[Show abstract][Hide abstract] ABSTRACT: There are limited data regarding the role of coronary computed tomographic angiography (CCTA) in asymptomatic patients with type 2 diabetes mellitus. We analyzed 557 asymptomatic type 2 diabetic patients who underwent CCTA. Cardiac event was defined as a composite of cardiac death, nonfatal myocardial infarction, acute coronary syndrome requiring hospitalization, or late revascularization. Atherosclerotic plaques were observed in 395 patients (70.9%), and 170 patients (30.5%) showed significant coronary artery disease (CAD) on CCTA. Ninety-two patients (16.5%) were associated with a significant stenosis in the left main or proximal left anterior descending artery. During the follow-up period (33.7 ± 7.8 months), although an excellent prognosis was observed in patients without significant CAD on CCTA, those with significant CAD showed more cardiac events (7.1% vs 0.5%) and lower 3-year event-free survival rates (99.2 ± 0.6% vs 90.9 ± 2.6%, p <0.001). Furthermore, in group with significant CAD, patients with significant CAD in the left main or proximal left anterior descending artery had more cardiac events (10.9% vs 2.6%) and lower 3-year event-free survival rates (97.4 ± 1.8% vs 86.1 ± 4.2%, p = 0.049). On multivariate analysis, family history of premature CAD, previous history of stroke, higher UK Prospective Diabetes Study 10-year risk scores, neuropathy, and retinopathy were independent clinical predictors of having significant CAD and left main or proximal left anterior descending artery significant CAD on CCTA. In conclusion, about 1/3 of asymptomatic type 2 diabetic patients had significant CAD on CCTA with a subsequent high risk for cardiac events. These findings suggest that CCTA may have a potential role in identifying patients with high cardiovascular risks in asymptomatic type 2 diabetes.
The American journal of cardiology 03/2014; 113(5):765-71. · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims
Increased sugar consumption may adversely affect glycemic control in patients with diabetes. Although patients with diabetes are generally thought to prefer sweet tastes, few data are available on the sucrose preference in these individuals. The aim of the present study was to evaluate sucrose preference in patients with type 2 diabetes in comparison with subjects without diabetes.
Sucrose preference was assessed in 200 subjects (100 type 2 diabetes patients and 100 age-, sex- and body mass index (BMI)-matched control subjects). Sucrose preference was evaluated together with sucrose perception (i.e., sucrose sensitivity). Clinical and biochemical factors affecting sucrose taste were also analyzed.
Participants with type 2 diabetes preferred lower sucrose concentrations compared with control subjects (p = 0.001), although they had a less sensitive palate for sucrose compared with subjects without diabetes (p = 0.012). Individual sucrose preference demonstrated a negative relationship with sensitivity to sucrose in control subjects. Notably, this relationship between sucrose preference and sensitivity was completely absent in participants with type 2 diabetes. Male patients with diabetes demonstrated a higher sucrose preference compared with female patients. There were no significant correlations between sucrose preference and glycemic control, duration of diabetes, or anti-diabetic medications.
Participants with type 2 diabetes demonstrate a lower preference for sweet tastes than control subjects despite their decreased perception of sucrose. Reduced sucrose preference is not associated with better glycemic control in individuals with diabetes.
Diabetes research and clinical practice 01/2014; · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: S-adenosyl methionine (SAM) is a key intermediate in the metabolism of sulfur amino acids and is a major methyl donor in the cell. Although the low plasma level of SAM has been associated with atherosclerosis, the effect of SAM administration on atherosclerosis is not known. Endothelial dysfunction is an early prerequisite for atherosclerosis. This study was undertaken to investigate the possible preventive effect of SAM on endothelial dysfunction and the molecular mechanism of its action. SAM treatment prevented endothelial dysfunction in high fat diet (HFD)-fed rats. In cultured human aortic endothelial cells, linoleic acid (LA) increased and SAM decreased cell apoptosis and endoplasmic reticulum stress. Both LA and SAM increased heme oxygenase-1 (HO-1) expression in an NF-E2-related factor 2-dependent manner. However, knockdown of HO-1 reversed only the SAM-induced preventive effect of cell apoptosis. The LA-induced HO-1 expression was dependent on PPARα, whereas SAM induced HO-1 in a PPAR-independent manner. These data demonstrate that SAM treatment prevents endothelial dysfunction in HFD-fed animals by inducing HO-1 in vascular endothelial cells. In cultured endothelial cells, SAM-induced HO-1 was responsible for the observed prevention of cell apoptosis. We propose that SAM treatment may represent a new therapeutic strategy for atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: AIMS: Although hyperphagia is a common manifestation of diabetes mellitus, data on food craving in patients with diabetes are limited. This study compared food craving in patients with Type 2 diabetes mellitus and a control group without diabetes. METHODS: A total of 210 subjects (105 with Type 2 diabetes and 105 age-, sex- and BMI-matched control subjects) participated in two food craving surveys. The surveys were as follows: the General Food Cravings Questionnaire-Trait, which assesses the general trait of food craving; and the Food Cravings Questionnaire-State, which assesses the state of food craving or current desire for high-carbohydrate or high-fat foods in response to pictures of food. Follow-up Food Cravings Questionnaire-State surveys were administered approximately 3 months later to the subjects with diabetes. Survey results were analysed to assess relationships between food craving and glycaemic control. RESULTS: The Food Cravings Questionnaire-Trait scores in the group with Type 2 diabetes and the control group were not significantly different. The group with Type 2 diabetes had higher carbohydrate craving scores, but lower fat craving scores, than the control group. Carbohydrate craving scores in subjects with diabetes were positively correlated with HbA1c. In follow-up surveys, carbohydrate craving scores declined in patients with improved glycaemic control. CONCLUSIONS: The surveys showed that patients with Type 2 diabetes had higher carbohydrate cravings and lower fat cravings than the age-, sex- and BMI-matched control group. Carbohydrate craving in patients with diabetes was associated with poor glycaemic control. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered the key determinants of insulin resistance. Impaired mitochondrial function in obese animals was shown to induce the ER stress response, resulting in reduced adiponectin synthesis in adipocytes. The expression of inducible nitric oxide synthase (iNOS) is increased in adipose tissues in genetic and dietary models of obesity. In this study, we examined whether activation of iNOS is responsible for palmitate-induced mitochondrial dysfunction, ER stress, and decreased adiponectin synthesis in 3T3L1 adipocytes. As expected, palmitate increased the expression levels of iNOS and ER stress response markers, and decreased mitochondrial contents. Treatment with iNOS inhibitor increased adiponectin synthesis and reversed the palmitate-induced ER stress response. However, the iNOS inhibitor did not affect the palmitate-induced decrease in mitochondrial contents. Chemicals that inhibit mitochondrial function increased iNOS expression and the ER stress response, whereas measures that increase mitochondrial biogenesis (rosiglitazone and adenoviral overexpression of nuclear respiratory factor-1) reversed them. Inhibition of mitochondrial biogenesis prevented the rosiglitazone-induced decrease in iNOS expression and increase in adiponectin synthesis. These results suggest that palmitate-induced mitochondrial dysfunction is the primary event that leads to iNOS induction, ER stress, and decreased adiponectin synthesis in cultured adipocytes.
Experimental and Molecular Medicine 07/2012; 44(9):562-70. · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fibroblast growth factor 21 (FGF21) was originally identified as a paroxysm proliferator activated receptor-α target gene product and is a hormone involved in metabolic regulation. The purpose of this study was to investigate the diurnal variation of serum FGF21 concentration in obese and non-obese healthy volunteers.
Blood samples were collected from five non-obese (body mass index [BMI] ≤23 kg/m(2)) and five obese (BMI ≥25 kg/m(2)) healthy young men every 30 to 60 minutes over 24 hours. Serum FGF21 concentrations were determined by radioimmunoassay. Anthropometric parameters, glucose, free fatty acid, insulin, leptin, and cortisol concentrations were also measured.
The serum FGF21 concentrations displayed various individual oscillation patterns. The oscillation frequency ranged between 6 and 12 times per day. The average duration of oscillation was 2.52 hours (range, 1.9 to 3.0 hours). The peaks and troughs of FGF21 oscillation showed no circadian rhythm. However, the oscillation frequency had a diurnal variation and was lower during the light-off period than during the light-on period (2.4 vs. 7.3 times, P<0.001). There was no difference in the total frequency or duration of oscillations between non-obese and obese subjects, but obese individuals had increased numbers of larger oscillations (amplitude ≥0.19 ng/mL).
Various oscillation patterns in serum FGF21 concentration were observed, and reduced oscillation frequencies were seen during sleep. The oscillation patterns of serum FGF21 concentration suggest that FGF21 may be secreted into systemic circulation in a pulsatile manner. Obesity appeared to affect the amplitude of oscillations of serum FGF21.
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are closely associated with β-cell dysfunction and peripheral insulin resistance. Thus, each of these factors contributes to the development of type 2 diabetes mellitus (DM). The accumulated evidence reveals structural and functional communications between mitochondria and the ER. It is now well established that ER stress causes apoptotic cell death by disturbing mitochondrial Ca(2+) homeostasis. In addition, recent studies have shown that mitochondrial dysfunction causes ER stress. In this paper, we summarize the roles that mitochondrial dysfunction and ER stress play in the pathogenesis of type 2 DM. Structural and functional communications between mitochondria and the ER are also discussed. Finally, we focus on recent findings supporting the hypothesis that mitochondrial dysfunction and the subsequent induction of ER stress play important roles in the pathogenesis of type 2 DM.
Experimental Diabetes Research 01/2012; 2012:242984. · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective The aim of this study was to determine whether the absence of coronary artery calcium (CAC) can safely exclude obstructive coronary artery disease (CAD) in asymptomatic patients with type 2 diabetes. Methods We enrolled 478 consecutive asymptomatic patients with type 2 diabetes who visited the diabetes clinic of the Asan Medical Center between October 1, 2009 and December 31, 2010. All patients underwent 64-slice dual-source computed tomography (DSCT) for CAC scoring as well as computed tomography angiography (CTA). Patients with at least one significant coronary stenosis with >50% luminal narrowing were classified as having obstructive CAD. The findings were confirmed using conventional coronary angiography (CAG). Results Among the 478 patients, 157 (33%) had a CAC score of 0 (CAC=0). Of these, 17 (11%) had obstructive CAD confirmed on CAG. The presence of CAC had a negative predictive value for obstructive CAD on CAG of 89% and a sensitivity of 88%, a specificity of 42% and a positive predictive value of 38%. A multivariate logistic regression analysis showed that current smoking habits were significantly associated with the presence of obstructive CAD in patients with CAC=0 after adjusting for traditional cardiovascular risk factors (odds ratio 4.87, 95% confidence interval 1.65-14.42, p=0.004). Conclusion Our findings suggest that CAC=0 on 64-slice DSCT cannot safely exclude obstructive CAD on CAG in asymptomatic patients with type 2 diabetes, particularly in current smokers. CTA should be combined with CAC scoring in screening for CAD in asymptomatic patients with type 2 diabetes.
Internal Medicine 01/2012; 51(21):3017-23. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A neutral loss scan of 141, corresponding to a phosphoethanolamine head group, has been commonly used for the determination of various glycerophosphoethanolamine species in complex lipid mixtures. However, the neutral loss of 141 Da is not a major fragmentation pathway in the collision-induced dissociation (CID) of ethanolamine plasmalogens in the positive-ion mode. Thus, the use of the neutral loss scan of 141 can be problematic to observe all possible ethanolamine phospholipids in biological samples. Ethanolamine plasmalogens could easily form adducts with Ag(I) ions, and the CID of Ag(I)-adducted ethanolamine plasmalogens provided abundant head group loss of 141 with higher collision energy. Thus, all ethanolamine plasmalogens could be identified from a neutral loss scan of 141 after Ag(I) adduction. This novel approach could be a useful diagnostic tool to observe most of the possible glycerophosphoethanolamine species in complex lipid mixtures.
[Show abstract][Hide abstract] ABSTRACT: Methionine and choline-deficient diet (MCD)-induced fatty liver is one of the best-studied animal models of fatty liver disease. The present study was performed to clarify the relative contributions of individual lipid metabolic pathways to the pathogenesis of MCD-induced fatty liver. Hepatic lipogenesis mediated by the sterol regulatory element-binding protein (SREBP-1c) was increased at 1 week, but not at 6 weeks, of MCD feeding. On the other hand, (14)C-palmitate oxidation did not change at 1 week, but significantly decreased at 6 weeks. This decrease was associated with increased expression of fatty acid translocase, a key enzyme involved in fatty acid uptake. Expression of endoplasmic reticulum stress markers was increased in mice given MCD for both 1 and 6 weeks. These findings suggest the presence of time-dependent differences in lipid metabolism in MCD-induced fatty liver disease: SREBP-1c-mediated lipogenesis is important in the early stages of fatty liver disease, whereas increased fatty acid uptake and decreased fatty acid oxidation become more important in the later stages.
Molecules and Cells 11/2011; 32(6):571-7. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis and is associated with significant morbidity and mortality. Diabetes is known to increase the risk of PAD two- to four-fold. The prevalence of PAD in Korean diabetic patients has not been established. In this study, we investigated the prevalence of PAD in Korean patients with type 2 diabetes attending a large university hospital and analyzed the factors associated with PAD.
A total of 2,002 patients with type 2 diabetes who underwent ankle-brachial index (ABI) measurement in an outpatient clinic were enrolled. PAD was defined as an ABI ≤0.9. Clinical characteristics of 64 patients with PAD were compared with those of 192 age- and sex-matched control patients without PAD.
Of the 2,002 type 2 diabetic patients, 64 (3.2%) were diagnosed as having PAD. PAD was associated with higher prevalences of retinopathy, nephropathy, neuropathy, cerebrovascular and coronary artery disease. Patients with PAD had higher systolic blood pressure and serum triglyceride level and reported higher pack-years of smoking. Multivariate analysis showed that the presence of micro- and macrovascular complications and high systolic blood pressure are factors independently associated with PAD.
The prevalence of PAD in diabetic patients was 3.2%, suggesting that the prevalence in Korean diabetic patients is lower than that of patients in Western countries.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to examine the possible association between serum ceruloplasmin, a copper carrying protein, and albuminuria in 456 males with type 2 diabetes. Multivariate regression analysis demonstrated that elevated serum ceruloplasmin was a determinant of albuminuria independently of conventional risk factors.
Diabetes research and clinical practice 07/2011; 94(1):e3-7. · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gamma-glutamyltransferase (GGT) has been reported to be useful in predicting cardiovascular disease. Arterial stiffness measured by brachial-ankle pulse wave velocity (baPWV) is not only a marker of vascular damage but a significant predictor of cardiovascular events. Gender difference has been reported in the association between GGT and baPWV. We assessed, therefore, the association between GGT and baPWV in a large population and determined whether there was gender difference.
This cross-sectional study was conducted at the Asan Medical Centre, Seoul, Republic of Korea.
Serum GGT, baPWV and conventional risk factors were measured in 10 988 apparently healthy subjects (7248 men, 3740 women) who participated in a routine health screening examination.
In both men and women, we observed positive linearity between GGT quartiles and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol, LDL cholesterol, triglycerides, uric acid, high-sensitive C-reactive protein (hsCRP) and homeostatic model assessment of insulin resistance (HOMA-IR) score (P for trends < 0·001). The proportion of individuals with diabetes, hypertension increased as the GGT quartile increased (P for trends < 0·001). Age-adjusted mean baPWV increased gradually in both males and females according to GGT quartiles (P for trends < 0·001 in both genders). The odds for higher baPWV (i.e. >75th percentile in each sex) were significantly higher in the highest compared with the lowest GGT quartiles, after adjustment for confounding variables, in both men [odds ratio (OR) = 1·63, 95% CI = 1·21-2·20] and women (OR = 1·56, 95% CI = 1·08-2·27).
These results suggest that GGT is independently associated with the increased level of arterial stiffness both in men and in women and the association between them appears to be stronger in men compared to women.
[Show abstract][Hide abstract] ABSTRACT: To investigate the rate of progression to insulin deficiency in Korean patients with Type 2 diabetes mellitus positive for anti-GAD antibody (GADA) and to determine the factors related to progression to insulin deficiency.
We retrospectively analysed data on 87 GADA-positive and 87 age- and sex-matched GADA-negative patients with Type 2 diabetes. GADA-positive patients were further subclassified into high-titre (≥ 250 WHO units/ml) (n = 24) and low-titre (< 250 WHO units/ml) (n = 63) subgroups. Cox proportional hazard analysis was used to identify factors associated with progression to insulin deficiency.
Over a period of 6 years, two of 87 (2.3%) GADA-negative and 37 of 87 (42.5%) GADA-positive patients had progressed to insulin deficiency. The rate of progression to insulin deficiency was higher in the high-titre than in the low-titre subgroup (75.0 vs. 30.2%). Multivariate analysis in GADA-positive patients showed that high-titre GADA and low BMI at diagnosis were independent factors significantly related to progression to insulin deficiency.
The presence of GADA predicted the progression to insulin deficiency in Korean patients with Type 2 diabetes. In GADA-positive patients, high-titre GADA and low BMI were associated with this progression.
Diabetic Medicine 03/2011; 28(3):319-24. · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: alpha-lipoic acid is an essential cofactor for mitochondrial respiratory enzymes that improves mitochondrial function. We previously reported that alpha-lipoic acid markedly reduced body weight gain in rodents. The purpose of this study was to determine whether alpha-lipoic acid reduces body weight in obese human subjects.
in this randomized, double-blind, placebo-controlled, 20-week trial, 360 obese individuals (body mass index [BMI] ≥ 30 kg/m(2) or BMI 27-30 kg/m(2) plus hypertension, diabetes mellitus, or hypercholesterolemia) were randomized to alpha-lipoic acid 1200 or 1800 mg/d or placebo. The primary end point was body weight change from baseline to end point.
the 1800 mg alpha-lipoic acid group lost significantly more weight than the placebo group (2.1%; 95% confidence interval, 1.4-2.8; P<.05). Urticaria and itching sensation were the most common adverse events in the alpha-lipoic acid groups, but these were generally mild and transient.
alpha-lipoic acid 1800 mg/d led to a modest weight loss in obese subjects. Alpha-lipoic acid may be considered as adjunctive therapy for obesity.
The American journal of medicine 01/2011; 124(1):85.e1-8. · 5.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kidney function is critical in homocysteine clearance, and plasma homocysteine level is frequently increased in patients with renal failure. On the other hand, recent studies in animals have shown that hyperhomocysteinemia induces renal injury. In this study, we determined whether hyperhomocysteinemia can be a risk factor for the development of microalbuminuria in patients with type 2 diabetes.
A nested case-control study. Of 887 patients with type 2 diabetes who did not have microalbuminuria at baseline, 76 developed microalbuminuria during follow-up (mean, 36.0 +/- 11.7 months; range, 18 to 76 months). The control group consisted of 152 age- and sex-matched subjects who did not develop microalbuminuria. Baseline plasma homocysteine concentrations were measured in stored samples.
Baseline plasma homocysteine concentrations and mean HbA1C levels during follow-up were significantly higher in patients who developed microalbuminuria than in those who remained normoalbuminuric. Multivariate logistic regression analysis showed that baseline plasma homocysteine level and mean HbA1C were independent predictors of microalbuminuria in type 2 diabetes.
Hyperhomocysteinemia was associated with increased risk of microalbuminuria in patients with type 2 diabetes supporting the concept that hyperhomocysteinemia has an etiologic role in the pathogenesis of diabetic nephropathy.
[Show abstract][Hide abstract] ABSTRACT: Mitochondria play key roles in energy production and intracellular reactive oxygen species (ROS) generation. Lines of evidence have shown that mitochondrial dysfunction contributes to the development of metabolic syndrome. The causes of mitochondrial dysfunction are complex, but overnutrition and sedentary living are among the best known causes of mitochondrial dysfunction. ATP synthesized in the mitochondria is exchanged for cytosolic ADP by adenine nucleotide translocator (ANT) to provide a continuous supply of ADP to mitochondria. We recently found that ANT function is essential for peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha)'s action on endothelial cells. PGC-1alpha is a transcriptional coactivator of nuclear receptors, playing an important role in fatty acid oxidation and mitochondrial biogenesis. Recent studies have shown that PGC-1alpha decreases intracellular ROS generation by increasing the expression of antioxidant genes. In our study, PGC-1alpha reduced cell apoptosis and ROS generation in endothelial cells by increasing ATP/ADP translocase activity of ANT and ANT1 expression. Here we review the role of ANT in maintaining proper mitochondrial function, and possible role of ANT dysfunction in the pathogenesis of metabolic syndrome.
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) stimulates mitochondrial biogenesis. We recently reported that adiponectin synthesis is regulated by mitochondrial function in adipocytes. This study was undertaken to test the hypothesis that endothelial NO synthase (eNOS) plays an important role in adiponectin synthesis by producing NO and enhancing mitochondrial function in adipocytes. We examined the effects of eNOS knockdown on adiponectin synthesis in 3T3-L1 adipocytes and also examined plasma adiponectin levels and the mitochondria in adipose tissue of eNOS knockout (eNOS(-/-)) mice with and without chronic administration of a NO donor. In cultured 3T3-L1 adipocytes, eNOS siRNA decreased rosiglitazone-induced adiponectin secretion, which was associated with decreases in mitochondrial proteins and biogenesis factors. Plasma adiponectin concentrations were reduced in adult eNOS(-/-) mice compared with age-matched wild-type mice. Mitochondrial contents in adipose tissue were reduced in eNOS(-/-) mice, and this was associated with decreased expression of mitochondrial biogenesis factors, increased levels of 8-hydroxyguanosine, a biomarker of oxidative stress, and morphological abnormalities in mitochondria. Rosiglitazone-induced increases in adiponectin expression and mitochondrial content were also reduced significantly in eNOS(-/-) mice. Chronic administration of a NO donor reversed mitochondrial abnormalities and increased adiponectin expression in adipose tissue of eNOS(-/-) mice. eNOS plays an important role in adiponectin synthesis in adipocytes by increasing mitochondrial biogenesis and enhancing mitochondrial function.
AJP Endocrinology and Metabolism 04/2010; 298(4):E846-53. · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serum cystatin C level is a more sensitive marker of renal dysfunction than serum creatinine level. Serum cystatin C level was recently reported to predict the development of cardiovascular disease. This study was performed to evaluate whether the cystatin C level is associated with coronary artery disease (CAD), independent of diabetic nephropathy.
We conducted a case-control study to assess the relationship between serum cystatin C level and coronary artery disease in diabetic patients. Among 460 diabetic patients, 38 diabetic patients had CAD. The control group consisted of 38 diabetic patients who were matched to cases by age, sex, and presence/absence of diabetic nephropathy. Serum cystatin C level was measured in stored samples.
Serum cystatin C level was significantly higher in patients with diabetic nephropathy, both in CAD and non-CAD patients. However, serum cystatin C level did not differ between CAD and non-CAD patients, regardless of diabetic nephropathy.
Serum cystatin C level is a marker of renal dysfunction, but not coronary artery disease, in diabetic patients.