weeks. Results In study 03-1, luseogliflozin significantly decreased glycated hemoglobin at the end of the 24-week double-blind period compared with the placebo (–0.88%, P

Aims/Introduction: Activation of the renin-angiotensin system (RAS) in the kidney plays an important role in renal function. The aim of this study was to investigate whether plasma and urinary angiotensinogen levels were associated with renal and cardiovascular prognosis in type 2 diabetic patients. Materials and Methods: We measured plasma and urinary angiotensinogen levels in the observational follow-up cohort of 234 Japanese type 2 diabetic patients (144 with normoalbuminuria, 90 with albuminuria) enrolled between 1998 and 1999 and followed them up until the end of 2008. The associations of these markers with the annual decline in the estimated glomerular filtration rate (eGFR) and incidence of renal and cardiovascular composite endpoints (chronic hemodialysis, myocardial infarction, angina pectoris, stroke and cerebral hemorrhage) were evaluated. Results: At baseline, urinary angiotensinogen levels correlated with urinary albumin-creatinine ratio, urinary β2-microglobulin and inversely with eGFR. In contrast, plasma angiotensinogen levels correlated neither with these renal factors nor with urinary angiotensinogen levels. In the follow-up study (median duration: 9 years), urinary angiotensinogen, but not plasma angiotensinogen, correlated inversely with the annual change in eGFR (r = −0.51, P

Anti-diabetic agent-related hypoglycemia is a serious complication in type 2 diabetic patients on hemodialysis. Therefore, we assessed the efficacy and tolerability of 24 weeks of monotherapy with vildagliptin, a dipeptidyl peptidase four inhibitor, which is a new class of antidiabetic agent. This open-label, single-arm clinical trial was performed on 26 patients on hemodialysis. The primary assessments were changes in postprandial glucose level and glycated albumin (GA). During the study, three patients dropped out, and data from 23 patients were analyzed. Significant reductions were seen in postprandial glucose (−2.60 ± 3.80 mmol/L, P

During the past 10 years, a global pandemic of end-stage renal disease (ESRD) attributed to diabetes mellitus has changed the therapeutic strategies based on landmark trials that have shown that diabetic micro- and macrovascular complications might be preventable. However, the remaining risk of the progression of diabetic kidney disease to ESRD is still high, despite newly introduced anti-diabetic, antihypertensive and dyslipidemic drugs in the 21st century. Here, we show the importance of targeting remission and regression of microalbuminuria in type 2 diabetic patients. To achieve the remission and regression of microalbuminuria, physicians have revised the management strategy of diabetic patients and have to act immediately. Early detection of microalbuminuria with continuous screening, the use of renin–angiotensin system blockades, and targets for HbA1c of

Concept of Diabetes Mellitus: Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long‐term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder.

To clarify the presence of the Rho family of small GTPases p21-activated kinase (pak) signaling pathway in the PNS, we have examined their expression, the association between the small GTPases and pak and the pak kinase activity in the PNS using immunoblot analysis, immunohistochemistry, co-immunoprecipitation study, and in vitro kinase assay. Immunoblot analysis showed the expression of Rac, cdc42, RhoA and pak in the dorsal root ganglion (DRG) and sciatic nerve. The localization of these proteins in the DRG neurons and axons and Schwann cells of the sciatic nerve was confirmed by immunohistochemistry. Co-immunoprecipitation studies indicated the in vivo associations of pak with Rac and cdc42, but not with RhoA, in both the DRG and sciatic nerve. The autophosphorylation of pak and phosphorylation of histone H4 by pak were also found in the DRG and sciatic nerve as well as in the CNS. These results suggest that the Rac/cdc42-pak signaling pathway exists and functions in the PNS and may mediate some intracellular signals.

Since diabetes now accounts for 35% of all new cases of end-stage renal disease in the United States, it is really important to prevent the onset of diabetic nephropathy. Activation of protein kinase C (PKC) is implicated to be one of the causal factors in the development of renal dysfunctions in diabetes. In this study, we have demonstrated that total diacylglycerol (DAG) contents and PKC activity in glomeruli were significantly increased in diabetic rats as compared to control rats, but intraperitoneal injection of d-alpha-tocopherol prevented these biochemical abnormalities in parallel with normalization of glomerular dysfunction such as increased glomerular filtration rate (GFR) in diabetic rats. Albuminuria in diabetic rats was also significantly increased as compared to control rats, whereas d-alpha-tocopherol treatment again ameriolated increased albuminuria in parallel with the inhibition of glomerular PKC activation by diabetes. Moreover, we have observed that the activity of DAG kinase, which metabolizes DAG to phosphatidic acid and acts as an attenuator for the DAG-PKC pathway, was enhanced by d-alpha-tocopherol treatment. These results suggest that the increase in the DAG-PKC pathway might play an important role for the development of glomerular dysfunctions in diabetes and d-alpha-tocopherol treatment could be helpful in diabetic nephropathy.

The case of a 56-year-old man who has been blind for 25 years due to retinal degeneration is herein described. The patient complained of elementary visual hallucination, during which it was difficult for him to read Braille. Brain magnetic resonance imaging showed marked atrophy of the bilateral striate cortex. Visual hallucination as a release phenomenon of the primary visual cortex has never been reported to cause alexia for Braille. The present case supports the results of recent functional imaging studies of the recruitment of striate and prestriate cortex for Braille reading.