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Adipose tissues accumulate excess energy as fat and heavily influence metabolic homeostasis. O-linked N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), which involves the addition of N-acetylglucosamine to proteins by O-GlcNAc transferase (Ogt), modulates multiple cellular processes. However, little is known about the role of O-GlcNAcylation in adipose tissues during body weight gain due to overnutrition. Here, we report on O-GlcNAcylation in mice with high-fat diet (HFD)-induced obesity. Mice with knockout of Ogt in adipose tissue achieved using adiponectin promoter-driven Cre recombinase (Ogt-FKO) gained less body weight than control mice under HFD. Surprisingly, Ogt-FKO mice exhibited glucose intolerance and insulin resistance, despite their reduced body weight gain, as well as decreased expression of de novo lipogenesis genes and increased expression of inflammatory genes, resulting in fibrosis at 24 weeks of age. Primary cultured adipocytes derived from Ogt-FKO mice showed decreased lipid accumulation. Both primary cultured adipocytes and 3T3-L1 adipocytes treated with OGT inhibitor showed increased secretion of free fatty acids. Medium derived from these adipocytes stimulated inflammatory genes in RAW 264.7 macrophages, suggesting that cell-to-cell communication via free fatty acids might be a cause of adipose inflammation in Ogt-FKO mice. In conclusion, O-GlcNAcylation is important for healthy adipose expansion in mice. Glucose flux into adipose tissues may be a signal to store excess energy as fat. [ABSTRACT FROM AUTHOR]

Background: Tooth loss is associated with nutritional status and significantly affects quality of life, particularly in older individuals. To date, several studies reveal that a high BMI is associated with tooth loss. However, there is a lack of large-scale studies that examined the impact of obesity on residual teeth with respect to age and tooth positions. Objective: We assessed the impact of obesity on the number and position of residual teeth by age groups using large scale of Japanese database. Methods: This was a cross-sectional study of 706150 subjects that were included in the database that combined the data from health insurance claims and health check-up, those lacking information about BMI, HbA1c level, smoking status, and the number of residual teeth were excluded. Thus, a total of 233517 aged 20–74 years were included. Subjects were classified into 4 categories based on BMI, and the number of teeth was compared between age-groups. The percentage of subjects with residual teeth in each position was compared between groups with obesity (BMI ≥25.0 kg/m2) and non-obesity. Logistic regression analysis was performed to clarify whether obesity predicts having <24 teeth. Results: Higher BMI was associated with fewer teeth over 40s (P for trend <0.0001 when <70s). Obesity was associated with the reduction of residual teeth in the maxillary; specifically, the molars were affected over the age 30. Smoking status further affected tooth loss at positions that were not affected by obesity alone. After adjusting for age, sex, smoking status, and HbA1c ≥6.5%, obesity remained an independent predictive factor for having <24 teeth (ORs: 1.35, 95% CIs: 1.30–1.40). Conclusions: We found that an increase in BMI was associated with a decrease in the number of residual teeth from younger ages independently of smoking status and diabetes in the large scale of Japanese database. [ABSTRACT FROM AUTHOR]

The intestinal microbiome produces short-chain fatty acids (SCFAs) from dietary fiber and has specific effects on other organs. During endurance exercise, fatty acids, glucose, and amino acids are major energy substrates. However, little is known about the role of SCFAs during exercise. To investigate this, mice were administered either multiple antibiotics or a low microbiome-accessible carbohydrate (LMC) diet, before endurance testing on a treadmill. Two-week antibiotic treatment significantly reduced endurance capacity versus the untreated group. In the cecum acetate, propionate, and butyrate became almost undetectable in the antibiotic-treated group, plasma SCFA concentrations were lower, and the microbiome was disrupted. Similarly, 6-wk LMC treatment significantly reduced exercise capacity, and fecal and plasma SCFA concentrations. Continuous acetate but not saline infusion in antibiotic-treated mice restored their exercise capacity (P = 0.05), suggesting that plasma acetate may be an important energy substrate during endurance exercise. In addition, running time was significantly improved in LMC-fed mice by fecal microbiome transplantation from others fed a high microbiome-accessible carbohydrate diet and administered a single portion of fermentable fiber (P = 0.05). In conclusion, the microbiome can contribute to endurance exercise by producing SCFAs. Our findings provide new insight into the effects of the microbiome on systemic metabolism. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes is frequently complicated with atherogenic dyslipidemia. This study aimed to evaluate the efficacy and safety of pemafibrate (K-877) in patients with type 2 diabetes comorbid with hypertriglyceridemia.Research Design and Methods: Patients were randomly assigned to three groups and received placebo (n = 57), 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks (treatment period 1). Subsequently, the patients received follow-up treatment for another 28 weeks (treatment period 2), in which the placebo was switched to 0.2 mg/day pemafibrate. This article presents the results of treatment period 1, which were the primary objectives.Results: The pemafibrate groups showed significantly reduced fasting serum triglyceride levels by ∼45% compared with the placebo group (P < 0.001). Additionally, the pemafibrate groups displayed significant decreases in non-HDL and remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, ApoB48, and ApoCIII levels and significant increases in HDL cholesterol and ApoA-I levels. LDL cholesterol levels were not considerably altered in the pemafibrate groups. Furthermore, the 0.2 mg/day pemafibrate group showed a significantly reduced HOMA-insulin resistance score compared with the placebo group; however, no significant changes compared with placebo were found in fasting plasma glucose, fasting insulin, glycoalbumin, or HbA1c levels. The pemafibrate groups also showed significantly increased fibroblast growth factor 21 levels compared with the placebo group. All groups displayed comparable rates of adverse events and drug reactions.Conclusions: Pemafibrate significantly ameliorated lipid abnormalities and was well tolerated in patients with type 2 diabetes comorbid with hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. O-linked N-acetylglucosamine (O-GlcNAc) modification is characterized by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of O-GlcNAc modification in adipose tissues. Here, we report the critical role of O-GlcNAc modification in cold-induced thermogenesis. Deletion of Ogt in WAT and BAT using adiponectin promoter-driven Cre recombinase resulted in severe cold intolerance with decreased uncoupling protein 1 (Ucp1) expression. Furthermore, Ogt deletion led to decreased mitochondrial protein expression in conjunction with decreased peroxisome proliferator-activated receptor γ coactivator 1-α protein expression. This phenotype was further confirmed by deletion of Ogt in BAT using Ucp1 promoter-driven Cre recombinase, suggesting that O-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a fatty acid-rich ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, O-GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses. [ABSTRACT FROM AUTHOR]

Background. O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development. Methods. O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogty/y/- and TM-Podo-Ogty/y/-, respectively) and analyzed their renal phenotypes. Results. Podo-Ogty/y/- mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo-Ogty/y/- mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogty/y/- mice. In contrast to Podo-Ogty/y/- mice, the induced TM-Podo-Ogty/y/- mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogty/y/- mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogty/y/- mice were prevented by Bis-T-23 treatment. Conclusions. O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and OGlcNAcylation. [ABSTRACT FROM AUTHOR]

N-3 polyunsaturated fatty acids (PUFAs) improve endothelial function. The arachidonic acid-derived metabolites (epoxyeicosatrienoic acids (EETs)) are part of the endothelial hyperpolarization factor and are vasodilators independent of nitric oxide. However, little is known regarding the regulation of EET concentration by docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in blood vessels. Sprague-Dawley rats were fed either a control or fish oil diet for 3 weeks. Compared with the control, the fish oil diet improved acetylcholine-induced vasodilation and reduced the protein expression of soluble epoxide hydrolase (sEH), a key EET metabolic enzyme, in aortic strips. Both DHA and EPA suppressed sEH protein expression in rat aorta endothelial cells (RAECs). Furthermore, the concentration of 4-hydroxy hexenal (4-HHE), a lipid peroxidation product of n-3 PUFAs, increased in n-3 PUFA-treated RAECs. In addition, 4-HHE treatment suppressed sEH expression in RAECs, suggesting that 4-HHE (derived from n-3 PUFAs) is involved in this phenomenon. The suppression of sEH was attenuated by the p38 kinase inhibitor (SB203580) and by treatment with the antioxidant N-acetyl-L-cysteine. In conclusion, sEH expression decreased after n-3 PUFAs treatment, potentially through oxidative stress and p38 kinase. Mild oxidative stress induced by n-3 PUFAs may contribute to their cardio-protective effect. [ABSTRACT FROM AUTHOR]

Postprandial hypertriglyceridemia is a potential target for cardiovascular disease prevention in patients with diabetic dyslipidemia. Metformin has been reported to reduce plasma triglyceride concentrations in the postprandial states. However, little is known about the mechanisms underlying the triglyceride-lowering effect of metformin. Here, we examined the effects of metformin on lipid metabolism after olive oil-loading in 129S mice fed a high fat diet for three weeks. Metformin administration (250 mg/kg) for one week decreased postprandial plasma triglycerides. Pre-administration (250 mg/kg) of metformin resulted in a stronger triglyceride-lowering effect (approximately 45% lower area under the curve) than post-administration. A single administration (250 mg/kg) of metformin lowered plasma postprandial triglycerides comparably to administration for one week, suggesting an acute effect of metformin on postprandial hypertriglyceridemia. To explore whole body lipid metabolism after fat-loading, stomach size, fat absorption in the intestine, and fat oxidation (13C/12C ratio in expired CO2 after administration of glyceryl-1-13C tripalmitate) were measured with and without metformin (250 mg/kg) pre-treatment. In metformin-treated mice, larger stomach size, lower fat oxidation, and no change in lipid absorption were observed. In conclusion, metformin administration before fat loading reduced postprandial hypertriglyceridemia, most likely by delaying gastric emptying. [ABSTRACT FROM AUTHOR]

Saturated fatty acid (SFA)-related lipotoxicity is a pathogenesis of diabetes-related renal proximal tubular epithelial cell (PTEC) damage, closely associated with a progressive decline in renal function. This study was designed to identify a free fatty acid (FFA) metabolism-related enzyme that can protect PTECs from SFA-related lipotoxicity. Among several enzymes involved in FFA metabolism, we identified stearoyl-CoA desaturase-1 (SCD1), whose expression level significantly decreased in the kidneys of high-fat diet (HFD)-induced diabetic mice, compared with non-diabetic mice. SCD1 is an enzyme that desaturates SFAs, converting them to monounsaturated fatty acids (MUFAs), leading to the formation of neutral lipid droplets. In culture, retrovirus-mediated overexpression of SCD1 or MUFA treatment significantly ameliorated SFA-induced apoptosis in PTECs by enhancing intracellular lipid droplet formation. In contrast, siRNA against SCD1 exacerbated the apoptosis. Both overexpression of SCD1 and MUFA treatment reduced SFA-induced apoptosis via reducing endoplasmic reticulum stress in cultured PTECs. Thus, HFD-induced decrease in renal SCD1 expression may play a pathogenic role in lipotoxicity-induced renal injury, and enhancing SCD1-mediated desaturation of SFA and subsequent formation of neutral lipid droplets may become a promising therapeutic target to reduce SFA-induced lipotoxicity. The present study provides a novel insight into lipotoxicity in the pathogenesis of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background: Management of postprandial hyperglycemia is a key aspect in diabetes treatment. We developed a novel system to measure glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET) for simple monitoring of postprandial glucose excursions. In this study, we evaluated the relationship between our system and continuous glucose monitoring (CGM) by comparing glucose AUC obtained using MIET with that obtained using CGM for a long duration. Methods: Twenty diabetic inpatients wearing a CGM system were enrolled. For MIET measurement, a plastic microneedle array was applied to the skin as pretreatment, and hydrogels were placed on the pretreated area to collect interstitial fluid. Hydrogels were replaced every 2 or 4 hours and AUC was predicted on the basis of glucose and sodium ion levels. Results: AUC predicted by MIET correlated well with that measured by CGM (r=0.93). Good performances of both consecutive 2- and 4-hour measurements were observed (measurement error: 11.7%±10.2% for 2 hours and 11.1%±7.9%for 4 hours), indicating the possibility of repetitive measurements up to 8 hours. The influence of neither glucose fluctuation nor average glucose level over the measurement accuracy was observed through 8 hours. Conclusion: Our system showed good relationship with AUC values from CGM up to 8 hours, indicating that single pretreatment can cover a large portion of glucose excursion in a day. These results indicated possibility of our system to contribute to convenient monitoring of glucose excursions for a long duration. [ABSTRACT FROM AUTHOR]

Overcoming refractory massive proteinuria remains a clinical and research issue in diabetic nephropathy. This study was designed to investigate the pathogenesis of massive proteinuria in diabetic nephropathy, with a special focus on podocyte autophagy, a system of intracellular degradation that maintains cell and organelle homeostasis, using human tissue samples and animal models. Insufficient podocyte autophagy was observed histologically in patients and rats with diabetes and massive proteinuria accompanied by podocyte loss, but not in those with no or minimal proteinuria. Podocyte-specific autophagy-deficient mice developed podocyte loss and massive proteinuria in a high-fat diet (HFD)-induced diabetic model for inducing minimal proteinuria. Interestingly, huge damaged lysosomes were found in the podocytes of diabetic rats with massive proteinuria and HFD-fed, podocyte-specific autophagy-deficient mice. Furthermore, stimulation of cultured podocytes with sera from patients and rats with diabetes and massive proteinuria impaired autophagy, resulting in lysosome dysfunction and apoptosis. These results suggest that autophagy plays a pivotal role in maintaining lysosome homeostasis in podocytes under diabetic conditions, and that its impairment is involved in the pathogenesis of podocyte loss, leading to massive proteinuria in diabetic nephropathy. These results may contribute to the development of a new therapeutic strategy for advanced diabetic nephropathy. [ABSTRACT FROM AUTHOR]

We examined the concentrations of water-soluble vitamins in blood and urinary excretion of 22 patients with type 2 diabetes mellitus (type 2DM) and 20 healthy control participants. Macronutrient and vitamin intakes of type 2DM subjects were measured using a weighed food record method. Control participants consumed a semipurified diet for eight days. Multiple linear regression models were used to determine whether significant differences existed in vitamin concentrations in blood independent of age, sex, and other confounding factors. Concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors. Renal clearances of vitamins B6, C, niacin, and folate were significantly higher in type 2DM subjects than in controls. In conclusion, concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors; based on the evidence of increased urinary clearance of these vitamins, the lower levels were likely due to impaired reabsorption processes. [ABSTRACT FROM AUTHOR]

N-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have protective effects against atherosclerosis. Monocyte chemotactic protein (MCP)-1 is a major inflammatory mediator in the progression of atherosclerosis. However, little is known about the regulation of MCP-1 by DHA and EPA in vessels and vascular smooth muscle cells (VSMCs). In this study, we compared the effect of DHA and EPA on the expression of Mcp-1 in rat arterial strips and rat VSMCs. DHA, but not EPA, suppressed Mcp-1 expression in arterial strips. Furthermore, DHA generated 4-hydroxy hexenal (4-HHE), an end product of n-3 polyunsaturated fatty acids (PUFAs), in arterial strips as measured by liquid chromatography-tandem mass spectrometry. In addition, 4-HHE treatment suppressed Mcp-1 expression in arterial strips, suggesting 4-HHE derived from DHA may be involved in the mechanism of this phenomenon. In contrast, Mcp-1 expression was stimulated by DHA, EPA and 4-HHE through p38 kinase and the Keap1-Nuclear factor erythroid-derived 2-like 2 (Nrf2) pathway in VSMCs. In conclusion, there is a dual effect of n-3 PUFAs on the regulation of Mcp-1 expression. Further study is necessary to elucidate the pathological role of this phenomenon. [ABSTRACT FROM AUTHOR]

Objective To determine whether serum concentrations of long chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in the incidence rate of coronary artery calcification (CAC) between Japanese men in Japan and white men in the USA. Methods In a population based, prospective cohort study, 214 Japanese men and 152 white men aged 40-49 years at baseline (2002-2006) with coronary calcium score (CCS)=0 were re-examined for CAC in 2007-2010. Among these, 175 Japanese men and 113 white men participated in the follow-up exam. Incident cases were defined as participants with CCS=10 at follow-up. A relative risk regression analysis was used to model the incidence rate ratio between the Japanese and white men. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline. Results Mean (SD) serum percentage of LCn3PUFA was >100% higher in Japanese men than in white men (9.08 (2.49) vs 3.84 (1.79), respectively, p<0.01). Japanese men had a significantly lower incidence rate of CAC compared to white men (0.9 vs 2.9/100 personyears, respectively, p<0.01). The incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% CI 0.150 to 0.690; p<0.01). After adjusting for age, systolic blood pressure, low density lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant (0.262, 95% CI 0.094 to 0.731; p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376, 95% CI 0.090 to 1.572; p=0.18). Conclusions LCn3PUFAs significantly contributed to the difference in the incidence of CAC between Japanese and white men. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. The multipronged drug approach still fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to improve the prognosis of diabetic nephropathy is urgently required. Nutrient-sensing signals and their related intracellular machinery have evolved to combat prolonged periods of starvation in mammals; and these systems are conserved in the kidney. Recent studies have suggested that the activity of three nutrient-sensing signals, mTORC1, AMPK, and Sirt1, is altered in the diabetic kidney. Furthermore, autophagy activity, which is regulated by the above-mentioned nutrient-sensing signals, is also altered in both podocytes and proximal tubular cells under diabetic conditions. Under diabetic conditions, an altered nutritional state owing to nutrient excess may disturb cellular homeostasis regulated by nutrient-responsible systems, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing relationships between nutrient-sensing signals, autophagy, and diabetic nephropathy and suggest the therapeutic potential of nutrient-sensing signals in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is the most frequent liver disease. Ezetimibe, an inhibitor of intestinal cholesterol absorption, has been reported to ameliorate hepatic steatosis in human and animal models. To explore how ezetimibe reduces hepatic steatosis, we investigated the effects of ezetimibe on the expression of lipogenic enzymes and intestinal lipid metabolism in mice fed a high-fat or a high-fructose diet. CBA/JN mice were fed a high-fat diet or a high-fructose diet for 8 wk with or without ezetimibe. High-fat diet induced hepatic steatosis accompanied by hyperinsulinemia. Treatment with ezetimibe reduced hepatic steatosis, insulin levels, and glucose production from pyruvate in mice fed the high-fat diet, suggesting a reduction of insulin resistance in the liver. In the intestinal analysis, ezetimibe reduced the expression of fatty acid transfer protein-4 and apoB-48 in mice fed the high-fat diet. However, treatment with ezetimibe did not prevent hepatic steatosis, hyperinsulinemia, and intestinal apoB-48 expression in mice fed the high-fructose diet. Ezetimibe decreased liver X receptor-α binding to the sterol regulatory element-binding protein-1c promoter but not expression of carbohydrate response element-binding protein and fatty acid synthase in mice fed the high-fructose diet, suggesting that ezetimibe did not reduce hepatic lipogenesis induced by the high-fructose diet. Elevation of hepatic and intestinal lipogenesis in mice fed a high-fructose diet may partly explain the differences in the effect of ezetimibe. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoking is a risk factor of coronary heart disease. Vascular calcification such as coronary artery calcium (CAC) and aortic calcium (AC) is associated with coronary heart disease. The authors hypothesised that cigarette smoking is associated with coronary artery and aortic calcifications in Japanese and Koreans with high smoking prevalence. Methods: Random samples from populations of 313 Japanese and 302 Korean men aged 40-49 years were examined for calcification of the coronary artery and aorta using electron beam CT. CAC and AC were quantified using the Agatston score. The authors examined the associations of cigarette smoking with CAC and AC after adjusting for conventional risk factors and alcohol consumption. Current and past smokers were combined and categorised into two groups using median pack-years as a cut-off point in each of Japanese and Koreans. The never-smoker group was used as a reference for the multiple logistic regression analyses. Results: The ORs of CAC (score ≥10) for smokers with higher pack-years were 2.9 in Japanese (p<0.05) and 1.3 in Koreans (non-significant) compared with neversmokers. The ORs of AC (score ≥100) for smokers with higher pack-years were 10.4 in Japanese (p<0.05) and 3.6 in Koreans (p<0.05). Conclusion: Cigarette smoking with higher pack-years is significantly associated with CAC and AC in Japanese men, while cigarette smoking with higher pack-years is significantly associated with AC but not significantly with CAC in Korean men. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to combat diabetic nephropathy is required. Autophagy is a catabolic process that degrades damaged proteins and organelles in mammalian cells and plays a critical role inmaintaining cellular homeostasis. The accumulation of proteins and organelles damaged by hyperglycemia and other diabetes-related metabolic changes is highly associated with the development of diabetic nephropathy. Recent studies have suggested that autophagy activity is altered in both podocytes and proximal tubular cells under diabetic conditions. Autophagy activity is regulated by both nutrient state and intracellular stresses. Under diabetic conditions, an altered nutritional state due to nutrient excess may interfere with the autophagic response stimulated by intracellular stresses, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing the relationships between autophagy and diabetic nephropathy and suggest the therapeutic potential of autophagy in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are important posttranscriptional regulators of various biological pathways. In this study, we focused on the role of miRNAs during mitochondrial biogenesis in skeletal muscle. The expression of miR-494 was markedly decreased in murine myoblast C2C12 cells during myogenic differentiation, accompanied by an increase in mtDNA. Furthermore, the expression of predicted target genes for miR-494, including mitochondrial transcription factor A (mtTFA) and Forkhead box j3 (Foxj3), was posttranscriptionally increased during myogenic differentiation. Knockdown of miR-494 resulted in increased mitochondrial content and upregulation of mtTFA and Foxj3 at the protein level. A 3'-untranslated region reporter assay revealed that miR-494 knockdown directly upregulated the luciferase activity of mtTFA and Foxj3. All of these observations were reversed by overexpression of miR-494. Furthermore, the miR-494 content significantly decreased after endurance exercise in C57BL/6J mice, accompanied by an increase in expression of mtTFA and Foxj3 proteins. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mt-TFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise. [ABSTRACT FROM AUTHOR]

This study examines the differences in circulating levels of cytokines among Japanese in Japan (JJ), Japanese Americans (JA), and whites and their associations with obesity and marine n-3 fatty acids (FA) in a cross-sectional population-based study of 297 men aged 40–49 (100 JJ, 99 whites, and 98 JA). Experimental studies show that cytokines are associated with obesity positively and marine n-3 FA inversely. Serum interleukin-1α (IL-1α), IL-1 receptor agonist (IL-1ra), IL-4, IL-8, IL-10, inducible protein-10 (IP-10), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and marine n-3 FA were determined. Body mass index (BMI), waist circumference, and computed tomography-measured visceral and subcutaneous adipose tissues were determined. The JJ had significantly lower levels of IL-1α, IL-4, IL-8, MCP-1, and TNF-α than whites and JA. Whites and JA had similar levels of IL-1α, IL-4, and IL-8 whereas whites had significantly higher levels of MCP-1 and TNF-α than JA. The JJ were least obese (BMI (kg/m2), mean ± standard deviation) 23.6 ± 2.8, 27.9 ± 4.6, and 27.9 ± 4.5 for JJ, whites, and JA, respectively. The JJ had marine n-3 FA about 100% higher than whites and JA (serum marine n-3 FA (%), median (interquartile range) 8.79 (7.41, 11.16), 3.47 (2.63, 4.83), and 4.44 (3.33, 6.01) for JJ, whites, and JA, respectively). Generally cytokines had weak and nonsignificant associations with indices of obesity and nonsignificant associations with marine n-3 FA. BMI had significant inverse associations with IL-1α, IL-4, and IL-8 in JA (P< 0.05). Marine n-3 FA had marginally significant inverse associations with IL-8 in JJ (P= 0.055) and TNF-α in whites (P= 0.076). The JJ had lower levels of many cytokines than whites and JA. Generally cytokines had weak and nonsignificant associations with indices of obesity and marine n-3 FA. Further investigation is needed to determine why JJ had lower circulating levels of cytokines. [ABSTRACT FROM AUTHOR]

Abstract Purpose  Postprandial hyperglycemia is recognized as an important risk factor for developing type 2 diabetes; it is also common in patients after a gastrectomy and is likely to become exacerbated after a total gastrectomy rather than after a distal gastrectomy. In this study, we investigated the glucose and insulin responses after oral glucose tolerance test (OGTT), and compared the incidence of postchallenge hyperglycemia after OGTT in patients after a distal and total gastrectomy. Methods  Forty-six patients, including 18 patients after a distal gastrectomy and 28 after a total gastrectomy, underwent a 75-g OGTT, and the plasma concentrations of glucose and insulin were measured after OGTT. Results  Glucose peaked at 30 min in the distal gastrectomy patients and 60 min in the total gastrectomy patients, and there were significant differences in the 1-h plasma glucose (PG) and 1.5-h PG levels between the distal and total gastrectomy patients. Insulin peaked at 60 min in both the distal and total gastrectomy patients, and there were significant differences in insulin levels at 60 min between the distal and total gastrectomy patients. The incidence of postchallenge hyperglycemia in the patients after a total gastrectomy (57.1%) was higher than in those after distal gastrectomy (27.8%). Moreover, significant positive correlations were found between 1-h PG and hemoglobin antigen HbA1c after a total gastrectomy but not after a distal gastrectomy. Conclusions  These results suggest that postchallenge hyperglycemia after OGTT may become more exacerbated after a total gastrectomy than after a distal gastrectomy. Postprandial hyperglycemia, especially after a total gastrectomy, may therefore be involved in the development of diabetes. [ABSTRACT FROM AUTHOR]

Coronary heart disease incidence and mortality remain very low in Japan despite major dietary changes and increases in risk factors that should have resulted in a substantial increase in coronary heart disease rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in coronary heart disease in Japanese migrating to the United States. For men aged 40–49 years, levels of total cholesterol and blood pressure have been similar in Japan and the United States throughout their lifetimes. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification, and intima-media thickness of the carotid artery in men aged 40–49 years are similar in Japan and the United States. They conducted a population-based study of 493 randomly selected men: 250 in Kusatsu City, Shiga, Japan, and 243 White men in Allegheny County, Pennsylvania, in 2002–2005. Compared with the Whites, the Japanese had a less favorable profile regarding many risk factors. The prevalence ratio for the presence of a coronary calcium score of ≥10 for the Japanese compared with the Whites was 0.52 (95% confidence interval: 0.35, 0.76). Mean intima-media thickness was significantly lower in the Japanese (0.616 mm (standard error, 0.005) vs. 0.672 (standard error, 0.005) mm, p < 0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations. [ABSTRACT FROM AUTHOR]

Investigates the frequency of the 3'-untranslated polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase one (PPP1R3) and its incorporation in Japanese patients with non-insulin-dependent diabetes or type two diabetes. Polymorphism frequency as increased in type two diabetic patients.