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1.  Serum 1,5-Anhydroglucitol Concentrations Are a Reliable Index of Glycemic Control in Type 2 Diabetes With Mild or Moderate Renal Dysfunction 
Diabetes Care  2012;35(2):281-286.
To assess the relationship between 1,5-anhydroglucitol (AG) levels, which are a marker of glycemic control, and stages of chronic kidney disease (CKD).
This was a cross-sectional study with 269 subjects with type 2 diabetes who were divided into four groups based on estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (eGFRMDRD) formula: 57 in control, 111 in CKD stages 1–2, 78 in stage 3, and 23 in stages 4–5.
The study groups differed significantly with respect to 1,5-AG and fasting plasma glucose (FPG), age, duration of diabetes, blood pressure, HDL, and percentage of antihypertension or antidyslipidemia medication use. Stepwise multivariate regression analyses showed that 1,5-AG levels in the control group, the CKD stages 1–2 group, and the CKD stage 3 group could be explained by HbA1c, age, duration of diabetes, FPG, and antihypertension medication. However, eGFRMDRD was the only independent determinant of 1,5-AG levels in CKD stages 4–5. Logarithmic transformed 1,5-AG values (ln[1,5-AG]) had significant inverse correlations with HbA1c and FPG levels for CKD stages 1–2 and CKD stage 3 (all P < 0.001). However, associations between ln(1,5-AG) and HbA1c or FPG were insignificant for CKD stages 4–5 (P = 0.274 and P = 0.080, respectively).
This study demonstrated that 1,5-AG levels do not appear to be influenced by mild or moderate renal dysfunction, suggesting it is a reliable glycemic marker in type 2 diabetes with CKD stages 1–3.
PMCID: PMC3263896  PMID: 22210564
2.  Genetic Variation in CYP17A1 Is Associated with Arterial Stiffness in Diabetic Subjects 
Experimental Diabetes Research  2012;2012:827172.
Hypertension and arterial stiffness are associated with an increasing risk of diabetes and cardiovascular diseases. This study aimed to identify genetic variants affecting hypertension and arterial stiffness in diabetic subjects and to compare genetic associations with hypertension between prediabetic and diabetic subjects. A total of 1,069 participants (326 prediabetic and 743 diabetic subjects) were assessed to determine the genetic variants affecting hypertension by analyzing 52 SNPs previously reported to be associated with hypertension. Moreover, the SNPs were tested for association with hemodynamic parameters related to hypertension. Out of the 52 SNPs analyzed, four SNPs including rs5326 (DRD1), rs1004467 (CYP17A1), rs2960306 (GRK4), and rs11191548 (near NT5C2) in diabetic subjects and rs1530440 (C10orf107) in prediabetic subjects showed a modest association with hypertension (P = 0.0265, 0.0020, 0.0066, 0.0078, and 0.0015, resp; all were insignificant after Bonferroni correction). Of these SNPs, rs1004467 in CYP17A1 was significantly associated with augmentation index in diabetic subjects who were not taking antihypertensive medication (P = 0.0001; corrected P = 0.006) but not in diabetic subjects receiving antihypertensive medication. This finding suggests that certain genetic variations found in diabetic subjects may confer arterial stiffness and the development of hypertension and also be affected by antihypertensive medication.
PMCID: PMC3485973  PMID: 23133444
3.  Flux variability scanning based on enforced objective flux for identifying gene amplification targets 
BMC Systems Biology  2012;6:106.
In order to reduce time and efforts to develop microbial strains with better capability of producing desired bioproducts, genome-scale metabolic simulations have proven useful in identifying gene knockout and amplification targets. Constraints-based flux analysis has successfully been employed for such simulation, but is limited in its ability to properly describe the complex nature of biological systems. Gene knockout simulations are relatively straightforward to implement, simply by constraining the flux values of the target reaction to zero, but the identification of reliable gene amplification targets is rather difficult. Here, we report a new algorithm which incorporates physiological data into a model to improve the model’s prediction capabilities and to capitalize on the relationships between genes and metabolic fluxes.
We developed an algorithm, flux variability scanning based on enforced objective flux (FVSEOF) with grouping reaction (GR) constraints, in an effort to identify gene amplification targets by considering reactions that co-carry flux values based on physiological omics data via “GR constraints”. This method scans changes in the variabilities of metabolic fluxes in response to an artificially enforced objective flux of product formation. The gene amplification targets predicted using this method were validated by comparing the predicted effects with the previous experimental results obtained for the production of shikimic acid and putrescine in Escherichia coli. Moreover, new gene amplification targets for further enhancing putrescine production were validated through experiments involving the overexpression of each identified targeted gene under condition-controlled batch cultivation.
FVSEOF with GR constraints allows identification of gene amplification targets for metabolic engineering of microbial strains in order to enhance the production of desired bioproducts. The algorithm was validated through the experiments on the enhanced production of putrescine in E. coli, in addition to the comparison with the previously reported experimental data. The FVSEOF strategy with GR constraints will be generally useful for developing industrially important microbial strains having enhanced capabilities of producing chemicals of interest.
PMCID: PMC3443430  PMID: 22909053
Flux variability scanning based on enforced objective flux; Grouping reaction constraints; Putrescine; Escherichia coli
5.  Retrospective Analysis on the Efficacy, Safety and Treatment Failure Group of Sitagliptin for Mean 10-Month Duration 
Diabetes & Metabolism Journal  2011;35(3):290-297.
To investigate the clinical results of sitagliptin (SITA) and the characteristics of the treatment failure group or of low responders to SITA.
A retrospective study of type 2 diabetic patients reviewed 99 cases, including 12 treatment failure cases, who stopped SITA because of worsening patients' condition, and 87 cases, who continued treatment over five visits (total 9.9±10.1 months) after receiving the prescription of SITA from December 2008 to June 2009. Subjects were classified as five groups administered SITA as an initial combination with metformin (MET), add-on to metformin or sulfonylurea, and switching from sulfonylurea or thiazolidinedione. The changes in HbA1c level from the first to last visit (ΔHbA1c) in treatment maintenance group were subanalyzed.
The HbA1c level was significantly reduced in four groups, including initial coadministration of SITA with metformin (ΔHbA1c=-1.1%, P<0.001), add-on to MET (ΔHbA1c=-0.6%, P=0.017), add-on to sulfonylurea (ΔHbA1c=-0.5%, P<0.001), and switching from thiazolidinedione (ΔHbA1c=-0.3%, P=0.013). SITA was noninferior to sulfonlyurea (ΔHbA1c=-0.2%, P=0.63). There was no significant adverse effect. The treatment failure group had a longer diabeties duration (P=0.008), higher HbA1c (P=0.001) and fasting plasma glucose (P=0.003) compared to the maintenance group. Subanalysis on the tertiles of ΔHbA1c showed that low-response to SITA (tertile 1) was associated with a longer diabetes duration (P=0.009) and lower HbA1c (P<0.001).
SITA was effective and safe for use in Korean type 2 diabetic patients. However, its clinical responses and long-term benefit-harm profile is yet to be established.
PMCID: PMC3138093  PMID: 21785750
Diabetes mellitus, type 2; Sitagliptin; Treatment outcome
6.  The Association of Unintentional Changes in Weight, Body Composition, and Homeostasis Model Assessment Index with Glycemic Progression in Non-Diabetic Healthy Subjects 
Diabetes & Metabolism Journal  2011;35(2):138-148.
We performed a retrospective longitudinal study on the effects of changes in weight, body composition, and homeostasis model assessment (HOMA) indices on glycemic progression in subjects without diabetes during a four-year follow-up period in a community cohort without intentional intervention.
From 28,440 non-diabetic subjects who participated in a medical check-up program in 2004, data on anthropometric and metabolic parameters were obtained after four years in 2008. Body composition analyses were performed with a bioelectrical impedance analyzer. Skeletal muscle index (SMI, %) was calculated with lean mass/weight×100. Subjects were divided into three groups according to weight change status in four years: weight loss (≤-5.0%), stable weight (-5.0 to 5.0%), weight gain (≥5.0%). Progressors were defined as the subjects who progressed to impaired fasting glucose or diabetes.
Progressors showed worse baseline metabolic profiles compared with non-progressors. In logistic regression analyses, the increase in changes of HOMA-insulin resistance (HOMA-IR) in four years presented higher odds ratios for glycemic progression compared with other changes during that period. Among the components of body composition, a change in waist-hip ratio was the strongest predictor, and SMI change in four years was a significant negative predictor for glycemic progression. Changes in HOMA β-cell function in four years was a negative predictor for glycemic progression.
Increased interval changes in HOMA-IR, weight gain and waist-hip ratio was associated with glycemic progression during a four-year period without intentional intervention in non-diabetic Korean subjects.
PMCID: PMC3122898  PMID: 21738896
Glycemic progression; Prediabetes; Skeletal muscle index; Visceral obesity; Weight change
7.  Activation of Peroxisome Proliferator-Activated Receptor Gamma by Rosiglitazone Increases Sirt6 Expression and Ameliorates Hepatic Steatosis in Rats 
PLoS ONE  2011;6(2):e17057.
Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ) on hepatic steatosis.
To investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg−1·day−1) by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes.
RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α) and Forkhead box O1 (Foxo1) in rat livers. AMP-activated protein kinase (AMPK) phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035), suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects.
Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.
PMCID: PMC3044155  PMID: 21373642
8.  The Association of Brachial-Ankle Pulse Wave Velocity with 30-Minute Post-Challenge Plasma Glucose Levels in Korean Adults with No History of Type 2 Diabetes 
Korean Diabetes Journal  2010;34(5):287-293.
Acute postprandial hyperglycemia is an important affector for atherosclerosis in subjects with glucose intolerance. We analyzed the relationship of brachial-ankle pulse wave velocity (baPWV) with fasting and post-challenge plasma glucose levels according to different time points during oral glucose tolerance test (OGTT).
In 663 subjects with fasting hyperglycemia, 75 g OGTT were performed to confirm the glucose tolerant status, and fasting, post-challenge 30-minute and 120-minute glucose levels were measured. Anthropometric measurements were done, and fasting lipid profiles were measured. baPWV were measured in all subjects and the relationship between fasting, 30- and 120-minute post-challenge glucose levels and baPWV were analyzed.
Among the participants, 62.9% were prediabetes and 31.7% were diabetes. Mean baPWV value was significantly higher in subjects with diabetes compared with prediabetes group. In bivariate correlation analyses, age, blood pressure, total cholesterol, low density lipoprotein cholesterol, 30-minute and 120-minute post-challenge glucose levels showed significant positive correlation with baPWV value. In multiple regression analysis, 30-minute post-challenge glucose level was a weak but significant determinant for mean baPWV value even after adjustment for other confounding variables.
Postprandial hyperglycemia, especially 30-minute glucose levels showed significant correlation with baPWV in subjects with fasting hyperglycemia. These results can imply the deleterious effect of acute hyperglycemic excursion on arterial stiffness in subjects with glucose intolerance.
PMCID: PMC2972488  PMID: 21076576
Arterial stiffness; Oral glucose tolerance test; Postprandial hyperglycemia; Pulse wave analysis
9.  The Relationship of Adiponectin/Leptin Ratio with Homeostasis Model Assessment Insulin Resistance Index and Metabolic Syndrome in Apparently Healthy Korean Male Adults 
Korean Diabetes Journal  2010;34(4):237-243.
We investigated the relationships of adiponectin/leptin (A/L) ratio with cardiovascular risk factors, insulin resistance index, and metabolic syndrome (MS) in apparently healthy Korean male adults.
Sixty-eight male subjects were enrolled among the participants of an annual health check-up program (mean age, 55.1 years). Percent body fat (%) was measured using a bioelectric impedance analyzer. Serum leptin level was measured via radioimmunoassay, and adiponectin level was measured using an enzyme-linked immunosorbent assay. Homeostasis model assessment (HOMA)-insulin resistance (IR) index was calculated, and the presence of metabolic syndrome was assessed.
Adiponectin, leptin, and A/L ratio showed significant correlations with percent body fat, lipid profile, and HOMA-IR. Mean leptin and HOMA-IR levels were significantly higher, while A/L ratio was significantly lower in subjects with MS. With increasing number of MS components, the mean values of leptin and HOMA-IR increased and the A/L ratio decreased. In multiple regression analysis, HOMA-IR was significantly correlated with triglyceride, fasting glucose, and A/L ratio, while A/L ratio was significantly correlated with body mass index and HOMA-IR. HOMA-IR and A/L ratio were significant predictors for each other after adjustment for other factors.
A/L ratio correlated well with lipid profile, HOMA-IR, and the presence and number of MS components in Korean male subjects.
PMCID: PMC2932893  PMID: 20835341
Adiponectin/leptin ratio; Insulin resistance; Metabolic syndrome

Results 1-9 (9)