Won Jun Kim

Activation of Peroxisome Proliferator-Activated Receptor Gamma by Rosiglitazone Increases Sirt6 Expression and Ameliorates Hepatic Steatosis in Rats

Background 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. Methods 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 RGZs regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes. Results 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. Conclusion 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.

1,5-Anhydroglucitol in diabetes mellitus

The measure of glycated hemoglobin (HbA1c) concentration is the gold standard of glycemic control index in diabetes management and is well known as a marker for diabetes complications. However, HbA1c level neither accurately reflect glucose fluctuations, nor does it provide a clear indication of glycemic control in recent days or weeks. HbA1c concentration measurement can be confounded in patients with anemia, hemoglobinopathy, liver disease, or renal impairment. 1,5-Anhydroglucitol (1,5-AG) structurally resembles glucose. It can be influenced by diet or medication, gender and race, especially severe renal disease and various pathological conditions. Most notably, 1,5-AG level is reflective of short-term glucose status, postprandial hyperglycemia, and glycemic variability which are not captured by HbA1c assay. 1,5-AG may suggest an alternative index of subtypes of diabetes and a warning sign of diabetes complications. This review provides an overview of our current understanding of the role of 1,5-AG marker in diabetes. However, further investigations on the associations between this glycemic marker and diabetes complications are needed.

Serum 1,5-Anhydroglucitol Concentrations Are a Reliable Index of Glycemic Control in Type 2 Diabetes With Mild or Moderate Renal Dysfunction

OBJECTIVE To assess the relationship between 1,5-anhydroglucitol (AG) levels, which are a marker of glycemic control, and stages of chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS 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. RESULTS 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). CONCLUSIONS 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.

High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria

OBJECTIVE Angiotensin-converting enzyme 2 (ACE2) plays an important role in glucose metabolism and renal function. However, the relationship between ACE2 and hyperglycemia or microalbuminuria has not been established in humans. We investigated whether urinary ACE2 levels are associated with abnormal glucose homeostasis and urinary albumin excretion. METHODS We developed an ELISA for quantifying ACE2 in urine. The ELISA was used to measure urinary ACE2 levels in 621 subjects with: normal glucose tolerance (NGT; n=77); impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (n=132); and type 2 diabetes mellitus (T2DM, n=412). Insulin resistance was assessed by homeostasis model assessment for insulin resistance (HOMA-IR) index and urinary albumin excretion by urine albumin-to-creatinine ratio (ACR). Other biochemical and anthropometric parameters were measured. RESULTS Urinary ACE2 levels were significantly higher in insulin-resistant subjects with IFG, IGT, and T2DM than in the NGT group (P<0.001). Urinary ACE2 concentrations appeared to correlate with HOMA-IR, fasting blood glucose, triglyceride, high-sensitivity C-reactive protein, serum creatinine, urinary ACR, and systolic blood pressure (all P<0.05). After adjustment for impaired renal function and other metabolic parameters, urinary ACE2 concentration was still associated with a higher risk for T2DM (OR 1.80, 95% CI 1.05-3.08, P=0.02). In addition, urinary ACE2 levels were highly predictive of microalbuminuria after adjusting for clinical risk factors (OR 2.68, 95% CI 1.55-4.64, P<0.001). CONCLUSION Our data suggest that the urinary ACE2 level is closely associated with T2DM and is an independent risk factor for microalbuminuria.

The association between regional arterial stiffness and diabetic retinopathy in type 2 diabetes

OBJECTIVES Although several studies have reported that PWV is associated with diabetic retinopathy, it remains controversial as to which segment provides the PWV that might best reflect the presence of retinopathy. The aim of this study was to determine the pulse wave velocity (PWV) of arterial segments that is most closely associated with diabetic retinopathy in subjects without a history of macrovascular complications. METHODS After excluding subjects with a history of ischemic heart disease, peripheral artery disease, ischemic stroke, renal insufficiency, overt proteinuria, and other nondiabetic ophthalmic lesions or insufficient retinal examinations, a total of 494 subjects were analyzed by cross-sectional study. The central PWVs, including the heart-femoral (hf), heart-carotid (hc), heart-ankle (ha), and carotid-brachial (cb) segments, and the peripheral PWVs, including brachial-ankle (ba) and femoral-ankle (fa), were measured for each subject. RESULTS The group with diabetic retinopathy exhibited significantly higher hfPWV, hcPWV, haPWV and baPWV, but notcbPWV, faPWV or augmentation index (AI). Age, duration of diabetes, systolic and diastolic BP and pulse pressure were all positively associated with hfPWV, hcPWV, haPWV and baPWV. Quartiles of hfPWV were significantly associated with diabetic retinopathy after adjustment for covariates and known risk factors of diabetic retinopathy (P for trend = 0.023). Conversely, all quartiles of haPWV, hcPWV and baPWV lost significance after adjustment. CONCLUSIONS We found that diabetic retinopathy was most closely associated with hfPWV, suggesting the most reliable index of regional arterial stiffness index in retinopathy.

Prevalence of and risk factors for diabetic retinopathy in Koreans with type II diabetes: baseline characteristics of Seoul Metropolitan City-Diabetes Prevention Program (SMC-DPP) participants

Objective To evaluate the prevalence of and risk factors for diabetic retinopathy (DR) in Koreans with type II diabetes. Methods Subjects (400 male, 296 female) aged 30–65 years (mean 55.3 years) with hyperglycaemia (fasting plasma glucose ≥7.0 mmol/ml) or known diabetes (mean±SD duration 6.36±5.73 years) were enrolled in the Seoul Metro-City Diabetes Prevention Program (SMC-DPP) from September 2008 to September 2009. The severity of DR was diagnosed by grading fundus photographs taken from five standard fields per eye and categorised following the Early Treatment of Diabetic Retinopathy Study grading protocol. All participants underwent routine clinical and laboratory examinations to evaluate risk factors for DR. Results The overall prevalence of any type of DR was 18.7%. Logistic regression analyses showed that the following factors were significantly associated with DR after adjustment for age and gender, duration of diabetes, serum glycated haemoglobin A1c (HbA1c), mean arterial pressure, serum total cholesterol and serum triglycerides: duration of diabetes (OR 1.14, 95% CI 1.10 to 1.18, for 1 year increase), HbA1c (OR 1.49, 95% CI 1.20 to 1.85, for 1% increase), serum concentration of insulin (OR 0.87, 95% CI 0.81 to 0.94, for 1 μIU/ml increase), homoeostasis model assessment of insulin resistance (OR 0.06, 95% CI 0.01 to 0.29, for 10 unit increase), and presence of macroalbuminuria (OR 5.14, 95% CI 1.45 to 18.20, albumin to creatinine ratio >300 mg/g). Conclusions In addition to traditional risk factors, insulin resistance was associated with an increased risk of DR in Koreans with type 2 diabetes.

Chronic administration of ezetimibe increases active glucagon-like peptide-1 and improves glycemic control and pancreatic beta cell mass in a rat model of type 2 diabetes

Ezetimibe is a cholesterol-lowering agent targeting Niemann-Pick C1-like 1, an intestinal cholesterol transporter. Inhibition of intestinal cholesterol absorption with ezetimibe may ameliorate several metabolic disorders including hepatic steatosis and insulin resistance. In this study, we investigated whether chronic ezetimibe treatment improves glycemic control and pancreatic beta cell mass, and alters levels of glucagon-like peptide-1 (GLP-1), an incretin hormone involved in glucose homeostasis. Male LETO and OLETF rats were treated with vehicle or ezetimibe (10 mg kg(-1)day(-1)) for 20 weeks via stomach gavage. OLETF rats were diabetic with hyperglycemia and significant decreases in pancreatic size and beta cell mass compared with LETO lean controls. Chronic treatment of OLETF rats with ezetimibe improved glycemic control during oral glucose tolerance test compared with OLETF controls. Moreover, ezetimibe treatment rescued the reduced pancreatic size and beta cell mass in OLETF rats. Interestingly, ezetimibe significantly decreased serum dipeptidyl peptidase-4 activity and increased serum active GLP-1 in OLETF rats without altering serum total GLP-1. These findings demonstrated that chronic administration of ezetimibe improves glycemic control and pancreatic beta cell mass, and increases serum active GLP-1 levels, suggesting possible involvement of GLP-1 in the ezetimibe-mediated beneficial effects on glycemic control.

The association of unintentional changes in weight, body composition, and homeostasis model assessment index with glycemic progression in non-diabetic healthy subjects.

Background 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. Methods 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. Results 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. Conclusion 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.

Sexual dysfunctions induced by stress of timed intercourse and medical treatment

Whats known on the subject? and What does the study add?

Genetic variation in CYP17A1 is associated with arterial stiffness in diabetic subjects.

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.