Long-term effectiveness of a disease management program to prevent diabetic nephropathy: a propensity score matching analysis using administrative data in Japan.

BACKGROUND: Existing reviews indicated that disease management for patients with diabetes may be effective in achieving better health outcomes with less resource utilization in the short term. However, the long-term results were inconsistent because of the heterogeneous nature of the study designs. In the present study, we evaluated the 5-year follow-up results of a local disease management program focused on diabetic nephropathy prevention under the universal public health insurance scheme in Japan. METHODS: Patients diagnosed with type 2 diabetes who had stage 3 or 4 diabetic kidney disease and were aged between 20 and 75 years were invited to join a disease management program to support self-management and receive a recommended treatment protocol between 2011 and 2013. Follow-up data were collected from an electronic claims database for the public insurance scheme. Considering the non-random selection process, we prepared two control groups matched by estimated propensity scores to compare the incidence of diabetes-related complications, death, and resource utilization. RESULTS: The treatment group was more likely to receive clinical management in accordance with the guideline-recommended medication. After propensity score matching, the treatment group had lower incidence of diabetic nephropathy and emergency care use than the control group selected from a beneficiary pool mainly under primary care. Comparisons between the treatment group and the control group with more selected clinical conditions did not show differences in the incidence rate and resource utilization. CONCLUSIONS: The present results demonstrated limited effectiveness of the program for reducing complication incidence and resource utilization during the 5-year follow-up. Further research on the long-term effectiveness of co-management by primary care physicians, subspecialists in endocrinology and nephrology, and nurse educators is required for effective management of diabetes-related nephropathy.

Characteristics of heart failure patients incurring high medical costs via matching specific health examination results and medical claim data: a cross-sectional study.

OBJECTIVE: We describe the characteristics of patients with high medical costs by matching specific annual medical examination results and medical claim data. Clarifying the relationships between examination items and high medical costs allows the screening of high-risk persons. DESIGN: A cross-sectional study. SUBJECTS: Subjects were persons insured by national health insurance in Hiroshima City, Hiroshima Prefecture, from April 2016 to March 2017. To identify true heart failure (HF) patients, the disease name listed in the medical claim data was compared with drugs prescribed for HF, with extraction of only subjects whose comparative data matched. DATA COLLECTION AND ANALYSIS: The specific health examination includes a questionnaire on areas such as lifestyle habits, anthropometry, blood pressure, blood tests and urine tests. The percentage of the total medical costs related to the medical care of subjects with HF was described using Pareto analysis. For specific health examination items, we compared the high-cost and low-cost groups. The normality and homoscedasticity of each variable was checked and Student's t-tests and χ² tests were applied. Finally, multiple logistic regression analysis was used to detect factors in the health examination items related to high medical costs. RESULTS: Pareto analysis showed that 80% of all medical costs were paid by 30% of the HF patient population. The fees for cardiovascular surgery accounted for 54% of the total surgical cost, 64% of which included preventable diseases. Levels of creatinine (Cr) and γ-glutamyl transpeptidase (γ-GTP) and a history of smoking were found to be related to high medical costs. CONCLUSION: Analysis of specific health examination results for HF patients revealed the association between high medical costs, γ-GTP, Cr, and smoking. These results can thus serve as a reference for screening persons at high risk of HF and help prevent the exacerbation of HF.

Identification of a novel advanced glycation end product derived from lactaldehyde.

Advanced glycation end products (AGEs) are implicated in the development of diabetic complications via the receptor for AGEs (RAGE). We have reported that the 3-hydroxypyridinium (3HP)-containing AGEs derived from α-hydroxyaldehydes physically interact with RAGE and show cytotoxicity. Lactaldehyde (LA) is formed from a reaction between threonine and myeloperoxidase, but no LA-derived AGEs have been characterized. Here, we identify the structure and physiological effects of an AGE derived from LA. We isolated a novel 3HP derivative, 2-acetamido-6-(3-hydroxy-5-methyl-pyridin-1-ium-1-yl)hexanoate, named as N-acetyl-LAPL (lactaldehyde-derived pyridinium-type lysine adduct), from a mixture of LA with Nα-acetyl-L-lysine. LAPL was also detected in the LA-modified protein. LAPL elicited toxicity in PC12 neuronal cells, but the effect was suppressed by the soluble form of RAGE as a decoy receptor. Moreover, surface plasmon resonance-based analysis revealed that LAPL specifically binds to recombinant RAGE. These results indicate that LA generates an AGE containing the 3HP moiety and contributes to RAGE-dependent cytotoxicity. Abbreviations: AGEs: advanced glycation end products; RAGE: receptor for advanced glycation end products; 3HP: 3-hydroxypyridinium; LA: lactaldehyde; LAPL: lactaldehyde-derived pyridinium-type lysine adduct; BSA: bovine serum albumin; GLAP: glyceraldehyde-derived pyridinium; MPO: myeloperoxidase; HFBA: heptafluorobutyric acid; TFA: trifluoroacetic acid; HPLC: high performance liquid chromatography; LC-ESI-QTOF-MS: liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry; NMR: nuclear magnetic resonance; LA-BSA: lactaldehyde-modified bovine serum albumin; PBS: phosphate buffered saline, GST, glutathione S-transferase; SPR: surface plasmon resonance; OP-lysine: 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate; GLO1: glyoxalase 1; MG, methylglyoxal.

Identification of pyridinoline, a collagen crosslink, as a novel intrinsic ligand for the receptor for advanced glycation end-products (RAGE).

Advanced glycation end-products (AGEs) elicit inflammatory responses via the receptor for AGEs (RAGE) and participate in the pathogenesis of diabetic complications. An earlier study showed that 3-hydroxypyridinium (3-HP), a common moiety of toxic AGEs such as glyceraldehyde-derived pyridinium (GLAP) and GA-pyridine, is essential for the interaction with RAGE. However, the physiological significance of 3-HP recognition by RAGE remains unclear. We hypothesized that pyridinoline (Pyr), a collagen crosslink containing the 3-HP moiety, could have agonist activity with RAGE. To test this hypothesis, we purified Pyr from bovine achilles tendons and examined its cytotoxicity to rat neuronal PC12 cells. Pyr elicited toxicity to PC12 cells in a concentration-dependent manner, and this effect was attenuated in the presence of either the anti-RAGE antibody or the soluble form of RAGE. Moreover, surface plasmon resonance-based analysis showed specific binding of Pyr to RAGE. These data indicate that Pyr is an intrinsic ligand for RAGE. ABBREVIATIONS: AGEs: advanced glycation end-products; RAGE: receptor for advanced glycation end-products; DAMPs: damage-associated molecular patterns; PRR: pattern recognition receptor; TLR: toll-like receptor; GLAP: glyceraldehyde-derived pyridinium; 3-HP: 3-hydroxypyridinium; Pyr: pyridinoline; HFBA: heptafluorobutyric acid; GST: glutathione S-transferase; SPR: surface plasmon resonance; ECM: extracellular matrix; EMT: epithelial to mesenchymal transition.

Receptor for advanced glycation end products (RAGE)-mediated cytotoxicity of 3-hydroxypyridinium derivatives.

Advanced glycation end products (AGEs) formed from glyceraldehyde (Gcer) and glycolaldehyde (Gcol) are involved in the pathogenesis of diabetic complications, via interactions with a receptor for AGEs (RAGE). In this study, we aimed to elucidate the RAGE-binding structure in Gcer and Gcol-derived AGEs and identify the minimal moiety recognized by RAGE. Among Gcer and Gcol-derived AGEs, GLAP (glyceraldehyde-derived pyridinium) and GA-pyridine elicited toxicity in PC12 neuronal cells. The toxic effects of GLAP and GA-pyridine were suppressed in the presence of anti-RAGE antibody or the soluble form of RAGE protein. Furthermore, the cytotoxicity test using GLAP analog compounds indicated that the 3-hydroxypyridinium (3-HP) structure is sufficient for RAGE-dependent toxicity. Surface plasmon resonance analysis showed that 3-HP derivatives directly interact with RAGE. These results indicate that GLAP and GA-pyridine are RAGE-binding epitopes, and that 3-HP, a common moiety of GLAP and GA-pyridine, is essential for the interaction with RAGE.

Observation of magnetic interactions between localized 4f- and itinerant π-electrons in a single crystal of cationic bisphthalocyanine complexes containing diluted spin centres.

Magnetic f-π interactions between localized 4f-electrons and itinerant π-electrons have been observed in a single crystal of bisphthalocyaninato yttrium(iii)/terbium(iii) tetrafluoroborate ([Pc2Y0.95Tb0.05][BF4]) by measuring electrical conductivity of the crystal in the presence of an external magnetic field.

Analysis of the cooked aroma and odorants that contribute to umami aftertaste of soy miso (Japanese soybean paste).

Soy miso, the traditional Japanese fermented soybean paste prepared using soybean koji, is used for imparting umami aftertaste to cooked dishes. The objective of this study was to identify the key odorants of cooked soy miso and their influence on umami aftertaste perception. Volatile compounds of soy miso and two rice misos were prepared using simultaneous distillation-extraction, and the key odorants were identified by using the gas chromatography-olfactometry/aroma extract dilution assay approach, and soy miso was compared with rice misos. Forty-one aroma-active compounds were detected in cooked soy miso, and malty, green, roasty and sulfury aromas were identified as the characteristic aromas. Finally, sensory evaluation was conducted to assess the contribution to the umami aftertaste of six key compounds with the highest flavour dilution factor. Results revealed that dimethyl trisulfide, which was newly identified in cooked miso, contributes to the umami aftertaste and palatability of cooked soy miso.

Identification of the blue pigment formed in a D-glucose-glycine reaction system.

D-Glucose (0.7 M), glycine (0.3 M), and sodium hydrogencarbonate (0.1 M) were dissolved in aqueous 30% ethanol at pH 8.0 and left at 50 °C for 4 d in a dark room under nitrogen displacement. The resulting blue pigment was isolated and purified from the blue solution by anionic exchange and gel filtration chromatography. This blue pigment, which is designated Blue-G1, was identified as 5-[1,4-bis-carboxymethyl-5-(2,3,4-trihydroxybutyl)-1,4-dihydropyrrolo[3,2-b]pyrrol-2-ylmethylene]-1,4-bis-carboxymethyl-2-(2,3,4-trihydroxybutyl)-4,5-dihydropyrrolo[3,2-b]pyrrol-1-ium. Blue-G1 had two symmetrical pyrrolopyrrole structures with a trihydroxybutyl group. Blue-G1 had a polymerizing activity, suggesting it to be an important Maillard reaction intermediate through the formation of melanoidins.

Identification of red pigments formed in a D-xylose-glycine reaction system.

Blue, red, and yellow pigments were formed in the D-xylose (1 M)-glycine (0.1 M) reaction system. Novel red pigments were isolated and purified from the reaction solution, designated Red-M1 (red Maillard intermediate-1) and Red-M2 (red Maillard intermediate-2). Red-M1 was identified as 1,4,6,9-tetracarboxymethyl-5-(1,2,3,4-tetrahydroxybutyl)-8-hydroxymethyl-3-(2,3-dihydroxypropyl)-5,6-dihydro-pyrrolo[2',3':4,5]pyrrolo[2,3-e]pyrrolo[3,2-b]azepine-9-ium. NMR and CD data indicated that Red-M2 was a diastereomer of Red-M1. They are assumed to be important Maillard reaction intermediates through the formation of melanoidins as well as blue pigments.

Biochemical and genomic analysis of neoculin compared to monocot mannose-binding lectins.

Neoculin occurring in an edible tropical fruit is a heterodimeric protein which has both sweetness and a taste-modifying activity that converts sourness to sweetness. Both the primary and the overall tertiary structures of neoculin resemble those of monocot mannose-binding lectins. This study investigated differences in biochemical properties between neoculin and the lectins. Structural comparison between the mannose-binding sites of lectins and the corresponding regions of neoculin showed that there is at least one amino acid substitution at each site in neoculin, suggesting a reason for the lack of its mannose-binding ability. This was consistent with hemagglutination assay data demonstrating that neoculin had no detectable agglutinin activity. DNA microarray analysis indicated that neoculin had no significant influence on gene expression in Caco-2 cell, whereas kidney bean lectin (Phaseolus vulgaris agglutinin) greatly influenced various gene expressions. These data strongly suggest that neoculin has no lectin-like properties, encouraging its practical use in the food industry.

The formation of argpyrimidine in glyceraldehyde-related glycation.

Three major glyceraldehyde-related advanced glycation end products (AGEs) were formed from a mixture of N(alpha)-acetyllysine, N(alpha)-acetylarginine, and glyceraldehyde. Two of the compounds were MG-H1 and GLAP, as previously reported, and the other compound was identified as N(alpha)-acetyl-N(delta)-(5-hydroxy-4,6-dimethyl-pyrimidin-2-yl)-ornithine, argpyrimidine (APN). APN is a modification product of arginine residue, but it did not form from glyceraldehyde with arginine residue. The coexistence of lysine residue was necessary to APN formation.

Formation mechanisms of melanoidins and fluorescent pyridinium compounds as advanced glycation end products.

The formation mechanisms of melanoidins as advanced glycation end products (AGEs) have not been resolved. Blue and red pigments generated in the D-xylose-glycine reaction system are postulated to be intermediate oligomers in the generation of melanoidins. A novel blue pigment, designated blue-M5, was identified as a similar structure to blue-M1 except for the side chain of two dihydroxypropyl groups. Blue pigments were also generated in the D-glucose-glycine and D-xylose-beta-alanine reaction systems as well as in the D-xylose-glycine reaction system. Blue pigments by the Maillard reaction might be formed by the decarboxylation of two molecules of pyrrolopyrrole-2-carbaldehydes (PPA). PPA, composed of a side chain of a dihydroxypropyl group, was identified as a precursor of blue pigments. In fact, blue-M5 was generated by the incubation of PPA alone. Blue pigments, which involved pyrrolopyrrole structures, were readily changed to brown polymers. Glyceraldehyde-derived pyridinium (GLAP) compound, a glyceraldehyde-derived fluorescent AGE, and lysyl-pyrropyridine, a 3-deoxyglucosone-derived fluorescent AGE, were detected at higher levels in the plasma proteins and the tail tendon collagen of streptozotocin-induced diabetic rats compared to normal rats. GLAP and lysyl-pyrropyridine, therefore, might be related to the progression of diabetic complications.

Identification and determination of alpha-dicarbonyl compounds formed in the degradation of sugars.

The alpha-dicarbonyl compounds formed in the degradation of glucose and fructose were analyzed by HPLC using 2,3-diaminonaphthalene as derivatizing reagent, and identified as glucosone (GLUCO), 3-deoxyglucosone (3DG), 3-deoxyxylosone (3DX), tetrosone (TSO), triosone (TRIO), 3-deoxytetrosone (3DT), glyoxal (GO), and methylglyoxal (MGO). The results suggest that alpha-dicarbonyl compounds were formed from glucose via non-oxidative 3-deoxyglucosone formation and oxidative glucosone formation in glucose degradation. In addition, TRIO, GO, and MGO were also formed from glyceraldehyde as intermediate. The alpha-dicarbonyl compounds might be formed from glucose via these pathways in diabetes.

Determination of glyceraldehyde formed in glucose degradation and glycation.

Glyceraldehyde (GLA) was determined in glucose degradation and glycation. GLA was detected as a decahydroacridine-1,8-dione derivative on reversed phase HPLC using cyclohexane-1,3-dione derivatizing reagent. The glucose-derived GLA level was higher than the glycation-derived GLA level, because GLA was converted to intermediates and advanced glycation end products (AGE) in glycation. GLA was also generated from 3-deoxyglucosone and glucosone as intermediates of glucose degradation and glycation. This study suggests that glyceraldehyde is generated by hyperglycemia in diabetes, and that it is also formed in medicines such as peritoneal dialysis solution.

Detection and determination of glyceraldehyde-derived pyridinium-type advanced glycation end product in streptozotocin-induced diabetic rats.

GLAP, glyceraldehyde-derived pyridinium-type advanced glycation end product (AGE), formed by glyceraldehyde-related glycation, was identified in the plasma protein and the tail tendon collagen of streptozotocin (STZ)-induced diabetic rats. It was detected in the plasma protein and the collagen in diabetic rats by LC-MS and LC-MS/MS analysis, but was not detected in normal rats. In addition, GLAP was formed from glyceraldehyde-3-phosphate (GA3P) with lysine as well as glyceraldehyde (GLA) with lysine in vitro. Accordingly, it is suggested that an increase in the GLAP level reflects an increase in the GLA level and the GA3P level. GLAP might be a biomarker for reduced activity of the glyceraldehyde-related enzymes in the metabolic diseases such as diabetic complications.

Chemistry and some biological effects of model melanoidins and pigments as Maillard intermediates.

Various pigments were formed in the D-xylose-glycine reaction system. Blue pigments (Blue-M1 and Blue-M2) and red pigments (Red-M1 and Red-M2) were generated in the Maillard reaction. Blue-M2 is presented to have been generated by the reaction between Blue-M1, which involved two pyrrolopyrrole structures as the major blue pigment, and di-D-xyluloseglycine. We identified red pigments as the isomers of addition compounds of D-xyluloseglycine to condensated compound between pyrroropyrrole-2-carbaldehyde and pyrrole-2-carbaldehyde compounds. These pigments have polymerizing activities, suggesting that they are important Maillard reaction intermediates through the formation of melanoidins. Blue-M1 as well as melanoidins effectively suppressed the peroxidation of linoleic acid. The scavenging activity toward Blue-M1 on hydroxyl and DPPH radicals was also as strong as that of melanoidins. Furthermore, Blue-M1 prevents the oxidative cell injury. Therefore, Blue-M1 will be an antioxidant which protects against the oxidative stress in biological systems. Melanoidins induced IFN-gamma mRNA and IL-12 mRNA expressions in spleen cells exposed to allergen and in macrophage-like J774.1 cells, respectively. These findings suggest that melanoidins have suppressive effect on allergic reaction as a novel physiological effect.

Identification of a novel blue pigment as a melanoidin intermediate in the D-xylose-glycine reaction system.

Some blue pigments were formed in the D-xylose (1 M)-glycine (0.1 M) reaction system. A novel blue pigment, designated as Blue-M2 (blue Maillard intermediate-2), was identified as 5-[1,4-dicarboxymethyl-5-(2,3-dihydroxypropyl)-1,4-dihydropyrrolo[3,2-b]pyrrole-2-ylmethylene]-1,4-dicarboxymethyl-2-{5-[N-carboxymethyl(2,3,4-trihydroxytetrahydrofuran-2-yl)methylamino]-2-hydroxymethyl-4-(1,2,3-trihydroxypropyl)tetrahydrofuran-3-yl}-4,5-dihydropyrrolo-[3,2-b]pyrrole-1-ium. Blue-M2 is presumed to have been generated by the reaction between Blue-M1, which was identified as the major blue pigment in a previous paper (Hayase et al., Biosci. Biotechnol. Biochem., 63, 1512-1514 (1999)), and di-D-xyluloseglycine. Blue pigments are important Maillard reaction intermediates through the formation of melanoidins.

Non-involvement of the human monocarboxylic acid transporter 1 (MCT1) in the transport of phenolic acid.

Phenolic acids such as p-coumaric acid and microbial metabolites of poorly absorbed polyphenols are absorbed by the monocarboxylic acid transporter (MCT)-mediated transport system which is identical to the fluorescein/H(+) cotransport system. We focus here on the physiological impact of MCT-mediated absorption and distribution. We examined whether MCT1, the best-characterized isoform found in almost all tissues, is involved in this MCT-mediated transport system. The induction of MCT1 expression in Caco-2 cells by a treatment with sodium butyrate (NaBut) did not increase the fluorescein permeability. Moreover, the transfection of Caco-2 cells with an expression vector encoding MCT1 caused no increase in either the permeability or uptake of fluorescein. Furthermore, in the MCT1-expressing oocytes, no increase of p-coumaric acid uptake was apparent, whereas the uptake of salicylic acid, a substrate of MCT1, nearly doubled. Our data therefore establish that MCT1 was not involved in the MCT-mediated transport of phenolic acids.

Isolation and identification of 5-methyl-imidazolin-4-one derivative as glyceraldehyde-derived advanced glycation end product.

We isolated and identified the glyceraldehyde-derived advanced glycation product (AGE) formed from glyceraldehyde and N(alpha)-acetylarginine. A major product was identified as N(alpha)-acetyl-N(delta)-(5-methyl-imidazolin-4-one-2-yl)-ornithine. The compound has been reported as methylglyoxal-derived AGE, MG-H1. This study suggests that MG-H1 is formed through both glyceraldehyde-related and methylglyoxal-related pathways. There is a possibility that MG-H1 becomes an index of injury to glyceraldehyde and methylglyoxal-related enzymes.

Chemistry and biological effects of melanoidins and glyceraldehyde-derived pyridinium as advanced glycation end products.

Blue pigments (blue-M1 and blue-M2) and red pigments (red-M1 and red-M2) were generated in a xylose-glycine reaction system. Blue-M2 was identified as an addition compound of di-xylulose-glycine to blue-M1 that involved two pyrrolopyrrole structures. We identified red pigments as isomers of addition compounds of xylulose-glycine to the condensed compound between pyrrolopyrrole-2-carbaldehyde and pyrrole-2-carbaldehyde. These pigments have polymerizing activity, suggesting that they are important Maillard reaction intermediates through the formation of melanoidins. Melanoidins induced IFN-gamma and IL-12 expression in spleen cells exposed to allergen and in macrophages, respectively. These findings suggest that melanoidins have a suppressive effect on allergic reaction as a novel physiological effect. On the other hand, we identified a glyceraldehyde-derived advanced glycation end product (AGE) formed from glyceraldehyde and N-acetylarginine as well as glyceraldehyde-derived pyridinium (GLAP) in physiological conditions. The AGE was identified as 5-methylimidazoline-4-one (MG-H1), which has been reported to be formed from arginine and methylglyoxal. GLAP, which induced reactive oxygen species (ROS) production in HL-60 cells, is supposed to be a toxic AGE, while MG-H1 is a nontoxic AGE.