[Show abstract][Hide abstract] ABSTRACT: To evaluate the efficacy of switching from insulin to the GLP-1 receptor agonist liraglutide in type 2 diabetes mellitus patients.
The subjects were 231 outpatients with type 2 diabetes mellitus being treated with liraglutide for the first time. For 161 patients, liraglutide was continued for 24 weeks (continuation group), and for 70 patients, liraglutide was discontinued before 24 weeks (discontinuation group). Fasting and postprandial blood glucose levels, HbA1c, body weight, and insulin dose were evaluated before the switch to liraglutide (baseline) and at 12 and 24 weeks of administration. Trends in HbA1c and weight were compared at 12 and 24 weeks of administration. Multiple regression analyses were conducted to identify clinical factors predicting a successful switch to liraglutide.
Multiple regression analysis with ΔHbA1c as the dependent variable in the continuation group indicated that HbA1c at 12 weeks of administration decreased with higher baseline HbA1c and increased with higher baseline daily insulin doses. Multiple regression analysis with Δweight as the dependent variable indicated that Δweight at 24 weeks of liraglutide administration was higher with higher baseline daily insulin doses and longer duration of diabetes. Based on the area under the receiver operating characteristic curve, cut-off values of 19 units for daily insulin dose and nine years for duration of diabetes were identified.
Switching from insulin to liraglutide therapy is possible for carefully selected patients. Daily insulin dosage and duration of insulin therapy appear to be clinically useful indicators for the efficacy of liraglutide therapy.
Journal of Clinical Medicine Research 04/2014; 6(2):138-44.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: A recent genome-wide association study for diabetic nephropathy in European type 1 diabetes identified 3 candidate loci for diabetic nephropathy. In this study, we examined the association of the 3 single nucleotide polymorphism (SNP) loci with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. METHODS: We genotyped 3 SNPs, rs7583877 in AFF3, rs12437854 in the RGMA-MCTP2 locus and rs7588550 in ERBB4, for 2,300 Japanese patients with type 2 diabetes [initial study, 1,055 nephropathy cases with overt proteinuria or with end-stage renal disease (ESRD) and 1,245 control patients with normoalbuminuria]. The association of these SNPs with diabetic nephropathy was examined by using a logistic regression analysis. RESULTS: We observed a significant association of rs7588550 in ERBB4 with diabetic nephropathy in the Japanese patients with type 2 diabetes, although the effect direction was not consistent with that in the European study [p = 0.0126, odds ratio (OR) = 0.79, 95 % confidence interval (CI): 0.65-0.95]. We further examined the association of rs7588550 with diabetic nephropathy in an independent Japanese cohort (596 nephropathy cases and 311 controls) and observed the same trend of the association with the initial study. We did not observe any association of the remaining 2 SNP loci with diabetic nephropathy in the present Japanese sample. CONCLUSION: The association of SNP loci derived from GWAS in European type 1 diabetes with diabetic nephropathy was not replicated in the Japanese patients with type 2 diabetes, although the ERBB4 locus may have some effect also in Japanese type 2 diabetes.
Clinical and Experimental Nephrology 03/2013; · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22-23, and polymorphisms within the carnosine dipeptidase 1 gene (CNDP1), located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the CNDP1/CNDP 2 locus with diabetic nephropathy in Japanese subjects with type 2 diabetes.
We genotyped a leucine repeat polymorphism (D18S880) that is within CNDP1 along with 29 single nucleotide polymorphisms (SNPs) in the CNDP1/CNDP2 locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the CNDP1/CNDP2 locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in CNDP1 was nominally associated with diabetic nephropathy in women (rs12604675-A; p = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19-2.61). Rs12604675 was associated with overt proteinuria (p = 0.002, OR = 2.18, 95% CI, 1.32-3.60), but not with ESRD in Japanese women with type 2 diabetes.
Rs12604675-A in CNDP1 may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.
PLoS ONE 01/2013; 8(1):e54064. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective To evaluate the effects of six-month liraglutide treatment on body weight, visceral and subcutaneous fat and related markers in Japanese type 2 diabetic patients. Methods A total of 59 patients with type 2 diabetes were treated with liraglutide (0.3 mg/day for ≥1 week and then 0.6 mg/day for ≥1 week, gradually increasing the dose to 0.9 mg/day) for six months. Changes in body weight, body mass index (BMI), HbA1c, the fasting blood glucose level, visceral and subcutaneous fat areas, hepatic and renal CT values and the associated markers proinsulin, adiponectin and pentraxin (PTX) 3 were measured. Results The study included one treatment-naïve patient, 10 patients who were switched from oral antidiabetic drugs and 35 patients who were switched from insulin therapy. At six months after treatment, the preprandial blood glucose levels were higher (148.8±40.5 mg/dL) than the baseline values (130.8±36.7, p<0.05); however, body weight, BMI and abdominal circumference were lower, and the liver/kidney CT ratio improved significantly from 1.64±0.44 at baseline to 1.78±0.42. An analysis of the patients who were not pretreated with insulin resistance ameliorators showed that six months of liraglutide treatment significantly decreased the subcutaneous but not visceral fat areas, significantly decreased the serum adiponectin levels and significantly increased the serum PTX3 levels. Conclusion In addition to its glucose-lowering effects, liraglutide exhibits weight loss promotion actions, reducing subcutaneous fat areas in particular. The weight and total fat area reduction properties of liraglutide are likely to be beneficial when this medication is used in combination with other oral antidiabetic drugs and insulin.
Internal Medicine 01/2013; 52(10):1029-34. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: To examine the clinical utility of once-daily insulin glargine, we studied the clinical course of patients who were switched to from twice-daily premixed insulin to once daily insulin glargine. Methods: The study was conducted at Tokai University hospital in 20 patients with type 2 diabetes, whose treatment regimens were switched from twice-a-day premixed insulin formulation to once-a-day insulin glargine. Changes in various clinical indexes were studied during a 3-year period after the switch. We also compared the well-controlled group (hemoglobin A1c, HbA1c, levels maintained at less than 6.9%) and poorly-controlled group (HbA1c levels at 7.4% or higher). Results: During the 3-year period, all patients showed significant decrease in HbA1c levels and tendency for reduced daily dose of insulin. Although both BMI and insulin dose tended to decrease in the well-controlled group, they increased in the poorly controlled group. Conclusion: The findings suggest that in type 2 diabetes, once-a-day insulin glargine could be more useful than twice-a-day premixed insulin formulation. Poor adherence was observed in the poorly-controlled group, namely lack of thoroughness in self-monitoring of blood glucose and adherence to diet and exercise therapy, thus emphasizing the importance of diabetes education.
The Tokai journal of experimental and clinical medicine 01/2013; 38(1):28-32.
[Show abstract][Hide abstract] ABSTRACT: Aims
To (1) measure urinary albumin and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus (DM) in Kanagawa Prefecture, (2) assess the validity of the diabetic nephropathy (DN) stage classification system and current chronic kidney disease (CKD) stage classification system from the Kidney Disease Outcomes Quality Initiative—Kidney Disease: Improving Global Outcomes (K/DOQI-KDIGO), and (3) validate the new CKD stage classification system of KIDIGO 2009.
Subjects and methods
The Kanagawa Physicians Association conducted a survey across 255 medical institutions over six months and measured urinary creatinine-corrected urinary albumin levels in 4,885 subjects, in addition to height, weight, blood pressure, sex, age, urinalysis, urinary albumin, blood glucose, hemoglobin A1c, and serum creatinine levels.
In stages 1 and 2 of the DN classification system, many patients with urinary albumin <300 mg/g Cr had low eGFR. More than 1,000 such cases were unclassifiable. Similarly, many patients had inconsistent urinary albumin levels and eGFRs and thus could not be classified. Using the current CKD stage classification system, 735 patients (15.0 %) were unclassifiable as they had normoalbuminuria with stage 1 renal function, and 1,921 patients (about 40 %) were excluded based on normoalbuminuria with stage 2 renal function. However, all patients were successfully classified by the new CKD stage classification system.
All of the patients were successfully classified by the new CKD stage classification system. However, many patients were elderly and hypertensive and thus likely to have diseases other than DN. Regular monitoring of diabetics for urinary albumin and eGFR should enhance the early detection of DN and enable appropriate intervention.
[Show abstract][Hide abstract] ABSTRACT: Background: Diabetic patients on hemodialysis often experience severe hypoglycemia during intensive insulin therapy using conventional neutral protamine hagedorn (NPH) or nonintensive therapy with premixed insulin. Insulin glargine can simulate normal basal insulin secretion. We investigated the efficacy and safety of switching from NPH to glargine in type 2 diabetes patients on hemodialysis. Methods: Hemodialysis patients who were being treated with NPH-based basal-bolus insulin therapy, regular insulin, NPH insulin or premixed insulin were switched to glargine. The target early morning fasting blood glucose (FBG) level was 110 mg/dL. Any increase in glargine dose was coupled with a reduction in the dose of any regular or rapid-acting insulin analogue as far as possible while maintaining a constant daily insulin dose. FBG, HbA1c, daily insulin dosage, percentage of basal insulin dose in total daily insulin dose, body weight and incidence of hypoglycemic events were evaluated during the study period. Quality of life (QOL) was measured with a short questionnaire. Results: HbA1c improved significantly during the observation period after switching. The daily insulin dose was reduced from 20.1 ± 15.2 to 18.1 ± 15.1 U/day, although the change was not statistically significant. FBG decreased significantly from 174.4 ± 58.7 to 126.2 ± 27.7 mg/dL. Body weight measured after dialysis did not change, and there were no changes in hemoglobin or hematocrit. The frequency of hypoglycemic episodes decreased significantly. QOL reports with switching to glargine were improved compared with those before switching. Conclusion: The results suggest that glargine is useful, can improve QOL of diabetic patients on hemodialysis, and achieve better glycemic control than NPH.
Journal of nephrology 02/2012; · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Attempts to achieve strict glycemic control with basal-bolus insulin therapy required increased dosages of neutral protamine Hagedorn (NPH) insulin. However, high dosage of NPH insulin often occurs nocturnal hypoglycemia. Insulin glargine can simulate normal basal insulin secretion with its flat time-action profiles. To confirm the efficacy of insulin glargine we investigated the type 2 diabetic patients on basal-bolus insulin therapy whose basal insulin was switched from NPH insulin to insulin glargine.
The Japanese 400 patients with type 2 diabetes on basal-bolus insulin therapy whose basal insulin was switched from NPH insulin to insulin glargine were followed-up. After the switching, the basal insulin was increased with reference to the self-monitoring of blood glucose results, with the aim of maintaining fasting blood sugar (FBS) level at 110 mg/dL, and simultaneously reducing the bolus insulin dosage to maintain the total daily insulin dosage.
We were able to lower FBS significantly with almost no serious hypoglycemia. HbA1c also improved significantly. The improvements in FBS and HbA1c levels did not require a significant increase in the total insulin dosage.
Our results suggest that basal insulin supplementation using insulin glargine is a useful method to control not only FBS but also HbA1c.
The Tokai journal of experimental and clinical medicine 01/2012; 37(2):35-40.
[Show abstract][Hide abstract] ABSTRACT: To determine the clinical usefulness of basal-supported oral therapy (BOT) using insulin glargine in Japanese patients with type 2 diabetes.
We compared HbA1c levels, body weight, and insulin doses before the introduction of BOT and in the final month of the observation period in 122 patients with type 2 diabetes who received BOT with insulin glargine between October 2007 and July 2009. To exclude the possible effects of seasonal changes in glycemic control, 57 of the 122 patients were followed-up for one year and examined for changes in HbA1c levels, body weight, and insulin dose.
Examination of all cases (n=122) showed a significant decrease in HbA1c (before BOT: 8.7±1.8, after: 7.1±1.1%), but no significant change in body weight (before: 63.1±16.1, after: 63.8±17.0 kg). The mean observation period was 10.5±6.4 months. Insulin doses were significantly increased during the study. HbA1c levels improved significantly in patients on non-insulin-secreting drugs (biguanide, α-glucosidase inhibitor and thiazolidine derivatives) than those on insulin-secreting drugs (SU agents and glinides).
BOT with insulin glargine is a useful strategy that can achieve good glycemic control in clinical practice without causing serious hypoglycemia. The introduction of BOT before exhaustion of pancreatic β cells may increase its effectiveness.
The Tokai journal of experimental and clinical medicine 01/2012; 37(2):41-6.
[Show abstract][Hide abstract] ABSTRACT: We previously reported that fibroblast-specific protein 1 (FSP1) is a marker of epithelial-mesenchymal transition (EMT) in tubulointerstitial fibrosis. The EMT-like changes observed in podocytes are reportedly associated with podocyte detachment which may cause focal glomerulosclerosis.
In cross-sectional studies, we analyzed podocyte expression of FSP1 immunohistochemically using renal biopsy specimens from 31 patients with focal segmental glomerulosclerosis (FSGS) and 39 patients with minimal change disease (MCD). We also semiquantitatively analyzed glomerular expression of FSP1 mRNA using laser capture microdissection and real-time PCR.
We found that FSP1 was localized to podocytes in both FSGS and MCD patients; however, the number of FSP1(+) podocytes per glomerular profile was significantly higher in patients with FSGS than in those with MCD, and there was a corresponding difference in the levels of FSP1 mRNA. FSP1(+) podocyte counts per glomerular profile in FSGS patients correlated significantly with the prevalence of glomerulosclerosis and the extent of interstitial type-I collagen-positive areas.
Taken together, these data suggest that podocyte expression of FSP1 could shed light on the potential linkage between EMT-like changes, detachment of podocytes from the glomerular basal membrane and the pathophysiology underlying FSGS.
Nephron Clinical Practice 11/2011; 120(1):c1-7. · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence has shown that diabetic patients are increasing in number, and renal and cardiovascular complications are the most common cause of death in diabetic patients. Thus, it would be of considerable value to identify the mechanisms involved in the progression of renal impairment and cardiovascular injury associated with diabetes. Recent evidence also indicated that multifactorial intervention is able to reduce the risk of cardiovascular disease and death among patients with diabetes and microalbuninuria. In this pilot study, we examined the effects of intensified multifactorial intervention, with tight glucose regulation and the use of valsartan and fluvastatin on ambulatory blood pressure (BP) profile, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio (UACR), in 20 hypertensive patients (16 male and 4 female) with type 2 diabetes mellitus and overt nephropathy. After 12 months of intensified treatment, office BP, fasting plasma glucose (FPG), and low-density lipoprotein cholesterol (LDLC) were significantly decreased compared to baseline (systolic blood pressure (SBP), 130 ± 2 vs. 150 ± 1 mmHg; diastolic blood pressure (DBP), 76 ± 1 vs. 86 ± 1 mmHg; FPG, 117 ± 5 vs. 153 ± 7 mg/dl; LDLC, 116 ± 8 vs. 162 ± 5 mg/dl, P < 0.0001). Also, compared to the baseline values, the daytime and nighttime ambulatory BP and short-term BP variability were significantly decreased after 12 months. Furthermore, while eGFR was not altered (44.3 ± 5.1 vs. 44.3 ± 6.5 ml/min/1.73 m(2), not significant (NS)), UACR showed a significant reduction after 12 months of intensified treatment (1228 ± 355 vs. 2340 ± 381 mg/g-cr, P < 0.05). These results suggest that the intensified multifactorial intervention is able to improve ambulatory BP profile, preserve renal function, and reduce urinary albumin excretion in type 2 diabetic hypertensive patients with overt nephropathy.
Clinical and Experimental Hypertension 07/2011; 33(4):255-63. · 1.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tubulointerstitial fibrosis (TIF) is seen as the final stage of progressive nephropathy, and the degree of TIF is reported to be a major determinant in renal outcomes. In recent years, epithelial-mesenchymal transition (EMT) and the zinc-finger transcription factor snail homolog 1 (Snai1) have each been implicated in the mechanism of TIF. The relationship between EMT and these transcription factors is unclear, however, so in this study we attempted to elucidate the correlation between the expression of Snai1 and clinical markers.
We performed immunohistochemical staining on human renal tissue obtained from patients with diabetic nephropathy (DN), IgA nephropathy (IgAN), minimal change disease (MCD) and minor glomerular abnormality (MGA) using anti-Snai1 and anti-vimentin antibodies. We counted Snai1-positive and Snai1/vimentin double positive tubular epithelial cells.
Snai1 protein was mainly observed in the nuclei of flattened, damaged tubular epithelial cells, especially in IgAN and DN, and positive cell numbers were significantly higher in IgAN than in MGA, MCD or DN. Snai1/vimentin double staining showed that some vimentin-positive tubular epithelial cells also contained Snai1-positive nuclei, and double positive cell numbers were increased in IgAN and DN. Statistical analysis revealed positive correlations between Snai1/vimentin double positive cell numbers and proteinuria and creatinine in IgAN. Positive correlations were also seen between Snai1/vimentin double positive cell numbers and the severity of proteinuria in DN.
The results of this study indicate that Snai1 plays an important role in TIF in patients with progressive nephropathy.
Journal of nephrology 06/2011; 25(2):233-9. · 2.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy.
We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran-Armitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association.
We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy (P < 0.05), and subsequent haplotype analysis revealed that a haplotype consisting of the 11 SNPs within SIRT1 locus had a stronger association (P = 0.0028).
These results indicate that SIRT1 may play a role in susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes.
Clinical and Experimental Nephrology 02/2011; 15(3):381-90. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The intrarenal renin-angiotensin system plays a crucial role in the regulation of renal circulation and sodium reabsorption through the activation of vascular, glomerular, and tubular angiotensin II type 1 (AT(1)) receptor signaling. We previously cloned a molecule that specifically interacted with the murine AT(1) receptor to inhibit AT(1) receptor signaling, which we named ATRAP (for AT(1) receptor-associated protein). Since murine ATRAP was shown to be highly expressed in the kidney, in the present study we investigated expression and distribution of human ATRAP in normal kidney and renal biopsy specimens from patients with IgA nephropathy. In the normal human kidney, both ATRAP mRNA and protein were widely and abundantly distributed along the renal tubules from Bowman's capsule to the medullary collecting ducts. In all renal tubular epithelial cells, the ATRAP protein colocalized with the AT(1) receptor. In renal biopsy specimens with IgA nephropathy, a significant positive correlation between ATRAP and AT(1) receptor gene expression was observed. There was also a positive relationship between tubulointerstitial ATRAP expression and the estimated glomerular filtration rate in patients with IgA nephropathy. Furthermore, we examined the function of the tubular AT(1) receptor using an immortalized cell line of mouse distal convoluted tubule cells (mDCT) and found that overexpression of ATRAP by adenoviral gene transfer suppressed the angiotensin II-mediated increases in transforming growth factor-β production in mDCT cells. These findings suggest that ATRAP might play a role in balancing the renal renin-angiotensin system synergistically with the AT(1) receptor by counterregulatory effects in IgA nephropathy and propose an antagonistic effect of tubular ATRAP on AT(1) receptor signaling.
[Show abstract][Hide abstract] ABSTRACT: Genetic factors are believed to contribute to the development and progression of diabetic nephropathy. Recently, a genome-wide association study for diabetic nephropathy revealed four novel candidate loci in European American subjects with type 1 diabetes. In this study, we determined the association of the four loci with diabetic nephropathy in Japanese subjects with type 2 diabetes.
We genotyped 11 singlenucleotide polymorphisms (SNPs) in four distinct loci (rs39059 and rs39075 in the CPVL/CHN2, rs1888747 and rs10868025 in FRMD3, rs739401 and rs451041 in CARS, and rs1041466, rs1411766, rs6492208, rs7989848, and rs9521445 in a chromosome 13q locus) in four independent Japanese populations.
Six SNPs were nominally associated with diabetic nephropathy in one of the four Japanese populations (P < 0.05; rs451041 in study 1; rs39059 and rs1888747 in study 3; rs1411766 in studies 1 and 4; and rs7989848 and rs9521445 in study 4); however, no significant association was observed for any SNP after correction for multiple testing errors in the individual populations. Nevertheless, a meta-analysis performed for the data obtained from all four populations revealed that one SNP (rs1411766) in chromosome 13q was significantly associated with diabetic nephropathy in the Japanese populations (nominal P = 0.004, corrected P = 0.04, odds ratio 1.26 [95% CI = 1.07-1.47]).
Our results suggest that the rs1411766 locus may be commonly involved in conferring susceptibility to diabetic nephropathy among subjects with type 1 or type 2 diabetes across different ethnic groups.
[Show abstract][Hide abstract] ABSTRACT: Genetic factors have been considered to contribute to the development and progression of diabetic nephropathy. The KCNQ1 gene (potassium voltage-gated channel, KQT-like subfamily, member 1) was originally identified as a strong susceptibility gene for type 2 diabetes in two Japanese genome-wide association studies. In this study, we examined the association of single nucleotide polymorphisms (SNPs) within KCNQ1 with diabetic nephropathy in Japanese subjects with type 2 diabetes.
We genotyped 33 SNPs in KCNQ1 using 754 type 2 diabetic patients with overt nephropathy and 558 control subjects (an initial study), and we further examined the association of a candidate SNP using three other independent Japanese populations (replications 1-3).
We found that five SNPs were nominally associated with diabetic nephropathy, and the association of rs2237897 was the strongest. We also found that the T allele frequencies of rs2237897 were consistently higher in the nephropathy groups than in the control groups for all study populations (initial study: 0.33 vs. 0.27; replication 1: 0.32 vs. 0.30; replication 2: 0.33 vs. 0.28; and replication 3: 0.32 vs. 0.28), although the individual associations did not reach statistically significant levels. Combined analysis by a meta-analysis revealed that the T allele of rs2237897 was significantly associated with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes (odds ratio 1.22 [95% CI 1.10-1.34], P = 3.1 x 10(-4), corrected P = 0.01).
These results suggest that KCNQ1 is a new candidate gene for conferring susceptibility to diabetic nephropathy.
Diabetes care 04/2010; 33(4):842-6. · 7.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Depletion of glomerular podocytes is an important feature of progressive diabetic nephropathy. Although the most plausible explanation for this podocyte depletion is detachment from the glomerular basement membrane after cellular apoptosis, the mechanism is unclear. Fibroblast-specific protein 1 (FSP1; encoded by the S100A4 gene) is a member of the S100 family of calcium-binding proteins and is constitutively expressed in the cytoplasm of tissue fibroblasts or epithelial cells converted into fibroblasts by means of epithelial-mesenchymal transition.
Retrospective cross-sectional analysis.
109 patients with type 2 diabetes mellitus, of whom 43 (39%) underwent kidney biopsy.
Clinical stage (4 categories) and histological grade (5 categories) of diabetic nephropathy.
FSP1 expression in podocytes in urine and glomeruli in kidney biopsy specimens.
Immunohistochemistry, real-time polymerase chain reaction, and in situ hybridization.
38 of 109 patients (35%) were normoalbuminuric, 16 (15%) had microalbuminuria, 8 (7%) had macroalbuminuria, and 47 (43%) had decreased kidney function. Approximately 95% of podocytes in urine sediment were not apoptotic, and 86% expressed FSP1. The number of FSP1-positive podocytes in urine sediment was significantly larger in patients with macroalbuminuria than in those with normoalbuminuria (P = 0.03). Intraglomerular expression of FSP1 occurred almost exclusively in podocytes from patients with diabetes, and the number of FSP1-positive podocytes was larger in glomeruli showing diffuse mesangiopathy than in those showing focal mesangiopathy (P = 0.01). The number also was larger in glomeruli with nodular lesions than in those without nodular lesions (P < 0.001). FSP1-positive podocytes selectively expressed Snail1 and integrin-linked kinase, a known trigger for epithelial-mesenchymal transition.
Nonrepresentative study population.
These results suggest that the appearance of FSP1 in podocytes of patients with diabetes is associated with more severe clinical and pathological findings of diabetic nephropathy, perhaps because of induction of podocyte detachment through epithelial-mesenchymal transition-like phenomena.
American Journal of Kidney Diseases 08/2009; 54(4):653-64. · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetic nephropathy (DN) is a common cause of end-stage renal disease. However, the precise mechanism of DN, which involves the role of lipid, is still not fully understood. Lectin-like oxidized LDL receptor-1 (LOX-1) is a type II single-transmembrane protein that binds oxidized low density lipoprotein (Ox-LDL). This study examined the expression of LOX-1 mRNA in renal tissues from type 2 diabetes patients with DN using in situ hybridization (ISH).
Renal tissues were obtained from 15 type 2 patients with DN and 5 minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN) and normal human kidney (NHK). Glomerular and tubulointerstitial LOX-1 mRNA expression was evaluated by ISH. Results The cells positive for LOX-1 mRNA were identified in the glomeruli of DN, MCNS, MN and NHK, however, there was no positive signal in the tubulointerstitial area in MCNS and NHK. Some cells positive for LOX-1 mRNA were detectable in the tubulointerstitial area in DN and MN. In the results of glomerular staining, there was no significant difference between them. There was a significant correlation between the tubulointerstitial LOX-1 expression and the degree of the tubulointerstitial damage and urinary protein in DN.
Increased expression of LOX-1 mRNA in the tubulointerstitial area may be closely linked to the development and progression of human DN, and in particular the tubulointerstitial damage.
Internal Medicine 02/2009; 48(4):189-94. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The loss of podocytes has been reported to have a role in the onset and progression of diabetic nephropathy (DN). Although structural changes such as podocyte hypertrophy are considered to be associated with podocyte loss, the relationship has not been thoroughly investigated using human DN renal tissues.
The subjects were 17 patients with DN diagnosed histopathologically by renal biopsy. Immunostaining was performed with antibodies for Wilm's tumor 1 (WT1) and synaptopodin (SPD), which are markers of podocytes, to determine the number of podocytes and assess podocyte hypertrophy.
The number of podocytes was decreased in DN patients compared with the controls. An inverse correlation was observed between the number of podocytes and both the urinary protein excretion and the extent of mesangial expansion. Podocyte hypertrophy was also more marked in DN patients compared with controls.
Based on these results, podocyte loss and hypertrophy were suggested to be involved in the development and progression of human DN.
Internal Medicine 01/2009; 48(18):1615-20. · 0.97 Impact Factor