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1.  Comparison of the Renoprotective Effect of Febuxostat for the Treatment of Hyperuricemia between Patients with and without Type 2 Diabetes Mellitus: A Retrospective Observational Study 
Internal Medicine  2016;55(22):3247-3256.
Objective The effects of febuxostat therapy on hyperuricemia in patients with and without type 2 diabetes were compared in this retrospective observational study after pair-matching using the propensity scores.
Methods In total, 160 patients with hyperuricemia were studied as the treated set, and the 155 subjects in whom the administration of febuxostat was not discontinued during the observation period were investigated in the full analysis. The study subjects were divided into two groups based on the style of initiation of febuxostat: initial and switching therapy from allopurinol administration.
Results The reduction in the serum uric acid (sUA) levels at six months after the initiation of febuxostat administration did not significantly differ between the patients with and without diabetes in both the initial (206±114 and 226±113 μmol/L in patients with and without diabetes, respectively) and switching (154±91 and 129±90 μmol/L in patients with and without diabetes, respectively) therapy groups. The eGFR values were significantly increased compared to the baseline levels only in the patients without diabetes. The changes in the eGFR values were significantly associated with the presence of diabetes and sUA at baseline in a multivariate analysis. The frequency of adverse events was not significantly different between the patients with and without diabetes.
Conclusion Although febuxostat exerted a similar sUA-lowering effect against hyperuricemia in patients with type 2 diabetes compared to those without, the renoprotective effect was attenuated in those with diabetes compared to nondiabetic subjects.
PMCID: PMC5173490  PMID: 27853065
allopurinol; febuxostat; xanthine oxidase inhibitor; hyperuricemia; renoprotection; type 2 diabetes mellitus
2.  Secular Trends in the Clinical Characteristics of Type 2 Diabetic Patients With Severe Hypoglycemia Between 2008 and 2013 
We investigated the trends in the clinical characteristics and prescriptions of type 2 diabetic patients with severe hypoglycemia because the prescription rate of antidiabetic agents has significantly changed recently.
A total of 193 patients with type 2 diabetes with severe hypoglycemia induced by antidiabetic agents between 2008 and 2013 were divided into three groups based on the period of visit: 2008 - 2009, 2010 - 2011 and 2012 - 2013.
While the proportion of patients with severe hypoglycemia using insulin (from 55% to 74%), biguanides (from 6% to 20%), glinides, and dipeptidyl peptidase-4 inhibitors significantly increased, those using sulfonylureas (from 45% to 20%) significantly decreased. Errors of drug use significantly increased as a trigger of hypoglycemia in recent years. The number of antidiabetic agents (from 1.9 ± 0.6 to 2.3 ± 0.7), non-diabetic agents (from 2.3 ± 2.4 to 4.3 ± 3.3), and total drugs prescribed were significantly higher in recent years among patients receiving insulin therapy.
Polypharmacy especially in patients receiving insulin therapy and errors of drug use have increased in type 2 diabetic patients with severe hypoglycemia in recent years. Intensive education in the usage rule of drugs is considered to be important in order to prevent severe hypoglycemia.
PMCID: PMC5012239  PMID: 27635175
Hypoglycemia; Insulin; Patient education; Polypharmacy; Sulfonylureas
3.  Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells 
PLoS ONE  2016;11(7):e0158290.
Internal tandem duplication (ITD) mutations in the Fms-related tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Due to the development of drug resistance, few FLT3-ITD inhibitors are effective against FLT3-ITD+ AML. In this study, we show that FLT3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates FLT3-ITD cell proliferation and is involved in the development of drug resistance. FLT3-ITD up-regulated p21 expression in both mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and Ba/F3 cells. The loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of concomitantly enriching the S+G2/M phase population and significantly increasing the expression of Pbx1, but not Evi-1, in FLT3-ITD+ cells. This enhanced cell proliferation following the loss of p21 was partially abrogated when Pbx1 expression was silenced in FLT3-ITD+ primary bone marrow colony-forming cells and Ba/F3 cells. When FLT3-ITD was antagonized with AC220, a selective inhibitor of FLT3-ITD, p21 expression was decreased coincident with Pbx1 mRNA up-regulation and a rapid decline in the number of viable FLT3-ITD+ Ba/F3 cells; however, the cells eventually became refractory to AC220. Overexpressing p21 in FLT3-ITD+ Ba/F3 cells delayed the emergence of cells that were refractory to AC220, whereas p21 silencing accelerated their development. These data indicate that FLT3-ITD is capable of inhibiting FLT3-ITD+ cell proliferation through the p21/Pbx1 axis and that treatments that antagonize FLT3-ITD contribute to the subsequent development of cells that are refractory to a FLT3-ITD inhibitor by disrupting p21 expression.
PMCID: PMC4936702  PMID: 27387666
4.  Survivin Modulates Genes with Divergent Molecular Functions and Regulates Proliferation of Hematopoietic Stem Cells through Evi-1 
Leukemia  2014;29(2):433-440.
The inhibitor of apoptosis protein Survivin regulates hematopoiesis, although its mechanisms of regulation of hematopoietic stem cells (HSCs) remain largely unknown. While investigating conditional Survivin deletion in mice, we found that Survivin was highly expressed in phenotypically defined HSCs and Survivin deletion in mice resulted in significantly reduced total marrow HSC and progenitor cells (HPC). Transcriptional analysis of Survivin−/− HSCs revealed altered expression of multiple genes not previously linked to Survivin activity. In particular, Survivin deletion significantly reduced expression of the Evi-1 transcription factor indispensable for HSC function, and the downstream Evi-1 target genes Gata2, Pbx1 and Sall2. The loss of HSCs following Survivin deletion and impaired long-term HSC repopulating function could be partially rescued by ectopic Evi-1 expression in Survivin −/− HSCs. These data demonstrate that Survivin partially regulates HSC function by modulating the Evi-1transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.
PMCID: PMC4258188  PMID: 24903482
5.  Flow Mediated Dilatation Is Reduced with the Progressive Stages of Glomerular Filtration Rate and Albuminuria in Type 2 Diabetic Patients without Coronary Heart Disease 
Journal of Diabetes Research  2015;2015:728127.
We aimed to clarify the usefulness of measuring the flow mediated dilatation (FMD) in patients with type 2 diabetes mellitus without and with coronary heart disease (CHD). The FMD was measured in 480 patients with type 2 diabetes and in 240 nondiabetic subjects. The FMD was significantly lower in the subjects with CHD (n = 145, 5.4 ± 3.2%) than in those without CHD (n = 95, 6.9 ± 3.5%) among the nondiabetic subjects. The FMD was also lower in the subjects both with CHD (n = 161, 5.6 ± 2.8%) and without CHD (n = 319, 6.1 ± 3.3%) among the patients with diabetes compared to those without both diabetes and CHD. The FMD showed a significant positive correlation with the estimated glomerular filtration rate (eGFR) in the diabetic patients without CHD, while there was no significant association in those with CHD. The FMD was significantly lower with the progressive stages of the GFR or albuminuria in the patients without CHD among those with diabetes, although the FMD was not different in those with CHD. In conclusion, the FMD is considered to be useful for the detection of atherosclerosis in patients with type 2 diabetes, even if overt macroangiopathy is not diagnosed.
PMCID: PMC4429217  PMID: 26064988
6.  Anagliptin in the treatment of type 2 diabetes: safety, efficacy, and patient acceptability 
Anagliptin is a novel dipeptidyl peptidase-4 inhibitor that has been available in Japan since 2012. Because anagliptin is not generally used in countries other than Japan, there are only a small number of reports investigating the effects of anagliptin. In the present article, we review the safety and efficacy of anagliptin according to data obtained from preclinical trials and postmarketing studies. The usual dose of anagliptin is 200 mg daily, and increases in the dose up to 400 mg daily have been approved in cases in which the blood glucose–lowering effect is insufficient. In a Phase II trial, the reduction in the HbA1c values from baseline after 12 weeks monotherapy with 200 mg and 400 mg of daily anagliptin was 0.75%±0.50% and 0.82%±0.46%, respectively, and more than 40% of the subjects receiving anagliptin at a dose of 200 mg or 400 mg daily achieved an HbA1c level below 6.9%. Furthermore, the levels of HbA1c, fasting blood glucose, and postprandial blood glucose were significantly decreased at 52 weeks compared with the baseline values in a Phase III trial investigating the effects of anagliptin included in combination therapy with other oral antidiabetic agents. In a pooled analysis of Phase II and Phase II/III trials, the goal achievement rates for an HbA1c level below 7.0% at 12 weeks were 40.3%, 39.4%, 30.0%, and 34.8% in the patients treated with anagliptin combined with α-glucosidase inhibitors, thiazolidinediones, sulfonylureas, and biguanides, respectively. Meanwhile, the serum lipid concentrations significantly improved after the administration of anagliptin in a pooled analysis of Phase III trials, and no serious adverse effects have been reported in preclinical trials. Therefore, the use of anagliptin in patients with type 2 diabetes is considered to be safe and effective for both monotherapy and combination therapy.
PMCID: PMC4370682  PMID: 25834461
dipeptidyl peptidase-4 inhibitor; type 2 diabetes mellitus; monotherapy; combination therapy; adverse effect
7.  Effects of switching from prandial premixed insulin therapy to basal plus two times bolus insulin therapy on glycemic control and quality of life in patients with type 2 diabetes mellitus 
The effects of switching from prandial premixed insulin therapy (PPT) injected three times a day to basal plus two times bolus insulin therapy (B2B) on glycemic control and quality of life were investigated in patients with type 2 diabetes mellitus.
The clinical course was prospectively observed during the first 16 weeks after switching to B2B (insulin glargine plus insulin glulisine before breakfast and dinner) in 27 subjects previously treated with PPT using 50/50 premixed insulin. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was administered at the start and end of the study.
The glycated hemoglobin (HbA1c) level (8.3%±1.8% to 8.2%±1.1%) and the DTSQ score did not change between the start and end of the study. An improvement in HbA1c level was found in nine (33%) subjects. The change in HbA1c showed a significant negative correlation with baseline HbA1c, and was significantly better in patients with a baseline HbA1c >8.0% than in those with an HbA1c ≤8.0% (−0.9±2.0 versus 0.3±0.6, respectively, P=0.02). The change in DTSQ score representing treatment satisfaction was significantly greater in patients whose HbA1c level was improved than in those in whom it was not (2.7±3.6 versus −0.8±3.5, P=0.04).
B2B was noninferior to PPT with regard to HbA1c levels in patients with type 2 diabetes mellitus. B2B should be considered particularly for subjects whose glycemic control is poor despite PPT.
PMCID: PMC4003145  PMID: 24790413
type 2 diabetes mellitus; insulin therapy; basal plus two times bolus insulin therapy; prandial premixed insulin therapy; Diabetes Treatment Satisfaction Questionnaire
8.  The Prevalence of the Risk Factors for Atherosclerosis among Type 2 Diabetic Patients Is Greater in the Progressive Stages of Chronic Kidney Disease 
Nephron Extra  2013;3(1):66-72.
The prevalence of the risk factors for atherosclerosis, other than diabetes mellitus, among type 2 diabetic patients with different stages of chronic kidney disease (CKD) determined by glomerular filtration rate (GFR) was investigated.
The prevalence of ten risk factors (age ≥65 years, history of smoking, male gender, obesity, albuminuria, hypertension, hypercholesterolemia, hypo-HDL-cholesterolemia, hyperuricemia and anemia) was determined in 2,107 Japanese type 2 diabetic patients with different stages of CKD (six stages according to GFR).
The risk factors for age ≥65 years and male gender were found in 49 and 62% of the study subjects, respectively. The percentages of subjects with a current history of smoking, obesity, albuminuria, hypertension, hypercholesterolemia, hypo-HDL-cholesterolemia, hyperuricemia and anemia were 35, 44, 47, 70, 61, 13, 21 and 26%, respectively. The prevalence of age ≥65 years, male gender, albuminuria, hypertension, hypo-HDL-cholesterolemia, hyperuricemia and anemia was greater in the later stages of GFR, whereas the prevalence of hypercholesterolemia and obesity did not differ between stages. The prevalence of a current history of smoking was lower in the later stages of GFR. The cumulative number of risk factors increased from 3.1 to 6.8 in the later stages of GFR.
Among type 2 diabetic patients with CKD, the total number of risk factors increases with the progression of renal dysfunction. It is important to pay attention to newly recognized risk factors for hyperuricemia and anemia, in addition to hypertension, albuminuria and hypo-HDL-cholesterolemia, in monitoring diabetic patients with later stages of CKD.
PMCID: PMC3728600  PMID: 23904855
Chronic kidney disease; Hyperuricemia; Atherosclerosis; Anemia; Diabetic nephropathy
9.  Vildagliptin is Effective for Glycemic Control in Diabetic Patients Undergoing either Hemodialysis or Peritoneal Dialysis 
Diabetes Therapy  2013;4(2):321-329.
Vildagliptin can be used in patients with type 2 diabetes mellitus and renal impairment. However, there have been few reports investigating the clinical effectiveness of vildagliptin in diabetic patients undergoing hemodialysis. No previous studies have evaluated the use of vildagliptin in patients undergoing peritoneal dialysis. The authors determined the usefulness of vildagliptin for treating type 2 diabetic patients receiving chronic dialysis, including peritoneal dialysis.
A retrospective study of ten diabetic patients undergoing peritoneal dialysis and five diabetic patients undergoing hemodialysis who were treated with 50 mg/day of vildagliptin was performed. Clinical parameters were investigated for a period of 6 months starting from the vildagliptin therapy.
The hemoglobin A1c (HbA1c) levels were significantly reduced after baseline in both the peritoneal dialysis and hemodialysis groups, whereas the hemoglobin levels did not change during the follow-up period. The mean change in the HbA1c level (ΔHbA1c) was −0.6 ± 0.9% and −0.5 ± 0.7% among the patients undergoing peritoneal dialysis and hemodialysis, respectively. The glycated albumin (GA) levels were also significantly reduced compared with baseline in the peritoneal dialysis group, although the serum albumin levels did not change. The mean change in the GA level (ΔGA) was −3.4 ± 3.1% and −2.1 ± 2.5% among the patients undergoing peritoneal dialysis and hemodialysis, respectively. Stepwise multivariate analyses demonstrated the level of HbA1c at baseline to be significantly associated with the ΔHbA1c and that the level of GA at baseline was significantly associated with the ΔGA.
Vildagliptin exhibits effectiveness in patients with type 2 diabetes mellitus undergoing peritoneal dialysis or hemodialysis. The degree of improvement in the HbA1c and GA levels was dependent on these levels at baseline, similar to the findings of previous reports of subjects without end-stage kidney disease.
PMCID: PMC3889330  PMID: 23801219
Diabetes; End-stage kidney disease; Hemodialysis; Hemoglobin A1c; Glycated albumin; Peritoneal dialysis; Renal impairment; Type 2 diabetes mellitus; Vildagliptin
10.  Hypertension resistant to antihypertensive agents commonly occurs with the progression of diabetic nephropathy in Japanese patients with type 2 diabetes mellitus: a prospective observational study 
BMC Nephrology  2012;13:48.
We investigated 1) the frequency of hypertension in patients with type 2 diabetes graded by the new classification of chronic kidney disease (CKD) reported by the Kidney Disease: Improving Global Outcomes (KDIGO) and 2) the number of antihypertensive agents needed to achieve treatment goals using a prospective observational study.
A population of 2018 patients with type 2 diabetes mellitus was recruited for the study. The CKD stage was classified according to the eGFR and the urinary albumin excretion levels.
Hypertension was found in 1420 (70%) of the patients, and the proportion of subjects showing a blood pressure < 130/80 mmHg was 31% at the baseline. Although the mean blood pressure was approximately 130/75 mmHg, the rate of patients with a blood pressure of < 130/80 mmHg became limited to 41-50% during the observation period. The number of antihypertensive agents required for treatment was significantly higher at the endpoint (2.0 ± 1.3) than at the baseline (1.6 ± 1.2). Furthermore, it increased with the progression of the CKD stage at both the baseline and the endpoint of the observation. However, the frequency of subjects who did not achieve the blood pressure target was found to increase in the group demonstrating the later stage of CKD.
Hypertension resistant to antihypertensive agents was common in the patients with type 2 diabetes mellitus and increased with the progression of CKD. Although powerful combination therapy using antihypertensive agents is considered necessary for the strict control of blood pressure, this became difficult in individuals who were in advanced stages as graded based on the eGFR and the urinary albumin excretion levels.
PMCID: PMC3437202  PMID: 22738384
Hypertension; Antihypertensive agents; Chronic kidney disease; CKD stage; Type 2 diabetes mellitus; KDIGO
11.  Hyperuricemia Is Independently Associated with Coronary Heart Disease and Renal Dysfunction in Patients with Type 2 Diabetes Mellitus 
PLoS ONE  2011;6(11):e27817.
To investigate the relationship between hyperuricemia (HUA) and the clinical backgrounds in Japanese patients with type 2 diabetes mellitus.
After a cross-sectional study evaluating the association of HUA with the clinical characteristics in 1,213 patients with type 2 diabetes mellitus, the estimated glomerular filtration rate (eGFR) and the incidence of diabetic macroangiopathies was investigated in a prospective observational study in 1,073 patients during a 3.5 year period. HUA was defined by serum uric acid levels >327 μmol/L or as patients using allopurinol.
The frequency of HUA was significantly higher in the diabetic patients (32% in men and 15% in women) than in the normal controls (14% in men and 1% in women). In total, HUA was found in 299 (25%) of the patients during the cross-sectional study. Even after adjusting for sex, drinking status, treatment for diabetes mellitus, body mass index, hypertension, use of diuretics, hyperlipidemia, HbA1c and/or the eGFR, the HUA was independently associated with some diabetic complications. The eGFR was significantly reduced in HUA patients compared to those with normouricemia in the 12 months after observation was started. HUA was also an independent risk factor for coronary heart disease even after adjustment in the Cox proportional hazard model.
HUA is a associated with diabetic micro- and macroangiopathies. HUA is a predictor of coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. However, the influence of HUA is considered to be limited.
PMCID: PMC3220675  PMID: 22125626
12.  Survivin Selectively Modulates Genes Deregulated in Human Leukemia Stem Cells 
Journal of Oncology  2010;2011:946936.
ITD-Flt3 mutations are detected in leukemia stem cells (LSCs) in acute myeloid leukemia (AML) patients. While antagonizing Survivin normalizes ITD-Flt3-induced acute leukemia, it also impairs hematopoietic stem cell (HSC) function, indicating that identification of differences in signaling pathways downstream of Survivin between LSC and HSC are crucial to develop selective Survivin-based therapeutic strategies for AML. Using a Survivin-deletion model, we identified 1,096 genes regulated by Survivin in ITD-Flt3-transformed c-kit+, Sca-1+, and lineageneg (KSL) cells, of which 137 are deregulated in human LSC. Of the 137, 124 genes were regulated by Survivin exclusively in ITD-Flt3+ KSL cells but not in normal CD34neg KSL cells. Survivin-regulated genes in LSC connect through a network associated with the epidermal growth factor receptor signaling pathway and falls into various functional categories independent of effects on apoptosis. Pathways downstream of Survivin in LSC that are distinct from HSC can be potentially targeted for selective anti-LSC therapy.
PMCID: PMC3021862  PMID: 21253548
13.  Mild anemia is frequent and associated with micro‐ and macroangiopathies in patients with type 2 diabetes mellitus 
Aims/Introduction:  The present study investigated the frequency of mild anemia, which is not an indication of intensive therapy using drugs, in Japanese patients with type 2 diabetes mellitus and the association of mild anemia with diabetic complications.
Materials and Methods:  This is a cross‐sectional study of 1189 patients with type 2 diabetes mellitus. Anemia was defined as a hemoglobin level <13.5 g/dL in men and <12.0 g/dL in women. The patients with anemia were divided into two groups: (i) grade 1 anemia with a hemoglobin level ≥11.0 g/dL; and (ii) grade 2 anemia with a hemoglobin level <11.0 g/dL.
Results:  The prevalence of anemia increased with the progression of the stage of diabetic nephropathy and chronic kidney disease. The frequencies of diabetic micro‐ and macroangiopathies increased with the progression of anemia among 798 patients without anemia, 300 with grade 1 anemia and 91 with grade 2 anemia. Both grade 1 and grade 2 anemia were associated with diabetic micro‐ and macroangiopathies. They remained independently associated with diabetic retinopathy, coronary heart disease and peripheral arterial disease after adjustment by age, sex, body mass index, use of angiotensin II receptor blocker, estimated glomerular filtration rate and stage of diabetic nephropathy.
Conclusions:  Mild anemia is frequent and associated with micro‐ and macroangiopathies in patients with type 2 diabetes mellitus. It is important to carry out intensive examinations for the detection of diabetic micro‐ and macroangiopathies in addition to evaluating the causes of anemia when mild anemia is found in patients with diabetes mellitus. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00060.x, 2010)
PMCID: PMC4014891  PMID: 24843443
Anemia; eGFR; Diabetic nephropathy
14.  Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus 
We aimed to investigate the long-term effect of metformin on the blood glucose control in non-obese patients with type 2 diabetes mellitus.
A retrospective study was performed in 213 patients with type 2 diabetes mellitus under the administration of metformin for more than one year. The clinical parameters were investigated for 3 years. The obese and non-obese individuals were defined as a body mass index (BMI) of 25 kg/m2 or over (n = 105) and a BMI of less than 25 kg/m2 (n = 108), respectively.
HbA1c levels were significantly decreased compared with those at the baseline time. The course of HbA1c was similar between the non-obese and the obese groups, while the dose of metformin required to control blood glucose was significantly lower in the non-obese group than in the obese group. The reductions in HbA1c were 1.2% and 1.1% at 12 months, 0.9% and 0.9% at 24 months, and 0.8% and 1.0% at 36 months in the non-obese and obese groups, respectively. BMI did not change during the observation periods. Approximately half of all patients required no additional antidiabetic agents or a reduction in other treatments after the initiation of metformin in either of the two groups.
The present study demonstrated the long-term beneficial effect of metformin in non-obese (BMI < 25 kg/m2) diabetic patients. This effect appears to be maintained even after the observation period of this study, because metformin was limited to a relatively low dose in the non-obese group and the observed worsening in glycemic control over time can probably be attenuated by increasing the dose of metformin.
PMCID: PMC2991324  PMID: 21070671

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