A Single Nucleotide Polymorphism within the Acetyl-Coenzyme A Carboxylase Beta Gene Is Associated with Proteinuria in Patients with Type 2 Diabetes

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 = 1.4×10−6, 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 = 5.35×10−8, 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 = 6×10−4, 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

Exercise Therapy for Management of Type 2 Diabetes Mellitus: Superior Efficacy of Activity Monitors over Pedometers

We compared the efficacy of activity monitor (which displays exercise intensity and number of steps) versus that of pedometer in exercise therapy for patients with type 2 diabetes. The study subjects were divided into the activity monitor group (n=92) and pedometer group (n=95). The primary goal was improvement in hemoglobin A1c (HbA1c). The exercise target was set at 8,000 steps/day and 20 minutes of moderate-intensity exercise (≥3.5 metabolic equivalents). The activity monitor is equipped with a triple-axis accelerometer sensor capable of measuring medium-intensity walking duration, number of steps, walking distance, calorie consumption, and total calorie consumption. The pedometer counts the number of steps. Blood samples for laboratory tests were obtained during the visits. The first examination was conducted at the start of the study and repeated at 2 and 6 months. A significant difference in the decrease in HbA1c level was observed between the two groups at 2 months. The results suggest that the use of activity level monitor that displays information on exercise intensity, in addition to the number of steps, is useful in exercise therapy as it enhances the concept of exercise therapy and promotes lowering of HbA1c in diabetic patients

A single nucleotide polymorphism in KCNQ1 is associated with susceptibility to diabetic nephropathy in japanese subjects with type 2 diabetes. Diabetes Care. 33:842–846. [PubMed: 20056949

OBJECTIVE -Genetic factors have been considered to contribute to the development and progression of diabetic nephropathy. The KCNQ1 gene (potassium voltage-gated channel, KQTlike 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. RESEARCH DESIGN AND METHODS -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). RESULTS -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 ϭ 3.1 ϫ 10 -4 , corrected P ϭ 0.01). CONCLUSIONS -These results suggest that KCNQ1 is a new candidate gene for conferring susceptibility to diabetic nephropathy

The Influence of a Single Nucleotide Polymorphism within <em>CNDP1</em> on Susceptibility to Diabetic Nephropathy in Japanese Women with Type 2 Diabetes

<div><h3>Background</h3><p>Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22–23, and polymorphisms within the carnosine dipeptidase 1 gene (<em>CNDP1)</em>, 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 <em>CNDP1/CNDP 2</em> locus with diabetic nephropathy in Japanese subjects with type 2 diabetes.</p> <h3>Methodology/Principal Findings</h3><p>We genotyped a leucine repeat polymorphism (D18S880) that is within <em>CNDP1</em> along with 29 single nucleotide polymorphisms (SNPs) in the <em>CNDP1</em>/<em>CNDP2</em> 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 <em>CNDP1/CNDP2</em> locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in <em>CNDP1</em> was nominally associated with diabetic nephropathy in women (rs12604675-A; <em>p</em> = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19−2.61). Rs12604675 was associated with overt proteinuria (<em>p</em> = 0.002, OR = 2.18, 95% CI, 1.32−3.60), but not with ESRD in Japanese women with type 2 diabetes.</p> <h3>Conclusions/Significance</h3><p>Rs12604675-A in <em>CNDP1</em> may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.</p> </div

Renal effects of sodium glucose co-transporter 2 inhibitors in Japanese type 2 diabetes mellitus patients with home blood pressure monitoring

Decrease in blood pressure contributes to the reno-protective effects of sodium-glucose cotransporter 2 inhibitors; however, its relationship with home monitoring of blood pressure is unclear. We retrospectively analyzed 101 visiting members of the Kanagawa Physicians Association with type 2 diabetes mellitus and chronic kidney disease who were taking sodium-glucose cotransporter 2 inhibitors and who monitored blood pressure at home for a median treatment period of 14 months. At baseline, the mean value of HbA1c was 59.3 mmol/mol (7.6%) and the median value of albumin-creatinine ratio was 30.9 mg/gCr that was evaluated in 88 patients. The mean blood pressure both at office and home significantly decreased, and there was a significant positive correlation between the change in albumin–creatinine ratio and both blood pressures. Controlled hypertension, masked hypertension, white coat hypertension, and sustained hypertension were observed in 10.9%, 13.9%, 12.9%, and 62.4% of patients at the initiation of therapy, which changed to 10.9%, 16.8%, 17.8%, and 54.5% at the time of the survey, respectively. In conclusion, management of blood pressure both at office and home was found to be important for the reno-protective effects of sodium-glucose cotransporter 2 inhibitors along with strict blood pressure management

A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10−4) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10−10. We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10−10). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes