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Background: Renal hypoxia is an aggravating factor for tubulointerstitial damage, which is strongly associated with renal prognosis in diabetic kidney disease (DKD). Therefore, urinary markers that can detect renal hypoxia are useful for monitoring DKD. Objective: To determine the correlation between urinary liver-type fatty acid-binding protein (L-FABP) and renal hypoxia using a novel animal model of type 2 diabetes. Methods: Male spontaneously diabetic Torii (SDT) fatty rats (n = 6) were used as an animal model of type 2 diabetes. Age- and sex-matched Sprague-Dawley (SD) rats (n = 8) were used as controls. Body weight, systolic blood pressure, and blood glucose levels were measured at 8, 12, 16, and 24 weeks of age. Urine samples and serum and kidney tissues were collected at 24 weeks of age. Microvascular blood flow index (BFI) was measured using diffuse correlation spectroscopy before sampling both the serum and kidneys for the evaluation of renal microcirculation at the corticomedullary junction. Results: Obesity, hyperglycemia, and hypertension were observed in the SDT fatty rats. Focal glomerular sclerosis, moderate interstitial inflammation, and fibrosis were significantly more frequent in SDT fatty rats than in SD rats. While the frequency of peritubular endothelial cells and phosphoendothelial nitric oxide synthase levels were similar in both types of rats, the degree of renal hypoxia-inducible factor-1α (HIF-1α) expression was significantly higher (and with no change in renal vascular endothelial growth factor expression levels) in the SDT fatty rats. Urinary L-FABP levels were significantly higher and renal microvascular BFI was significantly lower in the SDT fatty rats than in the SD rats. Urinary L-FABP levels exhibited a significant positive correlation with renal HIF-1α expression and a significant negative correlation with renal microvascular BFI. Conclusions: Urinary L-FABP levels reflect the degree of renal hypoxia in DKD in a type 2 diabetic animal model. Urinary L-FABP may thus prove useful as a renal hypoxia marker for monitoring DKD in patients with type 2 diabetes in clinical practice.

Background: We previously reported changes of body composition determined by dual-energy X-ray absorptiometry after treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In that study, mean body weight was decreased by 3.5 kg (4.3% of the baseline value) after ipragliflozin treatment at 50 mg/day, with fat mass and lean mass showing similar reductions of 1.7 and 1.8 kg, respectively. A long-term decrease of lean mass in patients treated with SGLT2 inhibitors may be associated with loss of skeletal muscle, which could potentially have an impact on quality of life. Methods: In this post hoc analysis, we investigated whether changes of body composition were influenced by other medications for diabetes in 20 patients (11 men and nine women) who received ipragliflozin for 24 weeks. Results: When we divided the patients into two subgroups with or without metformin treatment, fat mass showed a significant decrease in the ipragliflozin + metformin subgroup and a significantly greater decrease compared to the ipragliflozin subgroup (2.0 kg; 95% confidence interval (CI): 0.1 - 3.9; P = 0.038). Lean mass was significantly decreased in the ipragliflozin subgroup, but the decrease showed no significant difference from that in the ipragliflozin + metformin subgroup (1.9 kg; 95% CI: -4.1 - 0.3; P = 0.087). No significant differences of body composition changes were observed with other antidiabetic agents. Conclusions: More desirable weight reduction due to preferential fat loss and less muscle loss may be achieved by combining an SGLT2 inhibitor with metformin. J Clin Med Res. 2019;11(4):297-300 doi: https://doi.org/10.14740/jocmr3785

We have previously demonstrated that eating glutinous brown rice (GBR) for 1 day or 8 weeks was well accepted and improved glycemic control in patients with type 2 diabetes. The present study evaluated whether eating GBR could also improve glucose metabolism in subjects without diabetes. A prospective 6-week, single-center, randomized, open-label, parallel-group study was carried out in subjects receiving annual medical checkup at our hospital. A total of 42 subjects were randomly assigned to continue their regular diet (RD group) or to switch GBR twice a day (GBR group). The primary outcome was the change in the serum concentration of 1,5-anhydroglucitol (1,5-AG) from baseline after the 6-week dietary intervention. One subject was excluded from the analysis because of a traffic accident. After 6 weeks, the serum 1,5-AG was significantly increased in the GBR group and the mean treatment difference (GBR group − RD group) was 1.1 µg/mL (95% CI: 0.6 to 1.6, p = 0.022 ). Body mass index decreased significantly in both groups, with no significant difference between them ( p = 0.210 ). There were no changes in fasting plasma glucose, fasting insulin, or eating behavior. Intake of GBR for 6 weeks significantly increased serum 1,5-AG in Japanese subjects without diabetes. The increase of 1,5-AG may have been due to the alleviation of postprandial hyperglycemia, which could be effective for the primary prevention of diabetes.

The impact of tofogliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on peripheral glucose uptake in patients with type 2 diabetes mellitus (T2DM) was investigated using the hyperinsulinaemic‐euglycaemic clamp method in a single‐arm, open‐label study. The following variables were compared between before and after tofogliflozin administration for 12 weeks in 16 patients with T2DM who were receiving dipeptidyl peptidase‐4 inhibitor treatment: body weight (BW); blood pressure; glucose metabolism; liver function; lipid profile; and body composition. Peripheral glucose uptake (M value and M/I ratio) was examined by the hyperinsulinaemic‐euglycaemic clamp method. After 12 weeks, there was a significant decrease (P < .001) in glycated haemoglobin, BW, body fat mass and lean body mass. Peripheral glucose uptake, which indicates insulin sensitivity, increased significantly (M value by 0.90 and M/I ratio by 0.49; both P < .05). The change in the M value after 12 weeks of tofogliflozin therapy was correlated with the change in body fat mass (P < .05). Tofogliflozin significantly improved insulin sensitivity and peripheral glucose uptake in patients with T2DM. These improvements were significantly correlated with reduction in body fat mass.

Background: The aim of this study was to evaluate effect of ezetimibe monotherapy on serum low-density lipoprotein cholesterol (LDL-C) in Japanese patients and to investigate the association between changes of LDL-C and changes of markers for cholesterol synthesis and absorption. Methods: Seventy-six hypercholesterolemic patients without statin therapy were enrolled and randomized to two groups, which were an ezetimibe group (group E, n = 44) and a control group without ezetimibe treatment that received diet therapy alone (group C, n = 32). The study period was 12 weeks. In group E, 10 mg of ezetimibe was administered daily after breakfast. Serum lipids were measured every 4 weeks, while lathosterol (a cholesterol synthesis marker) and campesterol and sitosterol (cholesterol absorption markers) were examined at baseline and at 12 weeks. Results: A significant reduction of LDL-C was observed in group E at both 4 and 12 weeks (from 155 ± 3.9 to 128 ± 3.4 mg/dL and 132 ± 3.9 mg/dL, respectively, both P < 0.01), associated with an increase of high-density lipoprotein cholesterol (HDL-C)at 12 weeks (from 53 ± 1.3 to 55 ± 1.5 mg/dL, P < 0.05) and no change of triglycerides. In contrast, none of these lipids changed in group C. An increase of lathosterol and a decrease of campesterol and sitosterol were observed in group E, while none of these markers changed in group C. When group E was divided into two subgroups according to the reduction of LDL-C, which were a good response group (reduction ≥ 20 mg/dL, ΔLDL-C = -27.9 ± 1.3 mg/dL, n = 18) and a poor response group (reduction < 20 mg/dL, ΔLDL-C = -3.7 ± 2.5 mg/dL, n = 26), baseline levels of campesterol and sitosterol were higher in the good response group. Conclusion: Ezetimibe monotherapy reduced LDL-C and increased HDL-C, with the reduction of LDL-C being greater in patients with higher levels of cholesterol absorption markers. J Clin Med Res. 2017;9(6):476-481 doi: https://doi.org/10.14740/jocmr2782w

We recently investigated the effect of ipragliflozin, a sodium glucose co-transporter-2 inhibitor (SGLT-2I), in Japanese patients with type 2 diabetes by a 24-week. SGLT-2Is also have an anti-obesity effect, and reduction of body fat has been demonstrated by indirect methods. However, evaluation of the effect on the total visceral fat volume and intrahepatic lipid content has not been performed.We measured the abdominal subcutaneous fat volume (SFV) and visceral fat volume (VFV) by whole abdominal CT scanning, the intrahepatic lipid (IHL) content by proton magnetic resonance spectroscopy (1H-MRS), and the fat mass index (FI) and appendicular skeletal mass index (ASMI) by dual X-ray absorptiometry (DXA) in 20 patients from our previous study.Administration of ipragliflozin at 50 mg/day for 24 weeks significantly reduced SFV, VFV, and IHL. FI and ASMI were also significantly decreased. Changes of VFV and IHL content at 12 weeks were significantly correlated with the change of HbA1c, but no correlation was observed at 24 weeks.These findings demonstrate that ipragliflozin decreases visceral and hepatic fat, with improvement of glycemic control possibly being attributable to these changes at least up to 12 weeks.

Background In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to

Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as 'glucotoxicity'. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio.After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.

We previously designed and reported a simple new method (the cold-loaded pain sensation test) for quantitative evaluation of the function of small nerve fibers. In the study reported here, we investigated the clinical usefulness of this test to evaluate diabetic neuropathy by comparison with a device for quantitative measurement of the neuroselective current perception threshold (CPT). We evaluated 68 diabetic patients without cerebrovascular disease. After cooling the test site, the recovery time (RT) required for pain sensation to return to an equivalent level to that on the noncooled side was evaluated. The rapid screening mode was employed to measure CPT. RT measured at the great toe (77.8 ± 43.2 s) was significantly longer than that measured at the medial malleolus (53.8 ± 30.0 s) (p

A variation of the response to Sodium glucose co-transporter 2 (SGLT2) inhibitors with age has not been investigated in patients with diabetes. The aim of this study was to assess renal threshold of glucose (RTg) before and after administration of an SGLT2 inhibitor in young adult patients (≤40 years) and older adult patients (40 years) with type 2 diabetes (T2DM).Twenty Japanese patients with T2DM were enrolled. Baseline data were obtained on the first day and dapagliflozin (5 mg) was administered at 6:00 on the second day. Glucose excursions were assessed by continuous glucose monitoring and urine samples were collected every hour during the daytime (7:00 to 15:00) on both days. RTg was estimated from the regression line of the scatter plot of the hourly mean glucose concentrations.After a single dose of dapagliflozin, RTg decreased from 121.5 to 6.1 mg/dl in the young adult group and from 151.0 mg/dl to -15.8 mg/dl in the older group. After dapagliflozin, the slope of the regression line was significantly steeper in the young adult group.Dapagliflozin was more effective in young patients because they showed a larger response of urinary glucose excretion.

We have reported the association of variations in the activating protein-2beta (AP-2beta) transcription factor gene with type 2 diabetes. This gene was preferentially expressed in 3T3-L1 adipocytes in a differentiation stage-dependent manner, and preliminary experiments showed that subjects with the disease-susceptible allele showed stronger expression in adipose tissue than those without the susceptible allele. Thus, we overexpressed the AP-2beta gene in 3T3-L1 adipocytes to clarify whether AP-2beta might play a crucial role in the pathogenesis of type 2 diabetes through dysregulation of adipocyte function. In cells overexpressing AP-2beta, cells increased in size by accumulation of triglycerides accompanied by enhanced glucose uptake. On the contrary, suppression of AP-2beta expression by small interfering RNA inhibited glucose uptake. Enhancement of glucose uptake by AP-2beta overexpression was attenuated by inhibitors of phospholipase C (PLC) and atypical protein kinase Czeta/lambda (PKCzeta/lambda), but not by a phosphatidylinositol 3-kinase (PI3-K) inhibitor. Consistently, we found activation of PLC and atypical PKC, but not PI3-K, by AP-2beta expression. Furthermore, overexpression of PLCgamma enhanced glucose uptake, and this activation was inhibited by an atypical PKC inhibitor, suggesting that the enhanced glucose uptake may be mediated through PLC and atypical PKCzeta/lambda, but not PI3-K. Moreover, we observed the increased tyrosine phosphorylation of Grb2-associated binder-1 (Gab1) and its association with PLCgamma, indicating that Gab1 may be involved in AP-2beta-induced PLCgamma activation. Finally, AP-2beta overexpression was found to relate to the impaired insulin signaling. We propose that AP-2beta is a candidate gene for producing adipocyte hypertrophy and may relate to the abnormal characteristics of adipocytes observed in obesity.

To evaluate the genetic susceptibility to metabolic disorders induced by high fructose diet, we investigated the metabolic characteristics in 10 strains of inbred mice and found that they were separated into CBA and DBA groups according to the response to high fructose diet. The hepatic mRNA expression of the sterol regulatory element-binding protein-1 (SREBP-1) in CBA/JN was remarkably enhanced by high fructose diet but not in DBA/2N. Similar results were observed in primary hepatocytes after exposure to fructose. The nucleotide sequence at -468 bp from the putative starting point of the SREBP-1c gene was adenine in the DBA group while it was guanine in the CBA group. In hepatocytes from CBA/JN, the activity of CBA-SREBP-1c promoter was significantly increased by 2.4- and 2.2-fold, in response to 30 mm fructose or 10 nm insulin, respectively, whereas the activity of DBA-SREBP-1c promoter responded to insulin but not to fructose. In hepatocytes from DBA/2N, both types of SREBP-1c promoter activities in response to insulin were attenuated. Furthermore, electrophoretic mobility shift assay revealed an unidentified nuclear protein bound to the oligonucleotides made from the region between -453 to -480 bp of the SREBP-1c promoter of CBA/JN but not to the probe from DBA/2N. Thus, in DBA/2N, the reduced mRNA expression of SREBP-1 after fructose refeeding appeared to associate with two independent mechanisms, 1). loss of binding of unidentified proteins to the region between -453 to -480 bp of the SREBP-1c promoter and 2). impaired insulin stimulation of SREBP-1c promoter activity.

The postprandial glucose (PPG) level is reduced by α-GIs, glinides and DPP4Is through different pharmacological actions. The aim of this study was to compare the effect of sitagliptin (S) versus that of the combination of mitiglinide and voglibose (M+V) on markers of glycemic control.A randomized cross-over trial was performed in 20 patients with drug-naïve type 2 diabetes. The patients were randomized to receive S (50 mg/day) or M+V (1 tablet 3 times daily). Treatment was continued for 8 weeks, after which they were switched to the other regimen and treated for another 8 weeks. At baseline, after the first regimen, and after the second regimen, a meal test was performed.The markers of glycemic control were examined.Reduction of glucose excursion was significantly greater with M+V than with S. HbA1c did not change with either regimen. However, 1,5-anhydroglucitol showed a significant increase from baseline with both regimens (7.9 ± 4.3 μg/ml at baseline vs. 10.6 ± 5.5 with S, p0.05 and 15.1 ± 6.2 with M+V, p0.01). Compared with baseline, glycoalbumin was significantly reduced by M+V, but not S (19.6 ± 2.9% at baseline vs. 17.3 ± 3.8% with M+V, p0.05).M+V achieved better control of PPG excursion than S.

By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness.

To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-α (PPARα) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARα as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARα protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg · kg−1· day−1) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARα protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to β-oxidation and the enhancement of mitochondrial gene expression.

An improved procedure for the syntheses of the two isomeric 8-chloro (4) and 11-chlorobenzanthrone (6) was devised and their condensation, by Ullmann reaction, to the corresponding dibenzanthronyls was achieved with the object of synthesizing violanthronyl derivatives.The product (mp 118°C) of reduction of 1-chloroanthraquinone (2) by Sn and glacial acetic acid which had been reported to be 4-chloro-9-anthrone (5), was found, by chromatographical separation, to be mixed crystals of two isomeric (5) (mp 137°C) and 1-chloro-9-anthrone (3) (mp 118°C), whose ratio was about 2 : 1.(5) was converted into pure (6) (mp 178°C) in 46% yield by the glycerol condensation. On the other hand, (4) (mp 182°C) obtained from (3) in this manner was the same product as the one obtained by the glycerol condensation of the reduction product of (2) in cone. H2SO4 with Al powder. (2) was converted into isomeric chlorobenzanthrones by a simultaneous reaction of reduction with aniline sulfate and condensation with glycerol. The product was separated by alumina chlomatography to (6) in 18% yield and (4) in 15% yield.Ullmann reaction of (4) and (6) was carried out in naphthalene, and 95% yield of 8, 8'-dibenzanthronyl was obtained from the former, while 11, 11'-dibenzanthronyl was obtained only in 7.8% yield from the latter.

9, 9'-Dihalogeno-3, 3-dibenzanthronyls were prepared as intermediates for the synthesis of diviolanthronyl, a possible high molecular weight dyestuff or a possible electric semiconductor. They were fine yellow crystals and dissolved in concentrated sulfuric acid to give a dark red solution.The 9, 9'-dichloro derivative, mp 4425°C, of 3, 3'-dibenzanthronyl (6) was prepared by the dehydrogenation condensation of 9-chlorobenzanthrone in the presence of magnesium dioxide. 9-Chlorobenzanthrone was obtained by the condensation of α-naphthyl-m-chlorophenylketone in the presence of aluminum chloride or by the partial reduction of 4, 9-dichlorobenzanthrone.Though the 9, 9'-diiodo derivatve, mp 4168°C, of (6) was synthesized in a similar manner from 9-iodobenzanthrone, the reaction was extremely slow and the yield was only 18%. 9-iodo-benzanthrone, mp 1979°C, was prepared in 88% yield by the Griess reaction of 9-aminobenzanthrone in concentrated sulfuric acid.When (6) was treated with an excessive amount of bromine, 9, 9'-dibromo-3, 3'- dibenzanthronyl, mp 4414°C, was obtained in 64% yield. The product was identical with the authentic sample obtained by the dehydrogenation condensation of 9- bromobezanthrone. The 9, 9'-dibromo derivative was also prepared by the bromination of (6) in the presence of catalysts such as aluminum halides.

ポリリン酸中で2,5-ビス(2-カルボキシアニリノ)-1,4-ベンゾキノン(I)の脱水閉環反応を行ない,鮮明な黄色のキノ[2,3-b]-アクリジン-6,7,13,14-(5H,12H)-テトロン(以下キナクリドン・キノン)(II)をIに対し74～76%の収率で得た。つぎに,5,12-ジヒドロ-キノ-(2,3-b)-アクリジン-7,14-ジオン(以下キナクリドン)(III)の合成を目的として,ポリリン酸とスズをもちいてIIを還元したが,この還元は5,6,12,13-テトラヒドロ-キノ-[2,3-b]アクリジン-7,14-ジオン(以下6,13-ジヒドロ・キナクリドン)(IV)を生成しやすく,還元生成物には多量に混在するので,これをアルカリ性アルコール中ニトロベンゼン-m-スルホン酸ナトリウムと処理して酸化し, IIに対し, 最高収率85%でIIIを得た。また,Iをポリリン酸中で閉環後,IIを単離せずにただちにスズを加えて還元し,ついで上と同様な酸化処理をほどこし,Iに対し82%の収率でIIIを得た。

メタクロレインをシアン化ナトリウム, ナトリウム, ナフタリン, トリブチルホスフィンその他で重合させた。トリフェニルホスフィンでは重合が起こらなかった。生成ポリマーの構造は開始剤の種類によって異なった。シアン化ナトリウムを用いた場合,-25℃ 以上の反応ではオレフィン重合が起こった。トリブチルホスフィンでは-78℃ でもオレフィン重合が起こった。カリウム,ナフタリンでは低温でカルボニル重合が主体となった。シアン化ナトリウムにより得られたポリメタクロレインを用いて, アセトフェノン, ベンジリデンアセトン, アセチルナフタリンおよびアセチルアントラセンとの反応を行なわせ, 不飽和ケトン構造を持つポリマーを合成した。ナトリウム, ナトリウムナフタリン,トリメチルベンジルアンモニウムヒドロキシドが触媒として有効に働いた。得られたポリマー不飽和ケトンは黄色固体で,可溶可融性であった。

キナクリドン(キノ[2,3-b]アクリジン-7,14-ジオン)(I)系化合物合成研究の一環として, まず出発物質にP-ベンゾキノン(II)とアントラニル酸(III)を選び, 酢酸中で縮合させて2,5-ジアニリノ-P-ベンゾキノン-o',o''-ジカルボン酸(IV)とし,ついで熱濃硫酸中で脱水閉環反応を行なわせてキナクリドン・キノン(キノ-[2,3-b]アクリジン-6,7,13,14-テトラオン)(V)を合成した。この化合物は試みた有機溶剤にほとんど溶解せず,従ってその精製を目的としてVをいったんカリウム塩とし,ついでこれを酢酸と煮沸してVを再生させ,高収率で純粋かつ鮮明な黄色結晶性粉末を得た。モノカリウム塩はカッ赤色針状結晶であるのに対して,ジカリウム塩は黄色粉末である。またVをアルカリ性ハイドロサルファイト溶液または塩酸とスズ粉末で還元し,両方の場合とも98%の収率で不溶性の青紫色のロイコ体粉末をえた。

Several new polyesters were synthesized by the reaction of ethylene glycol with such carbazoledi-carboxylic acids as carbazole-3, 6-dicarboxylic, 9-ethylcarbazole-3, 6-dicarboxylic, carbazole-3, 6-dibutanoic and 9-methylcarbazole-3, 6-dibutanoic acid in the presence of various catalysts.

1)p-ベンゾキノンと5-メチルアントラニル酸を酢酸中で縮合させて2,5-ビス-(2-カルボキシ-4-メチルアニリノ)-1,4-ベンゾキノン(I)とし,これを熱濃硫酸またはポリリン酸中で閉環させ,2,9-ジメチル-キノ-[2,3-b]-アクリジン-6,7,13,14-(5H,12H)-テトロン(以下2,9-ジメチル・キナクリドン・キノン)(II)を合成した。この化合物の精製を目的として粗製品を水酸化カリウムと処理してモノカリウム塩(III)とし,ついでこれを酢酸と煮沸してIIを再生させ,硫酸閉環法では79.2%,リン酸閉環法では84.3%の収率(それぞれIからの通算収率)で純粋かつ鮮明な燈黄色結晶性粉末を得た。IIIは褐色結晶である。また,IIを塩酸とスズで処理し,ロイコ・2,9-ジメチル・キナクリドン・キノン(IV)の青色粉末を得た。収率98.6%。2)p-ベンゾキノンと4-クロルアントラニル酸を酢酸中縮合させ, 2,5-ビス-(2-カルボキシ-5-クロルアニリノ)-1,4-ンゾキノン(V)とし,これを熱濃硫酸または,ポリリン酸中で閉環させ,3,10-ジクロル-キノ-[2,3-b]-アクリジン-6,7,13,14-(5H,12H)-テトロン(以下3,10-ジクロル・キナクリドン・キノン)(VI)を合成した。この化合物の精製を目的として粗製品を水酸化カリウムと処理してモノカリウム塩(VII)とし,ついでこれを酢酸と煮沸してVIを再生させ,硫酸閉環法では82%,リン酸閉環法では78.5%の収率(それぞれVからの通算収率)で,純粋かつ鮮明な黄色結晶性粉末を得た。VIIは赤褐色結晶である。また,VIを塩酸とスズで処理し,ロイコ・3,10-ジクロル・キナクリドン・キノン(VIII)の紫青色粉末を得た。収率98.9%。番号を付した化合物はすべて文献未記載である。

キナクリドン・キノン(I)ないしロイコ・キナクリドン・キノン(III)の6,13位のカルボニル基ないし水酸基をそれぞれ選択的に還元してキナクリドン(II)を合成した。還元剤として塩化アルミニウムー亜鉛末系を選び,融解法と溶剤法の二方法について行なった。両方法ともIIの新合成法である。融解法では所定混合比の塩化アルミニウム-食塩混融物にIを溶かし,亜鉛末を加えて還元し,その還元生成物をニトロベンゼン-m-スルホン酸ナトリウムと処理して短時間に良好な精製品収率(77%)でIIを得た。同様の条件下でIIIを還元した場合の収率は向上し,82%となった。また溶剤法ではさらに収率が向上した。すなわち,o-ジクロルベンゼン中塩化アルミニウム-亜鉛でIを還元し,その還元生成物をニトロベンゼン-m-スルホン酸ナトリウムと処理して精製品収率86%でIIを,また同様にして IIIからは収率90%でIIを得た。

As bifunctional derivatives of 3, 3'-dibenzanthronyl, 9, 9'-diamine (1) and 9, 9'-dicarboxylic acid (2) were synthesized for the purpose of preparing new condensation polymers. Compound (1) was prepared as follows. m-Nitrobenzoyl chloride was treated with naphthalene by Friedel-Crafts reaction to give m-nitrophenyl naphtyl ketone (5), mp 125°C, in 30% yield. The ring closure of (5) proceeded at 100°C with a mixture of AlCl3 and NaCl (5:1), then the reaction mixture was treated in the usual method and seperated chromatographically to give 9-nitrobenzanthrone (6) as pale yellow needles, mp 292°C, in 13.3% yield.The dehydrogenation-condensation of (6) was performed under the conditions similar to those for the syntheses of 3, 3'-dibenzanthronyl and its halogen derivatives to give 9, 9'-dinitro-3, 3'-dibenzanthronyl (7), mp>460°C, in 20% yield, which was identified by i.r. spectra and elemental analysis.(8) was reduced by Pd-charcoal and hydrazine hydrate in DMF, to give red violet crystalline powder, mp>500°C, which was identified as (1). (1) was also characterized by comparing with the product obtained by ammonolysis of 9, 9'-dichloro-3, 3'-dibenzanthronyl with 28% aq. ammonia in the presence of As2O5.3, 3'-Dibenzanthronyl-9, 9'-dicarboxylic acid (2), mp 431°C, was synthesized by the oxidation of 9, 9'-dimethyl derivative (16) with KMnO4 in pyridine. The structure of (2) was identified by elemental analysis, i.r. and mass spectrometry. (16) was prepared by the same method as (7), but with shorter reaction time, from 9-methylbenzanthrone (15), as pale yellow needles, mp 3836°C, in 20% yield. Ring closure of 1-naphthyl-m-toluylketone (14) proceeded easily according to Fieser, in 48% yield, but there remained some problems in the synthesis of intermediates, such as m-toluic acid.Partial oxidation of m-xylene is known to give m-toluic acid (12) but in poor yields (less than 10%). We have oxidized m-xylene by dil-HNO3 in the presence of Co salt of naphthenic acid, and obtained (12) (mp 112°C) in 17% yield. Friedel-Crafts condensation of m-toluyl chloride with naphthalene gave (14), mp 75°C, in 33% yield.

Though a pyrazole hydroazine vat dye (1) was formed by the direct cyclization of pyrazoleanthrone with 1-amino-2-bromoanthraquinone, the yield was as low as 10%. I, however, was obtained in 58% over-all yield in a two -step synthesis via cyclization of the intermediate, 2-(1'-amino-2-anthraquinonyl)-pyrazoleanthrone, in pyridine-methanol containing potassium hydroxide . 2-(2'-Aminophenyl)-pyrazoleanthrone was also readily cyclized into a pyrazole hydroazine compound . Similar reactions using 2-(3'-pyrazoleanthronyl)-pyrazoleanthrone and 3-anilino - pyrazoleanthrone, however, failed to take place. It is assumed that the cyclization reaction proceeds through a link formation between a -NH anion formed as shown below and a carbonium cation induced by the electron withdrawing effect of the carbonyl group in the pyrazoleanthrone ring.

フッ化ホウ素エーテラート, トリエチルアルミニウムその他のイオン触媒を用いて, メタクロレインを重合し, 生成ポリマーの構造を検討した。塊重合ではポリマー収率が低かった。生成ポリマーは白色粉末で,エチレンジクロリド,ピリジンに可溶で,メタノール不溶の高分子部,[η]=0.06～0.09と,メタノール可溶の低分子部,[η]=0.03に分けられ,前者は220℃ 付近でとけ, 後者は100℃ 付近でとけた。生成ポリマーの構造は触媒の種類により, また反応条件によって異なるが,いずれもオレフィン重合,カルボニル重合の混ったものであり,1,4-付加重合も若干は混っているが,前二者に比べて少なかった。同一触媒を用いた重合でば,反応温度の低いほど,反応時間の長いほど,生成ポリマー中のアルデヒド含量が少なかったが,これは温度の低いほどアルデヒドが重合し易く,時間の長いほどアルデヒドの2次的反応が

SummaryIn patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM.

シアン化ナトリウム, ナトリウムナフタリンを始めとする各種無機, 有機のナトリウム化合物および各種アミンを開始剤としてクロトンアルデヒドの重合性を検討した。ナトリウム化合物を開始剤とした場合は,母体酸のpKa値が3～5以上から重合触媒能を持ち,アミン,ホスフィンを開始剤とした場合はPKa値が8.4以上から重合触媒能を持っていた。開始剤の塩基性が増すにつれて,低温でも重合触媒能を持つようになった。低温より高温になるにつれて,アルデヒドのカルボニル重合よりオレフィン重合を経て,水素転位重合が起こり易くなった。

Acetylation of carbazole with acetyl halide or acetic anhydride gave both monoacetyl and diacetylcarbazoles. Several carbazoledicarboxylic acids were prepared in quantative yields by oxidizing the corresponding diacetylcarbazoles.

ピレン-1-スルホン酸(I) はピレン(II) の低温スルホン化でつくられるが, われわれはIIをa) 硫酸(III) と硫酸ナトリウム(IV) の等モル混合物, またはb ) 硫酸水素ナトリウム(V) と150℃以上に加熱, そののち熱湯抽出という簡単な操作でIを好収率で得た。IIに対してIIIおよびIV各3モル比,180℃,6時間または150℃,11時間でIのナトリウム塩(ほとんど純粋)の収率100%,各2モル比のときは180℃,6時間で収率93%。硫酸がIVに対し等モルまたはそれ以下のときは反応条件を強めてもIのみが生成するが,等モルより多いときは,わずか過剰でもジスルホン酸の副生が認められる。bの場合は対応するa の場合よりも収率がやや低い。たとえばI に対してVを5.6モル比(IIとIII各2.8モル比に相当),180℃,6時間でIの塩の収率80%。冷却下にクロルスルホン酸を用い溶媒中で長時間かきまぜる文献の方法にくらべて,収率,反応時間,操作の点ですぐれていると考えうる。

プロピオンアルデヒドとホルムアルデヒドより酸触媒下にメタクロレインを合成した。フルオロホウ酸を触媒とすると,95℃,1～2時間の反応でプロピオンアルデヒドを基準として変化率24～36%,収率90～85%でメタクロレインが得られた。フッ化ホウ素水加物触媒の有効成分は分解して生じたフルオロホウ酸である。硫酸触媒の場合は変化率25～51%,収率84～70%であった。反応はホルムアルデヒドをプロピオンアルデヒドに対して等モル以上用いる必要があった。用いた触媒の有効性の序列は下記の通りであった。

第一級アミノ基を主鎖に持つポリマーは,その合成法が比較的複雑,困難なため収率も悪く,純度の点においてもまだ問題があるといわれている。そこでポリアクリルアミドを出発原料とするホフマン分解によりポリビニルアミンとその塩酸塩の合成法を研究した。出発原料のポリアクリルアミドは,アゾビスイソブチロニトリルを開始剤としてラジカル溶液重合を行なって得,その粘度平均分子量は45000であった。このポリアクリルアミド水溶液中でアルカリ性臭素溶液を反応させ,アセトンを沈殿剤としてポリビニルアミンを収率70%で得た。また,ホフマン分解後,この反応液中に6N塩酸を加えてポリビニルアミン塩酸塩を収率72%で得た。このものは,水には溶解するが,メタノール,酢酸,アセトンには溶解しない。元素分析,電位差滴定および伝導度滴定,赤外吸収スペクトルによってこの高分子の組成を検討した結果,この高分子は,94%のビニルアミン塩酸塩単位を持っており,残りはアクリル酸単位と未反応アクリルアミド単位であることが判った。