Mariko Abe

Hyperuricemia Is Independently Associated with Coronary Heart Disease and Renal Dysfunction in Patients with Type 2 Diabetes Mellitus

Aims To investigate the relationship between hyperuricemia (HUA) and the clinical backgrounds in Japanese patients with type 2 diabetes mellitus. Methods 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. Results 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. Conclusions 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.

Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3

Internal tandem duplication mutations in the Flt3 tyrosine kinase gene (ITD-Flt3) and overexpression of Survivin are frequently found in patients with acute myeloid leukemia (AML). We investigated whether Survivin mediates the enhanced survival of primary hematopoietic progenitor cells (HPCs) resulting from ITD-Flt3 signaling. Ectopic ITD-Flt3 mutants increased Survivin expression in Ba/F3 cells downstream of PI3-kinase/Akt. Treatment of ITD-Flt3(+) human MV4-11 leukemia cells with the ITD-Flt3 inhibitor SU5416 reduced Survivin expression and inhibited cell proliferation. ITD-Flt3 dramatically increased the number of primary mouse marrow c-kit(+), Sca-1(+), Lin(Neg) cells and colony-forming unit granulocyte-macrophages (CFU-GMs) able to proliferate in the absence of growth factors, whereas Survivin deletion significantly reduced growth factor-independent proliferation and increased apoptosis, which was further accentuated by SU5416. Ectopic ITD-Flt3 reduced differentiation of Lin(Neg) marrow cells cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus stem cell factor, which was partially blocked by Survivin deletion. In addition, Survivin deletion decreased secondary colony formation induced by ITD-Flt3. Dominant-negative (dn)-Survivin delayed development of acute leukemia in mice that received a transplant of Ba/F3 cells expressing ITD-Flt3. These results suggest that Survivin regulates expansion of ITD-Flt3-transformed HPCs with self-renewal capability and development of ITD-Flt3(+) acute leukemia and that antagonizing Survivin may provide therapeutic benefit for patients with acute leukemia expressing ITD-Flt3.

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.

The usefulness of the revised classification for chronic kidney disease by the KDIGO for determining the frequency of diabetic micro- and macroangiopathies in Japanese patients with type 2 diabetes mellitus

AIMS A new classification of chronic kidney disease (CKD) was proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) in 2011. The major point of revision of this classification was the introduction of a two-dimensional staging of the CKD according to the level of albuminuria in addition to the GFR level. Furthermore, the previous CKD stage 3 was subdivided into two stages (G3a and G3b). We examined the prevalence of diabetic micro- and macroangiopathies in patients with type 2 diabetes mellitus based on the new classification. METHODS A cross-sectional study was performed in 2018 patients with type 2 diabetes mellitus. RESULTS All of the diabetic micro- and macroangiopathies significantly more common in the later stages of both the GFR and albuminuria. The proportion of subjects with diabetic retinopathy, neuropathy, cerebrovascular disease and coronary heart disease was significantly higher in the G3b group than in the G3a group. The brachial-ankle pulse wave velocity, which is one of the surrogate markers for atherosclerosis, was also significantly greater in the G3b group compared to the G3a group. CONCLUSION The subdivision of the G3 stage in the revised classification proposed by the KDIGO is useful to evaluate the risk for diabetic vascular complications.

Ex Vivo Expanded Allogeneic Mesenchymal Stem Cells With Bone Marrow Transplantation Improved Osteogenesis in Infants With Severe Hypophosphatasia.

Patients with severe hypophosphatasia (HPP) develop osteogenic impairment with extremely low alkaline phosphatase (ALP) activity, resulting in a fatal course during infancy. Mesenchymal stem cells (MSCs) differentiate into various mesenchymal lineages, including bone and cartilage. The efficacy of allogeneic hematopoietic stem cell transplantation for congenital skeletal and storage disorders is limited, and therefore we focused on MSCs for the treatment of HPP. To determine the effect of MSCs on osteogenesis, we performed multiple infusions of ex vivo expanded allogeneic MSCs for two patients with severe HPP who had undergone bone marrow transplantation (BMT) from asymptomatic relatives harboring the heterozygous mutation. There were improvements in not only bone mineralization but also muscle mass, respiratory function, and mental development, resulting in the patients being alive at the age of 3. After the infusion of MSCs, chimerism analysis of the mesenchymal cell fraction isolated from bone marrow in the patients demonstrated that donor-derived DNA sequences existed. Adverse events of BMT were tolerated, whereas those of MSC infusion did not occur. However, restoration of ALP activity was limited, and normal bony architecture could not be achieved. Our data suggest that multiple MSC infusions, following BMT, were effective and brought about clinical benefits for patients with lethal HPP. Allogeneic MSC-based therapy would be useful for patients with other congenital bone diseases and tissue disorders if the curative strategy to restore clinically normal features, including bony architecture, can be established.

Survivin Selectively Modulates Genes Deregulated in Human Leukemia Stem Cells

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.

The Prevalence of the Risk Factors for Atherosclerosis among Type 2 Diabetic Patients Is Greater in the Progressive Stages of Chronic Kidney Disease

Background/Aims: 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. Methods: 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). Results: 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. Conclusion: 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.

Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1

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 HSCs and hematopoietic progenitor cells. 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-1 transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.

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

BackgroundWe 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.MethodsA 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.ResultsHypertension 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.ConclusionsHypertension 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.

Flow Mediated Dilatation Is Reduced with the Progressive Stages of Glomerular Filtration Rate and Albuminuria in Type 2 Diabetic Patients without Coronary Heart Disease

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.