Comparing Associations of Dietary Energy Density and Energy Intake, Macronutrients with Obesity in Patients with Type 2 Diabetes (JDDM 63).

To investigate the association between dietary energy density (DED) and obesity in people with type 2 diabetes mellitus. Moreover, we compared the strength of the associations of DED with intake of energy and macronutrients in terms of obesity as well as nutritional factors that have long been used for medical nutritional therapy. Cross-sectionally investigated were 1615 outpatients with type 2 diabetes who attended 26 clinics nationwide with diabetes specialists. Odds ratios (ORs) were calculated for the association between obesity and DED, energy, and macronutrients by quintile categories and a 1 SD increment with adjustment for potential confounders. ß coefficients were calculated for the association between body mass index (BMI) and each nutritional factor by 1 SD increments in nutritional values. Multi-adjusted OR for obesity between extreme quintiles of DED was 2.99 (95% confidence interval (95% CI): 2.01-3.12). Conversely, the ORs did not differ significantly according to the quintiles of other nutrient factors. Multi-adjusted ß coefficient of BMI per 1 SD according to DED was far higher than those of other nutrient factors (ß coefficient 0.65, 95% CI: 0.41-0.88). These findings indicated that DED in persons with type 2 diabetes was positively associated with BMI and the prevalence of obesity. DED was also much more potently associated with obesity and BMI than nutritional indicators such as intake of energy or macronutrients.

Combined Effects of Energy Intake and Physical Activity on Obesity in Japanese Patients with Type 2 Diabetes (JDDM 50): A Cross-Sectional Study.

INTRODUCTION: The combined effects of energy intake (EI) and physical activity (PA) on obesity have been poorly investigated. We have investigated the combined effects of EI and PA quantitatively in Japanese men and women with type 2 diabetes. METHODS: Data on 1395 patients with type 2 diabetes who attended 25 diabetes clinics located throughout Japan, obtained by questionnaire, were analyzed. A logistic regression model was used to calculate the odds ratio for obesity. RESULTS: Multi-adjusted odds ratios for the top versus the bottom tertile of EI and the bottom versus the top tertile of PA were 1.39 (95% confidence interval [CI] 1.02-1.89) and 1.64 (95% CI 1.22-2.22), respectively. The combination of EI (kcal/day) ≥ 1967 and PA (metabolic equivalents [METs] h/week) ≤ 9.9 for men and of EI ≥ 1815 and PA ≤ 8.3 for women were significantly associated with obesity. CONCLUSIONS: The existence of "allowable maximum EI" and "required minimum PA" that is significantly associated with "not being obese" is implied, suggesting the need for lifestyle education for Japanese patients with type 2 diabetes.

Relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetic patients (JDDM38).

AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.

Selective accumulation of platinum and formation of platinum-DNA adducts in hepatocellular carcinoma after transarterial chemoembolization with miriplatin.

AIM: Miriplatin, a lipophilic platinum complex, is a novel intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). Little is known about platinum-DNA adduct levels in human HCC after administration of platinum-based drugs. We investigated whether miriplatin selectively accumulates and forms platinum-DNA adducts in human HCC tumors. METHODS: Using inductively coupled plasma mass spectrometry, we determined the platinum concentrations and platinum-DNA adduct levels in paired HCC tumors and non-tumor liver tissues of four patients who received transcatheter arterial chemoembolization with miriplatin and subsequently underwent hepatic resection. RESULTS: The mean (± standard deviation) platinum concentrations were 730 ± 350 µg/g (range, 400-1100) in HCC tumors and 16 ± 9.2 µg/g (range, 9.2-29) in non-tumor liver tissues. The concentrations were approximately 50-fold higher in HCC tumors than in non-tumor liver tissues. The mean platinum-DNA adduct levels were 54 ± 16 pg Pt/µg DNA (range, 37-69) in HCC tumors and 13 ± 13 pg Pt/µg DNA (range, 4.8-33) in non-tumor liver tissues. The adduct levels were roughly 7.6-fold higher in HCC tumors than in non-tumor liver tissues. There were no significant correlations between platinum concentrations and platinum-DNA adduct levels in HCC tumors. CONCLUSION: Our results quantitatively demonstrate that there is a selective accumulation of platinum and formation of platinum-DNA adducts in human HCC tumors after transarterial chemoembolization with miriplatin. No correlation was observed between platinum concentrations and platinum-DNA adduct levels.

Self-reported rate of eating is significantly associated with body mass index in Japanese patients with type 2 diabetes. Japan Diabetes Clinical Data Management Study Group (JDDM26).

We examined whether the rate of eating was associated with the body mass index and glycemic control status in Japanese patients with type 2 diabetes (50% women, mean±SD age 59.4±7.5 years). Rapid eating was significantly associated with body mass index (p=0.047). The body mass index of those who reported eating quickly was 0.8 kg/m² higher than in individuals who reported eating at medium speed even after adjustment for known confounders. No significant association was observed between the rate of eating and HbA(1c). Our findings suggest an association between self-reported rapid eating and an elevated body mass index in patients with type 2 diabetes.

Histone deacetylase inhibitors activate INK4d gene through Sp1 site in its promoter.

Histone deacetylase (HDAC) inhibitors are known to arrest human tumor cells at the G1 phase of the cell cycle and activate the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1). However, several studies have suggested the existence of a p21(WAF1/Cip1)-independent molecular pathway. We report here that HDAC inhibitors activate a member of the INK4 family, the INK4d gene, causing G1 phase arrest, in the human T cell leukemia cell line, Jurkat. One of the major Trichostatin A (TSA)-responsive elements is a specific Sp1 binding site in the INK4d promoter. Electrophoretic mobility-shift assay revealed that Sp1 and Sp3 can specifically interact with this Sp1 binding site. Furthermore, using chromatin immunoprecipitation assay, we demonstrated that HDAC2 was present in the INK4d proximal promoter region in the absence, but not the presence, of TSA. Taken together, these results suggest that treatment with TSA transcriptionally activates INK4d by releasing HDAC2 from the histone-DNA complex at the INK4d promoter. Using a p21(WAF1/Cip1)-deleted human colorectal carcinoma cell line, HCT116 p21 (-/-), we show that upregulation of p19(INK4d) by TSA is associated with inhibition of cell proliferation. Moreover, mouse embryo fibroblasts lacking Ink4d were resistant to the growth inhibitory effects of TSA as compared to their wild-type counterpart. Our findings suggest that p19(INK4d) in addition to p21(WAF1/Cip1) is an important molecular target of HDAC inhibitors inducing growth arrest.

Molecular cloning and characterization of the human p19(INK4d) gene promoter.

p19(INK4d), a member of the INK4 family of cyclin-dependent kinase (CDK) inhibitors, negatively regulates the cyclin D-CDK4/6 complexes, which promote G1/S transition by phosphorylating the retinoblastoma tumor-suppressor gene product. To investigate the mechanism of transcriptional regulation of the p19(INK4d) gene, we characterized the 5'-flanking region of the human p19(INK4d) gene. The cap-site hunting method revealed that the transcription starts at -16 nucleotide (nt) upstream of the initiation codon. The 5'-flanking region of the human p19(INK4d) gene was ligated to a luciferase reporter gene and possessed functional promoter activity. Luciferase assay with a series of truncated 5'-flanking regions indicated that the region from -81 to -2 nt could drive the transcription of the p19(INK4d) gene. Several Sp1 and activating protein 2 binding sites are located within the region from -81 to -2 nt. Mutation of the second Sp1 binding site from -33 to -25 nt decreased the promoter activity. Collectively, it was demonstrated that the human p19(INK4d) gene is under the control of TATA-less promoter and the Sp1 binding site is involved in the transcription.