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Background: Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear. Methods: Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease. Results: During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24-2.55, P = 0.002) and Calsepa [High-Man (Man2-6)]: 1.56 (1.19-2.04, P = 0.001). Common glycan binding to these lectins was high-mannose type of N-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001-0.055, P = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045-0.692, P = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively]. Conclusion: The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal N-glycosylation occurring in patients with diabetes at higher risk of CVE. Trial Registration: This study was registered with the University Hospital Medical Information Network on June 26, 2012 (Clinical trial number: UMIN000011525, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013482).

DOI： 10.3389/fcvm.2021.668059

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The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

DOI： 10.1038/s41598-020-71946-3

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The leptin receptor-deficient db/db mouse model is an accepted in vivo model to study obesity, type 2 diabetes, and diabetic kidney disease. Healthy gastrointestinal (GI) microbiota has been linked to weight loss, improved glycemic control, and physiological benefits. We investigated the effect of various drugs on the GI microbiota of db/db mice as compared to control db/m mice. Treatment with long-acting pirfenidone (PFD) increased gut microbial diversity in diabetic db/db mice. Firmicutes, the most abundant phylum in db/m mice, decreased significantly in abundance in db/db mice but showed increased abundance with long-acting PFD treatment. Several bacterial taxa, including Lactobacillus and some Bacteroides, were less abundant in db/db mice and more abundant in long-acting-PFD-treated db/db mice. Long-acting PFD treatment reduced the abundance of Akkermansia muciniphila (5%) as compared to db/db mice (~15%). We conclude that gut microbial dysbiosis observed in db/db mice was partially reversed by long-acting PFD treatment and hypothesize that PFD has beneficial effects, in part, via its influence on the gut microbial metabolite profile. In quantitatively assessing urine metabolites, we observed a high abundance of diabetic ketoacidosis biomarkers, including 3-hydroxybutyric acid and acetoacetic acid in db/db mice, which were less abundant in the long-acting-PFD-treated db/db mice.

DOI： 10.3390/microorganisms8091347

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Exposure to chronic hyperglycemia because of diabetes mellitus can lead to development and progression of diabetic kidney disease (DKD). We recently reported that reduced superoxide production is associated with mitochondrial dysfunction in the kidneys of mouse models of type 1 DKD. We also demonstrated that humans with DKD have significantly reduced levels of mitochondrion-derived metabolites in their urine. Here we examined renal superoxide production in a type 2 diabetes animal model, the db/db mouse, and the role of a mitochondrial protectant, MTP-131 (also called elamipretide, SS-31, or Bendavia) in restoring renal superoxide production and ameliorating DKD. We found that 18-week-old db/db mice have reduced renal and cardiac superoxide levels, as measured by dihydroethidium oxidation, and increased levels of albuminuria, mesangial matrix accumulation, and urinary H2O2 Administration of MTP-131 significantly inhibited increases in albuminuria, urinary H2O2, and mesangial matrix accumulation in db/db mice and fully preserved levels of renal superoxide production in these mice. MTP-131 also reduced total renal lysocardiolipin and major lysocardiolipin subspecies and preserved lysocardiolipin acyltransferase 1 expression in db/db mice. These results indicate that, in type 2 diabetes, DKD is associated with reduced renal and cardiac superoxide levels and that MTP-131 protects against DKD and preserves physiological superoxide levels, possibly by regulating cardiolipin remodeling.

DOI： 10.1074/jbc.RA119.011110

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Aims/introduction: The predictive low glucose management (PLGM) system was introduced in March 2018 in Japan. Although there are some reports demonstrating the benefit of PLGM in preventing hypoglycemia, no data are currently available in Japanese patients with type 1 diabetes mellitus (T1DM). The aim of the present study is to evaluate the effect of PLGM with sensor-augmented pump therapy in the prevention of hypoglycemia in Japanese patients. Materials and methods: We included 16 patients with T1DM who used the MiniMed®640G system after switching from the MiniMed®620G system. We retrospectively analysed the data of the continuous glucose monitoring system in 1 month after switching to MiniMed®640G. Results: The area under the curve (AUC) of hypoglycemia of < 70 mg/dL was lowered from 0.42 ± 0.43 mg/dL day to 0.18 ± 0.18 mg/dL day (P = 0.012). Correspondingly, the duration of severe hypoglycemia (< 54 mg/dL) was reduced significantly from 15.3 ± 21.7 min/day to 4.8 ± 6.9 min/day (P = 0.019). The duration of hypoglycemia was reduced, but the reduction was not significant. Regarding the AUC for hyperglycemia > 180 mg/dL and the duration of hyperglycemia did not change. With the PLGM function, 79.3% of the predicted hypoglycemic events were avoided. Conclusions: The hypoglycemia avoidance rate was comparable to those in previous reports. In addition, we demonstrated that PLGM can markedly suppress severe hypoglycemia without deteriorating glycemic control in Japanese T1DM patients. It is necessary to further investigate the effective use of the PLGM feature such as establishing a lower limit and the timing of resumption.

DOI： 10.1007/s13340-019-00408-7

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AIMS/INTRODUCTION: To clarify the prevalence of albuminuria and renal dysfunction, and related factors in Japanese patients with diabetes, we analyzed the baseline data of the Japan Diabetes Complication and its Prevention prospective study. MATERIALS AND METHODS: We used the data of 355 patients with type 1 diabetes and 5,194 patients with type 2 diabetes to evaluate the prevalence of albuminuria and renal dysfunction, and related factors. A binomial logistic regression analysis was used to investigate independent contributing factors for estimated glomerular filtration rate <60 mL/min/1.73 m2 or albuminuria. RESULTS: The prevalence of microalbuminuria and macroalbuminuria was 15.2% (54/355) and 3.1% (11/355) in type 1 diabetes patients, and 25.0% (1,298/5,194) and 5.1% (265/5,194) in type 2 diabetes patients, respectively. The proportion of renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2 ) was 9.9% (35/355) in type 1 diabetes patients, and 15.3% (797/5,194) in type 2 diabetes patients. The proportion of patients with renal dysfunction with normoalbuminuria was 7.3% (26/355) for type 1 diabetes patients, and 9.0% (467/5,194) for type 2 diabetes patients. The factors related to albuminuria in type 2 diabetes patients were glycated hemoglobin, hypertension, age, duration of diabetes, body mass index and estimated glomerular filtration rate. In contrast, factors to related renal dysfunction were age, duration of diabetes, dyslipidemia, hypertension, body mass index, male sex and albuminuria. CONCLUSIONS: We showed the recent prevalence of albuminuria and renal dysfunction, and related factors in Japanese type 1 and type 2 diabetes patients using the baseline data of the Japan Diabetes Complication and its Prevention prospective study. The current results suggest that renal disease in patients with type 2 diabetes is heterogeneous, and different mechanisms might be involved in albuminuria and deterioration of renal function.

DOI： 10.1111/jdi.13116

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Diabetes Society  

The purpose of this retrospective observational study is to analyze the clinical course of sensor augmented pump (SAP) therapy after switching from insulin pump therapy and to evaluate the predictors of the therapeutic effects of SAP therapy. Twenty-two type 1 diabetes patients who received SAP therapy for more than one year after switching from insulin pump therapy were enrolled. HbAlc levels were unchanged at 6 months and significantly improved at 12 months. The HbAlc levels at 6 months were decreased in 14 patients and unchanged or increased in the other 8 patients. In the latter group with unchanged or increased HbAlc levels at 6 months, the mean HbAlc level at the induction of SAP therapy was significantly lower and the percentage of patients with SMBG &lt
70 mg/dL before SAP therapy was higher in comparison to the former group. A multiple regression analysis showed a significant negative correlation between the change in % TBD (6M) and the change in the HbAlc level (6M). Conclusively, in patients with frequent hypoglycemia, we should evaluate the therapeutic effects based on various parameters, such as average sensor glucose levels and AUC &lt
70 mg/dL, since it is possible that the HbAlc level may transiently increase after the induction of SAP therapy in such cases.

DOI： 10.11213/tonyobyo.62.315

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INTRODUCTION: Acquired partial lipoatrophy has been reported after bone marrow transplantation during childhood; however, no adult cases have previously been reported. We herein report two adult cases of acquired partial lipoatrophy after transplantation. CASE PRESENTATION: A 28-year-old Japanese woman developed diabetic ketoacidosis and received insulin therapy after bone marrow transplantation. She manifested partial lipoatrophy of the extremities, prominent insulin resistance, hyperglycemia, hypertriglyceridemia, and fatty liver. A 40-year-old Japanese woman underwent liver transplantation from a living donor for alcoholic liver disease after abstinence from alcohol. She newly developed non-alcoholic steatohepatitis and diabetes. Non-alcoholic steatohepatitis progressed to liver failure, and a second liver transplantation from a brain-dead donor was performed at 42 years of age. She demonstrated loss of subdermal fat of the upper and lower extremities, prominent insulin resistance, hyperglycemia, and hypertriglyceridemia. In both cases, the injection of recombinant methionyl human leptin reversed all of the metabolic abnormalities. CONCLUSIONS: Acquired partial lipoatrophy after transplantation is a manifestation of chronic graft-versus-host disease in adults. This entity is associated with diabetes with prominent insulin resistance and severe hypertriglycemia and can be successfully treated with metreleptin for the long term.

DOI： 10.1186/s13256-018-1901-y

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To derive new insights in diabetic complications, we integrated publicly available human protein-protein interaction (PPI) networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy. We focused on the participating proteins in the network that were computationally predicted to connect the urine metabolites. MDM2 had the highest significant number of PPI connections. As validation, significant downregulation of MDM2 gene expression was found in both glomerular and tubulointerstitial compartments of kidney biopsy tissue from 2 independent cohorts of patients with diabetic nephropathy. In diabetic mice, chemical inhibition of MDM2 with Nutlin-3a led to reduction in the number of podocytes, increased blood urea nitrogen, and increased mortality. Addition of Nutlin-3a decreased WT1+ cells in embryonic kidneys. Both podocyte- and tubule-specific MDM2-knockout mice exhibited severe glomerular and tubular dysfunction, respectively. Interestingly, the only 2 metabolites that were reduced in both podocyte and tubule-specific MDM2-knockout mice were 3-methylcrotonylglycine and uracil, both of which were also reduced in human diabetic kidney disease. Thus, our bioinformatics tool combined with multi-omics studies identified an important functional role for MDM2 in glomeruli and tubules of the diabetic nephropathic kidney and links MDM2 to a reduction in 2 key metabolite biomarkers.

DOI： 10.1172/jci.insight.87877

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AMP-activated protein kinase (AMPK) is suppressed in diabetes and may be due to a high ATP/AMP ratio, however the quantitation of nucleotides in vivo has been extremely difficult. Via matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to localize renal nucleotides we found that the diabetic kidney had a significant increase in glomerular ATP/AMP ratio. Untargeted MALDI-MSI analysis revealed that a specific sphingomyelin species (SM(d18:1/16:0)) accumulated in the glomeruli of diabetic and high-fat diet-fed mice compared with wild-type controls. In vitro studies in mesangial cells revealed that exogenous addition of SM(d18:1/16:0) significantly elevated ATP via increased glucose consumption and lactate production with a consequent reduction of AMPK and PGC1α. Furthermore, inhibition of sphingomyelin synthases reversed these effects. Our findings suggest that AMPK is reduced in the diabetic kidney due to an increase in the ATP/AMP ratio and that SM(d18:1/16:0) could be responsible for the enhanced ATP production via activation of the glycolytic pathway.

DOI： 10.1016/j.ebiom.2016.03.033

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Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.

DOI： 10.1152/ajprenal.00463.2014

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Diabetic nephropathy is characterized by diffuse mesangial matrix expansion and is largely dependent on the TGF-β/Smad signaling pathway. Smad4 is required for TGF-β signaling; however, its regulation has not been well characterized in diabetic kidney disease. Here, we report that high glucose is sufficient to stimulate nuclear translocation of Smad4 in mesangial cells and that stimulation of the major energy sensor AMP-activated protein kinase (AMPK) has a potent effect to block Smad4 nuclear translocation. Activation of AMPK by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) inhibited high glucose-induced and TGF-β stimulation of nuclear Smad4. To identify which of the catalytic α-subunits may be involved, small interfering (si) RNA-based inhibition of AMPK α1- or α2-subunit was employed. Inhibition of either subunit reduced overall AMPK activity and contributed to Smad4 nuclear accumulation. In an animal model of early diabetic kidney disease, induction of diabetes was found to markedly stimulate Smad4 protein levels and enhance nuclear accumulation. AMPK activation with AICAR completely prevented the upregulation of Smad4 and reduced mesangial matrix accumulation. We conclude that stimulation of Smad4 in cell culture and in in vivo models of early diabetic kidney disease is dependent on AMPK.

DOI： 10.1152/ajprenal.00234.2014

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INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. MATERIALS AND METHODS: Five-week-old male Sprague-Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. RESULTS: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. CONCLUSIONS: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.

DOI： 10.1016/j.bbrc.2013.12.049

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Increasing incidence of chronic kidney disease (CKD) which leads to end-stage renal disease (ESRD) is one of the major health issues in the modern world and requires novel strategies for treatment. Adipose tissue has been recognized to have endocrine function and secretes a variety of hormones called adipokines. Several adipokines have been implicated in the pathogenesis of CKD and may have a strong impact as a risk factor for renal decline. The aim of this review is to provide an overview of the role of adipokines in the progression of CKD, with focus on recent experimental and clinical advances.

DOI： 10.1093/ndt/gft261

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Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2(+/-)) mice had no evidence of increased renal disease, and Ampka2(-/-) mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.

DOI： 10.1172/JCI66218

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Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

DOI： 10.2337/db11-0402

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Glomerular hyperfiltration is a common pathway leading to glomerulosclerosis in various kinds of kidney diseases. The 5/6 renal ablation is an established experimental animal model for glomerular hyperfiltration. On the other hand, low-grade inflammation is also a common mechanism for the progression of kidney diseases including diabetic nephropathy and atherosclerosis. Here we analyzed the gene expression profile in the remnant kidney tissues of 5/6 nephrectomized mice using a DNA microarray system and compared it with that of sham-operated control mice. The 5/6 nephrectomized mice showed glomerular hypertrophy and an increase in the extracellular matrix in the glomeruli. DNA microarray analysis indicated the up-regulated expression of various kinds of genes related to the inflammatory process in remnant kidneys. We confirmed the up-regulated expression of platelet factor-4, and monocyte chemoattractant protein-1, 2, and 5 in remnant kidneys by RT-PCR. The current results suggest that the inflammatory process is involved in the progression of glomerulosclerosis and is a common pathway of the pathogenesis of kidney disease.

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OBJECTIVE: An inflammatory process is involved in the mechanism of obesity-related insulin resistance. Recent studies indicate that monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that promotes monocyte infiltration into adipose tissues; however, the adhesion pathway in adipose tissues remains unclear. We aimed to clarify the adhesion molecules that mediate monocyte infiltration into adipose tissue. RESEARCH DESIGN AND METHODS: We used a DNA microarray to compare the gene expression profiles in epididymal white adipose tissues (eWAT) between db/db mice and C57/BL6 mice each fed a high-fat diet (HFD) or a low-fat diet (LFD). We investigated the change of insulin resistance and inflammation in eWAT in P-selectin glycoprotein ligand-1 (PSGL-1) homozygous knockout (PSGL-1⁻(/)⁻) mice compared with wild-type (WT) mice fed HFD. RESULTS: DNA microarray analysis revealed that PSGL-1, a major ligand for selectins, is upregulated in eWAT from both db/db mice and WT mice fed HFD. Quantitative real-time RT-PCR and immunohistochemistry showed that PSGL-1 is expressed on both endothelial cells and macrophages in eWAT of obese mice. PSGL-1⁻(/)⁻ mice fed HFD showed a remarkable reduction of macrophage accumulation and expression of proinflammatory genes, including MCP-1 in eWAT. Moreover, adipocyte hypertrophy, insulin resistance, lipid metabolism, and hepatic fatty change were improved in PSGL-1⁻(/) ⁻mice compared with WT mice fed HFD. CONCLUSIONS: These results indicate that PSGL-1 is a crucial adhesion molecule for the recruitment of monocytes into adipose tissues in obese mice, making it a candidate for a novel therapeutic target for the prevention of obesity-related insulin resistance.

DOI： 10.2337/db09-1894

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BACKGROUND: The presence of metabolic syndrome has been shown to be predictors of cardiovascular morbidity and mortality in patients with type 2 diabetes. In a cross-sectional clinical study, we investigated the association of metabolic syndrome with asymptomatic lacunar strokes and cardiovascular disease (CVD) and we compared its significance with urinary protein markers. METHODS: We studied Japanese type 2 diabetes patients (n=233, men=124, women=109). The diagnosis of metabolic syndrome was made according to WHO and International Diabetes Federation (IDF) criteria. Cardiovascular events were recorded and asymptomatic lacunar lesions were evaluated with magnetic resonance imaging (MRI). We also measured urinary levels of albumin, type IV collagen, beta2-microglobulin (beta2MG), N-acetyl-beta-d-glucosaminidase (NAG) and lipocalin-type prostaglandin D synthase (PGDS). RESULTS: The prevalence of metabolic syndrome is 31.3% (IDF) and 52% (WHO) in 233 patients and microalbuminuria was present in 62 subjects (26.6%). Metabolic syndrome (WHO) significantly associated with asymptomatic lacunar lesions (p=0.035, OR=2.854, CI 1.075-7.579), while metabolic syndrome (IDF) or urinary markers failed to associate with presence of asymptomatic lacunar lesions. The presence of metabolic syndrome or microalbuminuria did not show significant association with CVD; however, the elevation of beta2MG, NAG and PGDS showed significant association with CVD. By a logistic regression analysis using urinary proteins as independent variables, the presence of higher PGDS excretion independently associated with history of CVD (p=0.025, OR=3.847, CI 1.180-12.545). CONCLUSIONS: In type 2 diabetes patients, the elevation of urinary PGDS secretion closely associated with cardiovascular events and may be a supplemental or additional marker to the criteria of metabolic syndrome.

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OBJECTIVE: To investigate clinical features and pathophysiology of a rare form of new-onset type 1 diabetes mellitus that was superimposed on established type 2 diabetes. PATIENTS AND METHODS: We retrospectively analyzed 126 consecutive type 2 diabetic patients, who were admitted to the hospital 2 or more times from July 2000 to December 2005 and had been repeatedly examined for islet-associated autoantibodies and insulin secretory capacity over a period of years. RESULTS: We experienced 2 patients in whom autoantibodies including ICA, GADAb, and IA-2Ab were initially all negative, but in whom at least 1 of these antibodies later became positive, whose endogenous insulin secretion decreased, and who eventually reached an insulin-dependent stage. At the time of seroconversion of antibodies, the patients had 15 to 23 years' history of diabetes, and had microvascular complications specific to diabetes mellitus, and before seroconversion insulin secretory capacities were preserved. The patients had HLA types associated with susceptibility to Japanese type 1 diabetes mellitus. CONCLUSIONS: Our findings suggest that autoimmune type 1 diabetes mellitus may be superimposed on well-established type 2 diabetes.

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

本研究はSAP導入後の効果を検討するため、CSIIからSAPに変更後1年以上経過した1型糖尿病22症例を解析した後ろ向き観察研究である。HbA1cはSAP前と比較して6ヵ月(6M)では不変、12Mで有意に低下した(各々7.6±0.7%、7.4±0.9%、7.1±0.9%)。6Mの時点でHbA1c0.1%以上低下した群を6M低下群、変化なし又は0.1%以上上昇した群を6M不変・上昇群と定義したところ、6M不変・上昇群で0MのHbA1cが有意に低値で、重回帰分析では基礎インスリン比率の変化(6M)がHbA1c変化量(6M)の有意な決定因子として採用され、負の相関を示した。また、6M不変・上昇群では0MのSMBGで低血糖頻度が有意に高く、1Mで有意に低下した。臨床的にSMBGでの低血糖が多い症例ではSAP導入後にHbA1c上昇を呈す事もあり、注意を要する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00926&link_issn=&doc_id=20190603330001&doc_link_id=10.11213%2Ftonyobyo.62.315&url=https%3A%2F%2Fdoi.org%2F10.11213%2Ftonyobyo.62.315&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：English   Publisher：(一社)日本腎臓学会  

DOI： 10.1007/s10157-018-1648-1

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(株)医学出版  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(株)医学書院  

＜POINT＞慢性炎症は糖尿病腎症の発症・進展に関与している.近年,慢性炎症のメカニズムにToll-like receptor(TLR)やインフラマソームの関与が示唆されている.(著者抄録)

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Language：Japanese   Publisher：(株)じほう  

＜Key Points＞糖尿病患者の診療の際には、定期的に(少なくとも年1回)尿中アルブミン/Cr比、eGFRを測定して、糖尿病性腎症の早期発見に努め、腎症を有する場合には病期分類に従って分類し、的確な治療を行う必要がある。糖尿病性腎症の治療は、心血管疾患の発症抑制と腎症の進展抑制(可能なら退縮・寛解)を目標に、血糖コントロールのみならず、レニン・アンジオテンシン系阻害薬を用いた血圧の管理、脂質の管理、および食事療法(蛋白質摂取制限)を集約的に行う必要がある。糖尿病性腎症を含めた細小血管合併症の発症・進展阻止のための血糖コントロールとしてHbA1c<7.0%を目指す。糖尿病性腎症患者の血圧は130/80mmHg未満を目標とし、第一選択薬としてレニン・アンジオテンシン系阻害薬で治療を開始する。脂質の管理目標値は、LDL-C<120mg/dL(冠動脈疾患の既往がある場合は<100mg/dL)、トリグリセリド<150mg/dL、HDL-C≧40mg/dL、non-HDL-C<150mg/dL(冠動脈疾患の既往がある場合は<130mg/dL)とする。(著者抄録)

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Language：Japanese   Publisher：岡山医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00175&link_issn=&doc_id=20140415220001&doc_link_id=10.4044%2Fjoma.126.1&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.126.1&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)医学書院  

糖尿病患者では,感染症が発症・重症化しやすく,健常者に比し死亡率も高い.高血糖状態では白血球機能の障害,特に遊走能・走化性,貪食能,殺菌能の低下をきたすことがこれまでに報告されている.血行障害や神経障害なども易感染性に寄与しており,合併症の進行した糖尿病患者では特に留意する必要がある.高血糖により低下した白血球機能は血糖の是正により改善することが報告されており,感染症の発症・増悪を防ぐためには良好な血糖コントロールが必要である.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J01541&link_issn=&doc_id=20100907210011&doc_link_id=10.11477%2Fmf.1542102388&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1542102388&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(株)文光堂  

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Language：Japanese   Publisher：医学出版  

CiNii Article

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2009340941

Language：Japanese   Publisher：日総研出版  

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J01205&link_issn=&doc_id=20081210200041&doc_link_id=%2Fag6niria%2F2008%2F0066s9%2F042%2F0230-0233%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2008%2F0066s9%2F042%2F0230-0233%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：医歯薬出版(株)  

糖尿病性腎症はCKDのなかでも近年増加しつづけている疾患であり、新規透析導入患者の主要原疾患のなかで42%を占め、生命予後も不良である。糖尿病性腎症を可能なかぎり早期に診断しかつ的確な治療を開始するため、最近になって糖尿病性腎症の早期診断基準が改訂され、日常の外来診療においても簡便に診断を行うことが可能となった。糖尿病性腎症の治療は血糖・脂質管理・蛋白摂取制限が主体であり、大規模臨床試験によりエビデンスが集積されてきている。とくに最近になって、進行した病期においても集約的治療によりアルブミン尿・蛋白尿が減少し組織学的な変化も改善しうるとの報告が散見されるようになった。腎症の進展を抑制するばかりではなく、remission(寛解)、regression(退縮)をめざした集約的治療を行うことがこれからの糖尿病性腎症治療に求められる。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J00060&link_issn=&doc_id=20070906100006&doc_link_id=%2Faa7ayuma%2F2007%2F022210%2F007%2F0795-0798%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2007%2F022210%2F007%2F0795-0798%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

58歳男、口渇・多飲・多尿を主訴とした。虫垂炎手術、急性膵炎、くも膜下出血、薬剤性肝障害の既往があった。C型慢性肝炎を指摘されインターフェロン(IFN)治療を受けたが、その後再び肝機能障害を認めた。当院の肝生険より慢性活動性肝炎と診断し、IFN-α+リバビリン併用治療を行った。その後、甲状腺機能低下症を認め、レボチロキシンナトリウムの内服を開始した。さらに、血糖値、HbA1c、glutamic acid decarboxylase抗体の高値を認めた。サイログロブリン抗体、トロンボポエチン抗体、膵島細胞質抗体は陽性であった。遺伝子検索では1型糖尿病に特徴のタイプを呈した。頻回インスリン療法を開始し、血糖は改善した。保存血清による各種自己抗体の抗体価と血糖の推移を検討したところ、IFN治療開始約3ヵ月後より各種抗体は上昇し、IFN治療終了約8ヵ月後より抗体価は低下したが陽性は続き、血糖値は上昇傾向にあった。

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

2004年の1年間に入院した2型糖尿病250例を対象に,入退院時の高感度C反応性蛋白(hs-CRP)を測定し,各種臨床マーカーとの相関,血管障害との関連性,入院治療によるhs-CRP値の変動要因を検討した.患者の平均年齢は60.4歳であった.平均2週間の入院期間でインスリン治療で血糖をほぼ正常化させた.その結果,入院時hs-CRPは糖尿病罹病年数・入院時BMI・入院時血清HDL-c値と有意に相関し,退院時hs-CRPにおいても同様の関連性を示したが,新たに頸動脈内膜中膜複合平均肥厚度との相関が認められた.hs-CRPは糖尿病やその血管病変の病態を知る上で意義が深いと考えられた

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

75歳女.グリベンクラミド投与によってもHbA1cが上昇し続け,スルホニル尿素剤の二次無効疑いで入院となった.スクリーニング目的の腹部エコー検査で膵頭部に腫大を認め,自己免疫性膵炎(AIP)の疑いで精査を行い,生検により確定診断した.ステロイド療法を行い,AIPとHbA1c値は改善したがインスリン分泌能は改善しなかった

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

67歳女.高血糖を主訴とした.糖尿病と診断され,gliclazide内服を開始したが,その後コントロール悪化のため入院した.gliclazide,voglibose,混合型インスリン注射の併用で退院となった.しかしその後,HbA1cの急激な悪化,抗IA-2抗体の陽性化を認めた.さらに,インスリン注射部位に局所アレルギー症状も出現した.入院時,糖尿病性末梢神経障害,単純型網膜症,糖尿病性腎症(2期)を認めた.食事・グルカゴン負荷試験での血中Cペプチド(CRP)は前後値ともに0.00ng/mlであった.HLAの血清タイピングはA24,B54,DR4,DNAタイピングはDRB1*0405を示し,1型糖尿病への疾患感受性を有していた.インスリン頻回注射を継続し,退院となった.約5年後,抗IA-2抗体は陰性化した

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

2型糖尿病入院患者250例(60.4±12.8歳)を対象に,血中アディポネクチン濃度と臨床検査成績との関連について検討した.その結果,血中アディポネクチン濃度は入院時と退院時で有意差はなく,入院時血中アディポネクチン濃度との単相関分析にて年齢,罹病期間,HDLコレステロール(HDL-c)に有意の正相関を認め,body mass index,グルカゴン負荷試験における血中Cペプチドの前値と6分値の差(△CPR),24時間クレアチニンクリアランス(Ccr),中性脂肪(TG),拡張期血圧に有意の逆相関を認めた.アディポネクチンを目的変数とする重回帰分析では△CPR,HDL-c,罹病期間,TG,Ccrが有意な説明変数であった.血中アディポネクチン濃度は脂質代謝,インスリン抵抗性,罹病期間,腎機能に関連するため,その臨床評価には配慮が必要であると考えられた

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

76歳男.64歳時に糖尿病と診断され,加療を受けていた.血糖コントロールは良好であったが,約2年前より血糖コントロール(HbA1c)の上昇がみられた.糖尿病教育入院となり,入院時検査ではインスリン分泌能の低下を認めた.腹部超音波検査と腹部造影CTでは膵尾部に3cm大の腫瘤影を認め,磁気共鳴膵胆管造影では主膵管が尾部で途絶していた.膵癌と診断し,膵体尾部切除,脾摘を行った.術中に胃,横行結腸間膜に浸潤を認め,病理診断は中分化型膵管細胞癌であった.術後1年5ヵ月が経過するが,再発所見はなく,糖尿病もコントロール良好である.本症例と通常の2型糖尿病症例との比較を行った結果,糖尿病が膵癌の高リスク群であると結論付けることはできないが,高齢,肥満,急激な血糖コントロールの悪化,インスリン分泌能の低下が2型糖尿病に合併する膵癌の臨床的特徴と思われた

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Language：Japanese   Publisher：(公財)大原記念倉敷中央医療機構倉敷中央病院  

61歳女.50歳時に高血圧,高脂血症,55歳時に統合失調症を発病している.また,50歳時より糖尿病あり,1年前より外来通院中,食事療法のみで経過観察していた.血糖値は193mg/dl,HbA1c 7.6%であった.1ヵ月後に心療内科でオランザピン5.0mg/日を開始された.その後,食欲の亢進,口渇を認め,2週間前より排尿時痛あり,発熱,腰痛も出現し尿路感染症と診断され入院となった.当初は血糖上昇の原因は特定できなかったが,緊急安全性情報がありオランザピンの内服を中止し,クエチアピン,リスペリドン,ビペリデンに変更した.インスリン頻回注射で血糖を改善,尿路感染が消退後にナテグリニドと眠前NPHインスリン療法に変更し良好な血糖が得られ退院となった

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