PubMed Health⌕ Search

Biomedical subjects

T Babazono

Publications and source records attributed to T Babazono.

At least 19 recordsLinked to original sources
PubMed2006

Lower haemoglobin level and subsequent decline in kidney function in type 2 diabetic adults without clinical albuminuria.

AIMS/HYPOTHESIS: Anaemia has been suggested to be an independent risk factor for subsequent progression of advanced diabetic nephropathy; however, the relationship between haemoglobin levels and progression of nephropathy in patients without clinical albuminuria is unknown. METHODS: We conducted this prospective hospital-based cohort study of 464 type 2 diabetic patients (149 women and 315 men, 55+/-13 [mean+/-SD] years of age) with serum creatinine <177 micromol/l (2.00 mg/dl) and urinary albumin : creatinine ratio <300 mg/g creatinine. GFR was estimated using the equation formulated by the Modification of Diet in Renal Disease Study group, refitted for Japanese individuals. Most patients had haemoglobin concentrations in the normal range (144+/-15 g/l), only modest renal impairment (GFR: 74.8+/-14.5 ml min(-1) 1.73 m(-2)), and normal urinary albumin levels (81.5/18.5% with normo-/microalbuminuria). The primary outcome measurement was the rate of change in GFR determined by regression analysis with GFR as a function of time. Patients were followed up for a mean observation period of 5.0+/-0.9 (range: 2.5 to 6.2) years. RESULTS: Univariate and multiple regression analyses yielded a significant association between the rate of change in GFR and baseline haemoglobin concentration. After adjusting for covariates, the rate of decline in GFR was significantly greater in patients in the lowest haemoglobin quartile (-3.27 ml min(-1) 1.73 m(-2) year(-1)) than in the third (-2.71 ml min(-1) 1.73 m(-2) year(-1), p = 0.024) and highest quartiles (-2.78 ml min(-1) 1.73 m(-2) year(-1), p = 0.046). CONCLUSIONS/INTERPRETATION: Lower haemoglobin concentrations in type 2 diabetic patients without clinical albuminuria may be a significant predictor of subsequent decline in GFR.

Adult↗
PubMed2005

Single nucleotide polymorphisms in the gene encoding Krüppel-like factor 7 are associated with type 2 diabetes.

AIMS/HYPOTHESIS: Although genetic susceptibility plays an important role in the pathogenesis of type 2 diabetes, most of the genes that influence susceptibility to type 2 diabetes have yet to be identified. Krüppel-like transcription factors are known to play important roles in development and cell differentiation, and have recently been implicated in the pathogenesis of type 2 diabetes. The present study aimed to examine the associations of single nucleotide polymorphisms (SNPs) in genes encoding members of the Krüppel-like-factor (KLF) family with type 2 diabetes in a large cohort of Japanese subjects. METHODS: We genotyped 33 SNP loci found in 12 KLF genes in subjects with type 2 diabetes and in subjects from the general population using the PCR-Invader assay. We also examined the effects of the overexpression of KLF7 on adipogenesis in 3T3-L1 cells. RESULTS: We identified a significant association between an SNP in KLF7 and type 2 diabetes (A vs C: p=0.004 after Bonferroni's correction, odds ratio=1.59, 95% CI 1.27-2.00). The expression of Klf7 decreased in response to the differentiation of 3T3-L1 adipocytes, and the overexpression of KLF7 resulted in significant inhibition of adipogenesis in 3T3-L1 cells. CONCLUSIONS/INTERPRETATION: These results indicate that the gene encoding KLF7 is a novel candidate for conferring genetic susceptibility to type 2 diabetes.

3T3 Cells↗
PubMed2001

Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in Japanese patients with diabetes mellitus and end stage renal disease.

The A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene (mt.3243A>G) is associated with both diabetes mellitus and myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recently, this mutation was found in three diabetic subjects with progressive kidney disease, suggesting that it may be a contributing factor in the development of kidney disease in patients with diabetes. The aim of this study was to evaluate the contribution of this mutation to the development of end stage renal disease (ESRD) in patients with diabetes. The study group consisted of 135 patients with diabetes and ESRD. The control group consisted of 92 non-diabetic subjects with ESRD who were receiving hemodialysis. The mt.3243A>G mutation was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found the mt.3243A>G mutation in eight patients (8/135; 5.9%), all of whom were initially diagnosed with type II diabetes. Five of the eight patients were subsequently also diagnosed with MELAS. We did not find the mutation in any of the 92 nondiabetic subjects with ESRD. The prevalence of this mutation was 6.5-fold higher in patients with diabetes and ESRD than in those with diabetes alone (8/135 vs 5/550, respectively; chi2 = 13.704; P = 0.0002). The mt.3243A>G mutation may be a contributing genetic factor in the development of ESRD in Japanese patients with diabetes.

Adult↗
PubMed2001

High glucose stimulates hyaluronan production by renal interstitial fibroblasts through the protein kinase C and transforming growth factor-beta cascade.

Deposition of hyaluronan has been implicated in the pathogenesis of diabetic glomerulosclerosis. We hypothesized the involvement of hyaluronan in diabetic tubulointerstitial fibrosis. We investigated high-glucose effect on hyaluronan production by rat renal interstitial fibroblasts (normal rat kidney [NRK] cells) and examined the role of hyaluronan in NRK cell proliferation. The involvement of protein kinase C (PKC) and transforming growth factor-beta (TGF-beta) in this response was also examined. After 24 hours of incubation in medium containing 25.6 mmol/L glucose, production of hyaluronan by NRK cells was significantly increased compared with medium containing 5.6 mmol/L glucose (P <.01). L-glucose and mannitol had no effect on hyaluronan production. High glucose enhanced basal in situ PKC activity (P <.01), and both an activator of PKC (phorbol 12-myristate 13-acetate; [PMA]) and TGF-beta 1 were able to increase hyaluronan production by NRK cells (P <.01). The effect of high glucose on hyaluronan production was diminished by coincubating cells with PKC inhibitors (staurosporine [Stp] or calphostin C [CpC]) or with an anti-TGF-beta neutralizing antibody. Stimulation of hyaluronan production by PMA was also normalized by anti TGFbeta neutralizing antibody, but the effect of TGF-beta1 was not affected by inhibition of PKC. Finally, incubating quiescent NRK cells with 50 or 100 ng/mL hyaluronan for 24 hours significantly increased NRK cell number (P <.01). In conclusion, high glucose stimulates hyaluronan production through the PKC/TGF-beta cascade. Increased hyaluronan promotes NRK cell proliferation. These results suggest that hyaluronan may play a role in the pathogenesis of interstitial fibrosis in diabetic kidney disease.

Animals↗
PubMed1999

Effect of high glucose on mesangial cell protein kinase C-delta and -epsilon is polyol pathway-dependent.

In diabetes mellitus, enhanced activity of mesangial cell protein kinase C (PKC) may contribute to nephropathy. The purpose of this study was to determine whether high glucose alters mesangial cell diacylglycerol-sensitive PKC-alpha, -beta2, -delta, and -epsilon content, cellular distribution, and activity through polyol pathway activation. Primary cultured rat mesangial cells (passage 10) were growth-arrested in 0.5% fetal bovine serum and cultured in 5.6 mM glucose (NG) or 30 mM glucose (HG) for 48 h, with or without the aldose reductase inhibitor tolrestat or ARI-509. PKC isoform content in total cell lysates, or cytosol, membrane (Triton X-soluble), and particulate (sodium dodecyl sulfate-soluble) fractions was analyzed by immunoblotting, and band density in HG was expressed as a percentage of corresponding NG values. In HG at 48 h, increased total PKC-alpha (222 +/- 17% of NG, P < 0.001), -beta2 (209 +/- 12%, P < 0.001), and -epsilon (195 +/- 19%, P < 0.001) were observed. L-Glucose had no effect on total PKC isoform content. HG caused increased membrane- and particulate-associated PKC-alpha (257 +/- 87 and 327 +/- 66%, respectively, P < 0.05), membrane-associated PKC-delta (143 +/- 10%, P < 0.05), and membrane-associated PKC-epsilon (186 +/- 11%, P < 0.001), with no change in cytosol contents. The HG effects were not mimicked by L-glucose. In NG or HG, PKC-beta2 was not detected in the cytosol fraction, and membrane and particulate association were unchanged with phorbol ester stimulation. Confocal immunofluorescence imaging revealed that in HG, PKC-alpha, -delta, and -epsilon translocate to the nucleus and plasma membrane. Total PKC activity measured by in situ 32P-phosphorylation of the epidermal growth factor receptor substrate increased from 18 +/- 1 pmol/min per mg cell protein in NG to 33 +/- 3 pmol/min per mg cell protein in HG (P < 0.002 versus NG). In NG, tolrestat and ARI-509 exposure caused increased PKC activity, enhanced accumulation of total PKC-alpha and -beta2, with no change in total or fractional recovery of PKC-delta or -epsilon. In HG, tolrestat and ARI-509 prevented the increase in total PKC-epsilon and membrane-associated PKC-delta and -epsilon. It is concluded that within 48 h of HG, enhanced mesangial cell PKC activity is associated with accumulation and cellular redistribution of diacylglycerol-sensitive PKC isoforms, and that increased PKC-epsilon content and membrane-associated PKC-delta and -epsilon are dependent on polyol pathway activation.

Animals↗
PubMed1999

[Current status and future prospect of pancreas and islet transplantation].

As of November 1997, 9,891 pancreas transplantation were reported to the International Pancreas Transplant Registry. In the United States, for all 1994-97, SPK, PAK, and PTA transplants, one-year graft survival rates were 82%, 71%, and 62%, respectively. The 1994-97 pancreas survival rates in all categories were higher than in previous eras. The improvement in graft survival rates has been associated with the introduction of FK506 and MMF, but excellent results are seen with cyclosporine, so the improvement may in part be due to the increasing experience that centers now have with pancreas transplantation. Although the standard surgical procedure remains pancreas-exocrine bladder drainage, the number of enteric drainage cases is increasing. It has been reported that the portal venous and enteric drainages are safe, with outcomes similar to those of standard technique. It appears that these will become the standard methods in the near future. Although 15 pancreas transplantations have been carried out in Japan, they ceased after 1994. Currently, social debate to determine the rules governing such procedures is ongoing. As of December 1995, 306 adult islet allotransplantation were reported to the Islet Transplant Registry. One-year islet survival rates were 27% in cases for 1990-94. Islet transplantation has the potential to be the most physiological advantage for the treatment of diabetes mellitus. However, the endocrine function provided by these transplants has been far from optimal.

Adult↗
PubMed1998

High glucose-induced mesangial cell altered contractility: role of the polyol pathway.

Glomerular mesangial cells cultured in high glucose conditions display impaired contractile responsiveness. It was postulated that glucose metabolism through the polyol pathway leads to altered mesangial cell contractility involving protein kinase C. Rat mesangial cells were growth-arrested for 24 h with 0.5% fetal bovine serum in either normal (5.6 mmol/l) or high (30 mmol/l) glucose concentrations or high glucose plus the aldose reductase inhibitor, ARI-509 (100 micromol/l). The reduction of cell planar surface area (contraction) in response to endothelin-1 (0.1 micromol/l), or to phorbol 12-myristate 13-acetate (50 pmol/l), was studied by videomicroscopy. In response to endothelin-1, mesangial cells in normal glucose contracted to 52+/-3% of initial planar area. In high glucose, the significantly (p < 0.05) smaller cell size and no contractile responsiveness to endothelin-1 were normalized with ARI-509. Membrane-associated diacylglycerol, measured by a kinase specific 32P-phosphorylation assay, in high glucose was unchanged after 3 h, but significantly increased (p < 0.05) after 24 h which was normalized with ARI-509. Protein kinase C activity, measured by in situ 32P-phosphorylation of the epidermal growth factor receptor substrate was: increased by 32% at 3 h of high glucose, unchanged by ARI-509; and decreased significantly (p < 0.05) at 24 h compared to cells in normal glucose, normalized by ARI-509. Total cellular protein kinase C-alpha, -delta and -epsilon, analysed by immunoblotting, were unchanged in high glucose at 24 h. Only protein kinase C-epsilon content was reduced by ARI-509 in both normal and high glucose. Therefore, high glucose-induced loss of mesangial cell contractility, diacylglycerol accumulation and altered protein kinase C activity are mediated through activation of the polyol-pathway, although no specific relationship between elevated diacylglycerol and protein kinase C activity was observed. In high glucose, altered protein kinase C function, or another mechanism related to the polyol pathway, contribute to loss of mesangial cell contractile responsiveness.

Aldehyde Reductase↗
PubMed1998

Circulating proinsulin levels in insulin-dependent diabetic patients after whole pancreas-kidney transplantation.

Disproportional hyperproinsulinemia is a sensitive marker for beta-cell dysfunction. The objective of this study was to assess the proinsulin profile in persons with insulin-dependent diabetes mellitus (IDDM) after pancreas-kidney transplantation. We determined serum insulin, C-peptide, and proinsulin concentrations during an oral glucose challenge in five pancreas-kidney transplant recipients, nine nondiabetic kidney transplant recipients, and 17 normal subjects. Basal proinsulin concentrations were significantly increased in pancreas-kidney recipients (geometric mean [+/-1 SE range], 6.0 [5.5 to 6.4] pmol/L) and kidney recipients (6.4 [5.4 to 7.5] pmol/L) compared with the normal subjects (2.8 [2.5 to 3.2] pmol/L). Integrated proinsulin concentrations during the oral glucose load were also higher in pancreas-kidney recipients (1.4 [1.1 to 1.8] nmol/L x min) and kidney recipients (1.5 [1.2 to 2.0] nmol/L x min) versus normal subjects (0.8 [0.7 to 0.9] nmol/L x min). There was no difference in basal or integrated proinsulin concentrations between the two transplant groups. Even after adjustment for the glomerular filtration rate (GFR), basal and incremental proinsulin concentrations continued to be higher in the transplant groups than in the normal subjects. Proinsulin to C-peptide molar ratios both before and after the glucose load were similar in the three groups. From these findings, we conclude that pancreas-kidney transplantation provokes proportional hyperproinsulinemia, which is closely associated with its reduced clearance in the kidneys.

Adult↗
PubMed1998

An IDDM patient who complained of chest oppression with ischemic changes on ECG in insulin-induced hypoglycemia.

A 34-year-old female IDDM patient complained of chest oppression in hypoglycemic episodes and electrocardiograms revealed reversible ischemic changes occurring concomitantly with hypoglycemia. The ECG changes improved and the chest oppression disappeared following increasing blood glucose level by glucose intake. Master's double load test and treadmill load test were positive for ischemic changes. Radioisotopic myocardial scintigraphy by thallium and BMIPP did not show any filling defects and coronary angiography revealed no remarked stenosis in the coronary arteries. She had no mitochondrial tRNA(Leu) (A-->G) gene mutation at nucleotide position 3243, but both the patient and her mother had a G-to-A transition within the replication origin of the light strand at nucleotide position 5744 of the mitochondrial gene. As the patient's maternal family had no history of ischemic heart disease, it is not clear whether mitochondrial gene mutation at nucleotide position 5744 reflects the occurrence of cardiac ischemia. Some disorders of microcirculation in capillary vessels in cardiac muscles may occur in such patients.

Adult↗
PubMed1998

Altered expression and subcellular localization of diacylglycerol-sensitive protein kinase C isoforms in diabetic rat glomerular cells.

Protein kinase C (PKC) is implicated in the pathogenesis of diabetic nephropathy. This study was designed to identify the expression of diacylglycerol (DAG)-sensitive PKC-alpha, -betaII, -delta, and -epsilon isoforms in normal and diabetic rat glomerular cells and to determine the effects of high glucose and insulin on PKC isoform cellular compartmentalization and PKC activity. Diabetic rats treated with or without insulin and normal rats were examined 2 and 4 weeks after streptozotocin/vehicle injection. Renal cortical tissue immunogold-labeled with anti-PKC-alpha, -betaII, -delta, or -epsilon antibody was visualized by electron microscopy. From isolated glomeruli, total cell lysate and cytosol and membrane fractions were immunoblotted with the same anti-PKC isoform antibodies. PKC activity in isolated glomeruli was measured by 32P-phosphorylation of the epidermal growth factor (EGF)-receptor substrate. Immunogold labeling revealed expression of the four PKC isoforms by glomerular visceral epithelial, endothelial, and mesangial cells of both normal and diabetic rats. Immunoblot analysis of the diabetic rat glomeruli at 2 weeks demonstrated a significant increase in membrane-associated PKC-alpha, -delta, and -epsilon and a significant decrease in membrane PKC-betaII content compared with normal, which were similar at 4 weeks. Insulin treatment normalized membrane PKC isoform contents and caused a significant decrease in the cytosol content of PKC-alpha, -betaII, and -delta and total cellular PKC-alpha compared with normal. Although PKC activity in the cells of diabetic rat glomeruli was increased by 20% compared with normal, the difference did not reach statistical significance. In insulin-treated diabetic rat glomeruli, PKC activity was significantly decreased compared with non-insulin-treated diabetic rat glomeruli. In conclusion, DAG-sensitive PKC-alpha, -betaII, -delta, and -epsilon isoforms are all found in the three major glomerular cell types in rats, and the expression, compartmentalization, and activity are modulated independently by high glucose and insulin.

Animals↗
PubMed1997

Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients.

A progressive decline in glomerular function occurs in diabetic nephropathy. The predictive effects of progression promoters were examined in 182 non-insulin-dependent diabetic patients from a baseline serum creatinine concentration of 133 mumol/l. During a total of 605 person-years follow-up, 107 patients developed end-stage renal failure requiring dialysis. The rate of decline of renal function was highly variable. Urinary protein excretion was the strongest predictor correlated to the rate of decline, followed by diastolic and systolic blood pressure, total cholesterol and platelet count, while the protective effects were seen in serum albumin and haematocrit. Adjustment for urinary protein excretion revealed that diastolic blood pressure, familial predisposition to hypertension, serum albumin, and smoking were independent significant predictors. Angiotensin converting enzyme inhibitors (ACE-I) significantly retarded the development of end-stage renal failure compared to antihypertensives other than ACE-I (mostly nifedipine), and the effect was evident particularly in patients with proteinuria below the median (2.5 g/24 h) (presumably those who responded to ACE-I). A complex effect of proteinuria in association with blood pressure elevation, familial predisposition to hypertension, hypoalbuminaemia, and smoking may play an important role in the progression of nephropathy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Assessment of insulin resistance in acromegaly associated with diabetes mellitus before and after transsphenoidal adenomectomy.

With a euglycemic hyperinsulinemic clamp method, whole-body insulin resistance was assessed in 6 cases with acromegaly associated with diabetes mellitus before and after transsphenoidal adenomectomy. The glucose infusion rate (GIR) correlated well with the plasma IGF-I level but poorly with that of GH. Further improvement in insulin sensitivity occurred 3-4 months after operation without substantial changes in plasma levels of both GH and IGF-I or glycemic control. These results indicate that GH excess can induce insulin resistance in association with plasma IGF-I and also through undefined secondary effect.

Acromegaly↗