15-Deoxy-Δ12,14-prostaglandin J2 inhibits IL-1β–induced cyclooxygenase-2 expression in mesangial cells

15-Deoxy-Δ12,14-prostaglandin J2 inhibits IL-1β–induced cyclooxygenase-2 expression in mesangial cells.BackgroundCyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins, is induced in mesangial cells in response to proinflammatory cytokines. Recently, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the natural ligands of peroxisome proliferator-activated receptor γ (PPARγ), has been reported to have an anti-inflammatory effect. Therefore, we examined the effect of 15d-PGJ2 on COX-2 expression in cultured rat mesangial cells.MethodsMesangial cells were incubated with 15d-PGJ2 for 30 minutes and then exposed to interleukin-1β (IL-1β). The expression of COX-2 mRNA and proteins was determined by Northern blot and immunoblot analyses, respectively. Accumulation of prostaglandin E2 (PGE2) was measured by an enzyme-linked immunosorbent assay (ELISA). Activities of mitogen-activated protein kinases (MAPKs) were evaluated by an immunoblot analysis. DNA binding activities of activator protein-1 (AP-1) or nuclear factor-κB (NF-κB) were examined by an electrophoretic mobility shift assay (EMSA). The activities of PPAR responsive elements (PPRE) and COX-2 promoter were measured by a luciferase reporter assay.Results15D-PGJ2 significantly suppressed IL-1β–induced COX-2 expression and PGE2 production, but thiazolidinediones, synthetic PPARγ ligands, did not affect COX-2 expression. Moreover, the cells transfected with a PPRE luciferase reporter did not respond to 15d-PGJ2. IL-1β rapidly activated extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), which were involved in the up-regulation of COX-2 induction, but 15d-PGJ2 inhibited the activation of these kinases. 15d-PGJ2 inhibited the IL-1β–induced increase in binding activities of nuclear proteins to consensus AP-1 site and AP-1–like site of COX-2 promoter but not of NF-κB. IL-1β was unable to activate the COX-2 promoter when the AP-1–like site was mutated.ConclusionsThese data suggest that 15d-PGJ2 inhibits IL-1β–induced COX-2 expression, independent of PPARγ activation, by suppression of ERK and JNK pathways and AP-1 activation in mesangial cells. Thus, 15d-PGJ2 may play an important role in the negative feedback mechanism of COX-2 expression in renal inflammation and may be useful as an anti-inflammatory agent

Octreotide-Treated Diabetes Accompanied by Endogenous Hyperinsulinemic Hypoglycemia and Protein-Losing Gastroenteropathy

Occurrence of hypoglycemia in diabetes patients is very rare. We report here a case of frequent hypoglycemic attacks caused by inappropriate endogenous hyperinsulinemia in a female patient with poorly controlled diabetes and protein-losing gastroenteropathy. The blood glucose profiles of the patient were unstable. Results of the fasting test performed to investigate the cause of hypoglycemia suggested endogenous hyperinsulinism. Repeated selective arterial calcium injection tests suggested that hyperinsulinemia might be extrapancreatic in origin. However, efforts to detect a responsible lesion such as insulinoma were unsuccessful. Octreotide was used for the treatment of hypoglycemia and protein-losing gastroenteropathy. After treatment, although her leg edema caused by hypoalbuminemia persisted, hypoglycemia almost disappeared

Efficacy and safety of luseogliflozin added to various oral antidiabetic drugs in Japanese patients with type 2 diabetes mellitus

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 < 0.001), and glycated hemoglobin reduction from baseline at week 52 was –0.63%. In study 03‐2, luseogliflozin added to other OADs significantly decreased glycated hemoglobin from baseline at week 52 (–0.52 to –0.68%, P < 0.001 for all OADs). Bodyweight reduction was observed in all add‐on therapies, even with agents associated with weight gain, such as sulfonylureas and thiazolidinediones. Most adverse events were mild in severity. When added to a sulfonylurea, incidences of hypoglycemia during the double‐blind period were 8.7% and 4.2% for luseogliflozin and placebo, respectively, but no major hypoglycemic episodes occurred. The frequency and incidences of adverse events of special interest for sodium glucose cotransporter 2 inhibitors and adverse events associated with combined OADs were acceptable. Conclusions: Add‐on therapies of luseogliflozin to existing OADs improved glycemic control, reduced bodyweight and were well tolerated in Japanese type 2 diabetic patients. These trials were registered with the Japan Pharmaceutical Information Center (add on to sulfonylurea: JapicCTI‐111507; add on to other OADs: JapicCTI‐111508)

Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin: A Possible Role of HIF-1α Expression and Oxygen Metabolism

http://dx.doi.org/10.2337/db10-0655OBJECTIVE : Chronic hypoxia has been recognized as a key regulator in renal tubulointerstitial fibrosis, as seen in diabetic nephropathy, which is associated with the activation of hypoxia-inducible factor (HIF)-1α. We assess here the effects of the biguanide, metformin, on the expression of HIF-1α in diabetic nephropathy using renal proximal tubular cells and type 2 diabetic rats. RESEARCH DESIGN AND METHODS : We explored the effects of metformin on the expression of HIF-1α using human renal proximal tubular epithelial cells (HRPTECs). Male Zucker diabetic fatty (ZDF; Gmi-fa/fa) rats were treated from 9 to 39 weeks with metformin (250 mg/kg^/day^) or insulin. RESULTS : Metformin inhibited hypoxia-induced HIF-1α accumulation and the expression of HIF-1–targeted genes in HRPTECs. Although metformin activated the downstream pathways of AMP-activated protein kinase (AMPK), neither the AMPK activator, AICAR, nor the mTOR inhibitor, rapamycin, suppressed hypoxia-induced HIF-1α expression. In addition, knockdown of AMPK-α did not abolish the inhibitory effects of metformin on HIF-1α expression. The proteasome inhibitor, MG-132, completely eradicated the suppression of hypoxia-induced HIF-1α accumulation by metformin. The inhibitors of mitochondrial respiration similarly suppressed hypoxia-induced HIF-1α expression. Metformin significantly decreased ATP production and oxygen consumption rates, which subsequently led to increased cellular oxygen tension. Finally, metformin, but not insulin, attenuated tubular HIF-1α expression and pimonidazole staining and ameliorated tubular injury in ZDF rats. CONCLUSIONS : Our data suggest that hypoxia-induced HIF-1α accumulation in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxygen consumption

Receptor-Mediated Bioassay Reflects Dynamic Change of Glucose-Dependent Insulinotropic Polypeptide by Dipeptidyl Peptidase 4 Inhibitor Treatment in Subjects With Type 2 Diabetes.

Objective: We recently observed a greater increase in plasma levels of bioactive glucose-dependent insulinotropic polypeptide (GIP) than glucagon-like peptide 1 (GLP-1) using the receptor-mediated bioassays in the subjects with normal glycemic tolerance (NGT) treated with dipeptidyl peptidase 4 (DPP-4) inhibitors, which may be unappreciated using conventional enzyme-linked immunosorbent assays (ELISAs) during oral glucose tolerance test. Thus, we determined incretin levels in addition to glucagon level using the bioassays in type 2 diabetes mellitus (T2DM) subjects with or without treatment of DPP-4 inhibitor, to evaluate whether these assays can accurately measure bioactivity of these peptides.Methods: We performed single meal tolerance test (MTT) by using a cookie meal (carbohydrate 75.0 g, protein 8.0 g, fat 28.5 g) in the subjects with NGT (n = 9), the subjects with T2DM treated without DPP-4 inhibitor (n = 7) and the subjects with T2DM treated with DPP-4 inhibitor (n = 10). All subjects fasted for 10-12 h before the MTT, and blood samples were collected at 0, 30, 60, and 120 min. We used the cell lines stably cotransfected with human-form GIP, GLP-1 or glucagon receptor, and a cyclic adenosine monophosphate-inducible luciferase expression construct for the bioassays. We measured active GIP, active GLP-1, and glucagon by the bioassays. To evaluate the efficacy of bioassay, we measured identical samples via ELISA kits.Results: During the single MTT study, postprandial active GIP bioassay levels of T2DM with DPP-4 inhibitor treatment were drastically higher than those of NGT and T2DM without DPP-4 inhibitor, although the DPP-4 inhibitor-treated group showed moderate increase of active GIPELISA and active GLP-1 bioassay , while active GLP-1 bioassay levels of T2DM subjects without DPP-4 inhibitor were comparable to those of NGT subjects. During the serial MTT, administration of DPP-4 inhibitor significantly increased active GIP bioassay levels, but not active GLP-1 bioassay .Conclusions: In comparison to conventional ELISA, receptor-mediated bioassay reflects dynamic change of GIP polypeptide by DPP-4 inhibitor treatment in subjects with type 2 diabetes

Octreotide-Treated Diabetes Accompanied by Endogenous Hyperinsulinemic Hypoglycemia and Protein-Losing Gastroenteropathy

Occurrence of hypoglycemia in diabetes patients is very rare. We report here a case of frequent hypoglycemic attacks caused by inappropriate endogenous hyperinsulinemia in a female patient with poorly controlled diabetes and protein-losing gastroenteropathy. The blood glucose profiles of the patient were unstable. Results of the fasting test performed to investigate the cause of hypoglycemia suggested endogenous hyperinsulinism. Repeated selective arterial calcium injection tests suggested that hyperinsulinemia might be extrapancreatic in origin. However, efforts to detect a responsible lesion such as insulinoma were unsuccessful. Octreotide was used for the treatment of hypoglycemia and protein-losing gastroenteropathy. After treatment, although her leg edema caused by hypoalbuminemia persisted, hypoglycemia almost disappeared

Successful recovery of infective endocarditis-induced rapidly progressive glomerulonephritis by steroid therapy combined with antibiotics: a case report

BACKGROUND: The mortality rate among patients with infective endocarditis, especially associated with the presence of complications or coexisting conditions such as renal failure and the use of combined medical and surgical therapy remains still high. Prolonged parenteral administration of a bactericidal antimicrobial agent or combination of agents is usually recommended, however, the optimal therapy for infective endocarditis associated with renal injury is not adequately defined. CASE PRESENTATION: Patient was a 24-years old man who presented to our hospital with fever, fatigue, and rapidly progressive glomerulonephritis. He had a history of ventricular septum defect (VSD). A renal biopsy specimen revealed crescentic glomerulonephritis and echocardiogram revealed VSD with vegetation on the tricuspid valve. Specimens of blood demonstrated Propionibacterium Acnes. The intensive antibiotic therapy with penicillin G was started without clinical improvement of renal function or resolution of fever over the next 7 days. After the short-term treatment of low dose of corticosteroid combined with continuous antibiotics, high fever and renal insufficiency were dramatically improved. CONCLUSION: Although renal function in our case worsened despite therapy with antibiotics, a short-term and low dose of corticosteroid therapy with antibiotics was able to recover renal function and the patient finally underwent tricuspid valve-plasty and VSD closure. We suggest that the patients with rapidly progressive glomerulonephritis associated with infective endocarditis might be treated with a short-term and low dose of corticosteroid successfully

Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients

WSTĘP. Mikroalbuminuria u chorych na cukrzycę typu 2 jest predyktorem nefropatii cukrzycowej oraz chorób układu sercowo-naczyniowego. Celem niniejszego badania obserwacyjnego była ocena efektu klinicznego redukcji mikroalbuminurii u chorych na cukrzycę typu 2. MATERIAŁ I METODY. W ciągu pierwszych 2 lat badania do projektu włączono 216 chorych na cukrzycę typu 2 z mikroalbuminurią, których obserwowano przez następne 8 lat. Za remisję lub 50-procentowe zmniejszenie mikroalbuminurii przyjęto odpowiednio powrót do wartości prawidłowych lub zmniejszenie poziomu mikroalbuminurii o połowę w porównaniu z poziomem wyjściowym. Analizowano zależność między redukcją poziomu mikroalbuminurii a czasem wystąpienia pierwszych objawów zaburzeń nerkowych lub sercowo-naczyniowych oraz oznaczanym co roku wskaźnikiem estymowanej filtracji kłębuszkowej (eGFR). WYNIKI. W grupie 93 chorych z 50-procentowym zmniejszeniem poziomów mikroalbuminurii odnotowano 12 incydentów nerkowych lub sercowo-naczyniowych w porównaniu z 35 w grupie 123 chorych bez takiej redukcji. Skumulowany wskaźnik częstości wspomnianych powikłań cukrzycy był istotnie mniejszy w grupie chorych z 50-procentową redukcją poziomów mikroalbuminurii. Analiza przy użyciu sumarycznej regresji logistycznej wykazała skorygowane ryzyko powikłań 0,41 (95% CI: 0,15-0,96) u chorych z 50-procentową redukcją mikroalbuminurii. Oznaczany co roku wskaźnik spadku eGFR u tych osób pogarszał się wolniej w porównaniu z grupą bez 50-procentowej redukcji mikroalbuminurii. Podobne dane uzyskano, analizując dane dotyczące okresów remisji. WNIOSKI. W przedstawionym badaniu dowiedziono, że redukcja mikroalbuminurii u chorych na cukrzycę typu 2 istotnie wpływa na zmniejszenie ryzyka powikłań nerkowych i sercowo-naczyniowych cukrzycy.OBJECTIVE. Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study. RESEARCH DESIGN AND METHODS. We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction < 50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated. RESULTS. Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI: 0.15-0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred. CONCLUSIONS. The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction

Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction : the randomized MARLINA-T2D trial

Aims: The MARLINA-T2D study (ClinicalTrials. gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/ mol), estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m(2) and urinary albumin-tocreatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% +/- 0.9% (62.2 +/- 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.Peer reviewe

Development of the treatment of diabetic nephropathy by targeting the TGF-β signaling

科学研究費補助金研究成果報告書研究種目: 基盤研究(B)研究期間: 2000～2002課題番号: 12470227研究代表者: 吉川 隆一（滋賀医科大学・学長）研究分担者: 羽田 勝計（滋賀医科大学・医学部・講師）研究分担者: 古家 大祐（滋賀医科大学・医学部・助手）研究分担者: 前川 聡（滋賀医科大学・医学部・助手