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Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in lipolytic processing. Previous studies have shown that GPIHBP1 mutations cause severe hypertriglyceridemia and that serum GPIHBP1 levels are marginally higher in patients with coronary heart disease; however, the role of GPIHBP1 in type 2 diabetes mellitus (T2DM) remains unknown.We investigated the association between circulating GPIHBP1 levels and the prevalence of microvascular complications in T2DM.A total of 237 subjects with T2DM and 235 non-diabetic control subjects were enrolled in this study. Their serum GPIHBP1 levels were evaluated using ELISA assays.Circulating GPIHBP1 levels were higher in patients with T2DM (952.7 pg/mL [761.3-1234.6], p0.0001) than in non-diabetic subjects (700.6 [570.8-829.6]), but did not differ in T2DM patients with or without hypertriglyceridemia. Serum GPIHBP1 levels were significantly higher in patients with T2DM with diabetic retinopathy (DR), diabetic nephropathy (DN), and microvascular complications than in those without these complications. Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses revealed that the presence of microvascular complications, but not macrovascular complications, was independently associated with serum GPIHBP1 levels, which could predict the presence of diabetic microvascular complications.Elevated GPIHBP1 levels are associated with microvascular complications in T2DM and may help to predict their progression.

Argonaute 2 (Ago2) is the main component of the RNA-induced silencing complex. We recently showed that liver-specific Ago2-deficiency in mice (L-Ago2 knockout [KO] mice) enhances mitochondrial oxidation and alleviates obesity-associated pathophysiology. However, the precise mechanisms behind the role of hepatic Ago2 in regulating the mitochondrial oxidation associated with glucose metabolism are still unclear. Here, we show that hepatic Ago2 regulates the function of peroxisome proliferator–activated receptor α (PPARα) for oxidative metabolism. In both genetically and diet-induced severe obese conditions, L-Ago2 KO mice developed obesity and hepatic steatosis but exhibited improved glucose metabolism accompanied by lowered expression levels of pathologic microRNAs (miRNAs), including miR-802, miR-103/107, and miR-152, and enhanced expression of PPARα and its target genes regulating oxidative metabolism in the liver. We then investigated the role of hepatic Ago2 in the outcomes of vertical sleeve gastrectomy (VSG) in which PPARα plays a crucial role in a drastic transcription reprogram associated with improved glycemia post VSG. Whereas VSG reduced body weight and improved fatty liver in wild-type mice, these effects were not observed in hepatic Ago2-deficient mice. Conversely, glucose metabolism was improved in a hepatic Ago2-dependent manner post VSG. Treating Ago2-deficient primary hepatocytes with WY-14643, a PPARα agonist, showed that Ago2-deficiency enhances sensitivity to WY-14643 and increases expression of PPARα target genes and mitochondrial oxidation. Our findings suggest that hepatic Ago2 function is intrinsically associated with PPARα that links Ago2-mediated RNA silencing with mitochondrial functions for oxidation and obesity-associated pathophysiology.

RNA silencing inhibits mRNA translation. While mRNA translation accounts for the majority of cellular energy expenditure, it is unclear if RNA silencing regulates energy homeostasis. Here, we report that hepatic Argonaute 2 (Ago2)-mediated RNA silencing regulates both intrinsic energy production and consumption and disturbs energy metabolism in the pathogenesis of obesity. Ago2 regulates expression of specific miRNAs including miR-802, miR-103/107, and miR-148a/152, causing metabolic disruption, while simultaneously suppressing the expression of genes regulating glucose and lipid metabolism, including Hnf1β, Cav1, and Ampka1. Liver-specific Ago2-deletion enhances mitochondrial oxidation and ATP consumption associated with mRNA translation, which results in AMPK activation, and improves obesity-associated pathophysiology. Notably, hepatic Ago2-deficiency improves glucose metabolism in conditions of insulin receptor antagonist treatment, high-fat diet challenge, and hepatic AMPKα1-deletion. The regulation of energy metabolism by Ago2 provides a novel paradigm in which RNA silencing plays an integral role in determining basal metabolic activity in obesity-associated sequelae., The RNA-induced silencing complex (RISC) represses gene expression via micro-RNA guided mRNA silencing. Here, the authors show that RISC component Argonaute 2 in the liver regulates energy metabolism by inducing microRNAs that cause metabolic disruption and by suppressing protein translation linked to AMPK activation.

Purpose The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice. Basic Procedures We selected four miRNAs, miR-101, miR-335, miR-375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT). Main Findings The serum concentrations of miRNAs, log 10 miR-101, log 10 miR-375, and log 10 miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41 ± 2.01 v.s . − 0.57 ± 1.05 (P = 1.36 × 10 − 5 ), 0.20 ± 0.58 v.s. 0.038 ± 1.00 (P = 3.06 × 10 − 6 ), and 2.45 ± 1.27 v.s . 0.97 ± 0.98 (P = 0.014), respectively). The log 10 miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (− 1.08 ± 1.35 v.s . − 0.38 ± 1.21 (P = 0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants. Principal Conclusions The present findings demonstrated that the circulating miR-101, miR-375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes.

Rationale: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. Objective: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. Methods and Results: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using 125 I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10 –9 m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca 2+ influx and subsequent apoptosis. Conclusions: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.

It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 2012

Telmisartan partially activates the peroxisome proliferator-activated receptor γ (PPARγ), which may ameliorate the accumulation of visceral adipose tissues and sensitise insulin action. Nineteen patients with essential hypertension and metabolic syndrome were randomly assigned to receive 40 mg of telmisartan (TELMI group) once daily or 80 mg of valsartan (VAL group) once daily for 24 weeks. The visceral fat area (VFA) measured by computed tomography (CT) was significantly reduced from 150.4±15.5 to 127.7±16.7 cm2 in the TELMI group ( p=0.049). Although VFA was also reduced in the VAL group from 169.8±14.8 to 155.3±14.8 cm2, the change was not significant ( p=0.173). There were no significant changes in body weight, body mass index (BMI), waist circumference, subdermal fat area (SFA), fasting plasma glucose, and homeostasis model assessment of insulin resistance (HOMA-IR) in comparison to the baseline and follow-up data in both groups. In conclusion, telmisartan may have a benefit in the reduction of visceral adipose tissues in comparison to valsartan.

A 27-year-old woman visited our hospital because of high fever. She had been diagnosed as 22q11.2 deletion syndrome (22q11.2DS) due to her cardiac history (tetralogy of Fallot), thymic hypoplasia and 22q11.2 deletion. She had a normal CD4/CD8 ratio, a slightly decreased lymphocyte count and normal serum immunoglobulin levels. Blood cultures were positive for Staphylococcus lugdunensis (S. lugdunensis). Infection route of S. lugdunensis in this case was unclear. The patient was successfully treated with several intravenous antibiotics. Infection should be considered when managing patients with 22q.11.2DS. regardless of whether their immune system is impaired.

A 53-year-old man visited our hospital complaining of high fever. Chest computed tomography showed left pleural effusion and mediastinitis. He developed painful red subcutaneous nodules in his bilateral lower extremities. Thoracoscopy-assisted exploratory excision showed visceral pleura thickening; panniculitis in the periaortic area was histologically proven. The patient was treated with corticosteroid therapy which immediately reduced the fever. Subsequent imaging examinations after corticosteroid therapy showed improvement of mediastinitis and pleural effusion. This case reminds us that Weber-Christian disease (WCD) should be included in the differential diagnosis of mediastinitis although WCD is rarely associated with thoracic involvement.

Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt−/− mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53 and Pemt−/− mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70.We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity.The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm1l and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opa1, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow.The Timm44 gene may be a new target for the treatment of type 2 diabetes.

Background Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (TH1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27Kip1 and p21Cip1. Methods We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n=182). Results Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 ± 105.4 pg/ml and Log10Gal-9 levels significantly and positively correlated with age (r=0.227, p=0.002), creatinine (r=0.175, p=0.018), urea nitrogen (r=0.162, p=0.028) and osmotic pressure (r=0.187, p=0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r=−0.188, p=0.011). Log10Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p=0.012). Log10Gal-9 levels remained similar levels in albuminuria stages of A1 to A3. Conclusion The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.

Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats. Objective: We investigated genetic and nongenetic factors that define serum concentrations of vaspin. Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138). Results: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950. Conclusions: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012)

A 46-year-old Japanese man visited our hospital for chronic abdominal pain, persistent diarrhea and discharge of proglottids for 7 years. He had been living in Lao People's Democratic Republic. Ileography using meglumine/diatrizoate sodium (Gastrografin) revealed a long tapeworm. A Taenia saginata including the scolex was excreted through the intestinal tract by the administration of total 780 ml of Gastrografin. Taeniasis is an important disease in the differential diagnosis of imported diseases in Japan. Parasite infection should be suspected in patients with chronic abdominal pain or persistent diarrhea regardless of the findings for small bowel obstruction when there is a history of overseas travel.

The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G0 + G1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G0 /G1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.

A 78-year-old woman visited our hospital complaining of high fever. Since the fever did not improve with antibiotics and nonsteroidal anti-inflammatory drugs, she was admitted to the hospital. On admission a test for C reactive protein demonstrated 17.0 mg/dL. She did not have tenderness or swelling in temporal arteries. She showed laterality in radial pulse and her left radial pulse was weakened. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) identified uptake of FDG in the aortic arch, abdominal aorta and left brachial artery, etc. (Picture 1). Magnetic resonance angiography (MRA) revealed left brachial artery stenosis (Picture 2). The presumable diagnosis of a giant cell arteritis (GCA) developing into brachial artery stenosis was made. The patient was treated with 30 mg/day of prednisolone, which immediately reduced the fever. Subsequent MRA after steroid therapy showed improvement of brachial artery stenosis (Picture 3). GCA may cause severe complications such as aortic aneurysm, dissec

We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Sia alpha 2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40 +/- 0.43; A2, 0.60 +/- 0.53; A3 1.57 +/- 1.13 ng/gCr; p = 7.29x10(-8)) and of GFR stages (G1, 0.39 +/- 0.39; G2, 0.49 +/- 0.45; G3, 1.25 +/- 1.18; G4, 1.34 +/- 0.80 ng/gCr; p = 3.89x10(-4)). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR