Transdifferentiation of pancreatic ductal cells to endocrine β-cells,”

Abstract The regenerative process in the pancreas is of particular interest, since diabetes, whether Type 1 or Type 2, results from an inadequate amount of insulin-producing β-cells. Islet neogenesis, or the formation of new islets, seen as budding of hormone-positive cells from the ductal epithelium, has long been considered to be one of the mechanisms of normal islet growth after birth and in regeneration, and suggested the presence of pancreatic stem cells. Results from the rat regeneration model of partial pancreatectomy led us to hypothesize that differentiated pancreatic ductal cells were the pancreatic progenitors after birth, and that with replication they regressed to a less differentiated phenotype and then could differentiate to form new acini and islets. There are numerous supportive results for this hypothesis of neogenesis, including the ability of purified primary human ducts to form insulin-positive cells budding from ducts. However, to rigorously test this hypothesis, we took a direct approach of genetically marking ductal cells using CAII (carbonic anhydrase II) as a duct-cell-specific promoter to drive Cre recombinase in lineage-tracing experiments using the Cre-Lox system. We show that CAII-expressing pancreatic cells act as progenitors that give rise to both new islets and acini after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes either in vivo or ex vivo

Malondialdehyde-modified LDL-related variables are associated with diabetic kidney disease in type 2 diabetes

Background and aimsOxidized low-density lipoprotein (oxLDL) causes the development of atherosclerosis and kidney injury. Although circulating oxLDL levels were reportedly increased in type 2 diabetic patients with macroalbuminuria, it remains unclear whether albuminuria or the reduced glomerular filtration rate (GFR) is independently associated with the circulating oxLDL level. This study aimed to elucidate the association between the stage of diabetic nephropathy and serum malondialdehyde-modified LDL (MDA-LDL) and the ratio of MDA-LDL to LDL-cholesterol (MDA-LDL/LDL).Methods and resultsThis retroactive cross-sectional study used data from 402 patients with type 2 diabetes. Patients undergoing hemodialysis were excluded. Serum MDA-LDL levels were significantly increased with increases in severity of albuminuria (103 ± 44 U/L, 109 ± 54 U/L, and 135 ± 72 U/L for normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively; P for trend = 0.020) but not according to the estimated GFR (eGFR). An increased MDA-LDL/LDL ratio was significantly associated with both increased albuminuria (35 ± 13, 37 ± 14, and 40 ± 15 for normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively; P for trend = 0.003) and reduced eGFR (34 ± 13, 36 ± 13, 38 ± 12, and 51 ± 28 for grade 1, 2, 3 and 4, respectively; P for trend = 0.002). Multiple linear regression analysis showed that neither the albumin excretion rate nor eGFR but ln-transformed triglycerides and LDL-C levels were independent determinants of both serum MDA-LDL levels and MDA-LDL/LDL ratios.ConclusionSerum MDA-LDL levels and MDA-LDL/LDL ratios were increased in those with dyslipidemia associated with diabetic kidney disease

Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice

Aims/IntroductionPeroxisome proliferator-activated receptor-α (PPARα) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists.Materials and MethodsTo compare the effects of K-877 on PPARα transcriptional activity with those of the classical PPARα agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARα transactivation luciferase assay was carried out. WT and Ppara−/− mice were fed with a moderate-fat (MF) diet for 6 days, and methionine–choline-deficient (MCD) diet for 4 weeks containing Feno or K-877.ResultsIn luciferase assays, K-877 activated PPARα transcriptional activity more efficiently than the classical PPARα agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Ppara−/− mice, confirming that K-877 activates PPARα. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes.ConclusionsThe present data show that K-877 is an attractive PPARα-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism

Octacosanol and policosanol prevent high-fat diet-induced obesity and metabolic disorders by activating brown adipose tissue and improving liver metabolism

Brown adipose tissue (BAT) is an attractive therapeutic target for treating obesity and metabolic diseases. Octacosanol is the main component of policosanol, a mixture of very long chain aliphatic alcohols obtained from plants. The current study aimed to investigate the effect of octacosanol and policosanol on high-fat diet (HFD)-induced obesity. Mice were fed on chow, or HFD, with or without octacosanol or policosanol treatment for four weeks. HFD-fed mice showed significantly higher body weight and body fat compared with chow-fed mice. However, mice fed on HFD treated with octacosanol or policosanol (HFDo/p) showed lower body weight gain, body fat gain, insulin resistance and hepatic lipid content. Lower body fat gain after octacosanol or policosanol was associated with increased BAT activity, reduced expression of genes involved in lipogenesis and cholesterol uptake in the liver, and amelioration of white adipose tissue (WAT) inflammation. Moreover, octacosanol and policosanol significantly increased the expression of Ffar4, a gene encoding polyunsaturated fatty acid receptor, which activates BAT thermogenesis. Together, these results suggest that octacosanol and policosanol ameliorate diet-induced obesity and metabolic disorders by increasing BAT activity and improving hepatic lipid metabolism. Thus, these lipids represent promising therapeutic targets for the prevention and treatment of obesity and obesity-related metabolic disorders

血中脂肪酸濃度を利用した新しい２型糖尿病診療の試行とその有効性の検証

科学研究費助成事業 研究成果報告書：基盤研究(C)2013-2015課題番号 : 2535083

Circulating Malondialdehyde-Modified LDL-Related Variables and Coronary Artery Stenosis in Asymptomatic Patients with Type 2 Diabetes

Aims. To elucidate the levels of malondialdehyde-modified LDL (MDA-LDL)-related variables for predicting coronary artery stenosis (CAS) by coronary CT angiography (CCTA) in asymptomatic patients with type 2 diabetes (T2DM). Methods. Enrolled were 36 Japanese patients with T2DM who underwent CCTA and in whom MDA-LDL levels were measured. Definition of CAS was luminal narrowing of ≥50%. Trends through tertiles of each MDA-LDL-related variable were analyzed with a general linear model. The ability of each MDA-LDL-related variable to predict CAS was compared to areas under the curve (AUCs) in receiver operating characteristic curve (ROC) analysis. Results. Seventeen patients had CAS. Each MDA-LDL-related variable was an independent predictor of CAS (P=0.039 for MDALDL, P=0.013 for MDA-LDL/LDL-C, P=0.047 for MDA-LDL/HDL-C, and P=0.013 for (MDA-LDL/LDL-C)/HDL-C). AUCs of MDA-LDL, MDA-LDL/LDL-C, MDA-LDL/HDL-C, and (MDA-LDL/LDL-C)/HDL-C were 0.675 (95% CI 0.496–0.854), 0.765 (0.602–0.927), 0.752 (0.592–0.913), and 0.799 (0.643–0.955), respectively, for predicting CAS. Trends throughout the tertiles showed significant associations between MDA-LDL/LDL-C, MDA-LDL/HDL-C, or (MDALDL/LDL-C)/HDL-C and CAS (P=0.003 for MDA-LDL/LDL-C, P=0.042 for MDA-LDL/HDL-C, and P=0.001 for (MDA-LDL/LDL-C)/HDL-C). Conclusions. Data suggest that measurements of MDA-LDL/LDL-C, MDA-LDL/HDLC, and (MDA-LDL/LDL-C)/HDL-C are useful for predicting CAS