Ying-Tsung Chen

A relationship between serum ferritin and the insulin resistance syndrome is present in non‐diabetic women but not in non‐diabetic men

background Previous studies have suggested that serum ferritin is one of the components of the insulin resistance syndrome in Caucasians. Because serum ferritin levels differ significantly between men and women, variation in the role of ferritin in insulin resistance between the sexes, particularly in Asian populations, is still unknown.

Plasma homocysteine concentrations and insulin sensitivity in hypertensive subjects

Hyperhomocysteinemia is associated with several cardiovascular disease risk factors including endothelial dysfunction and abnormalities of clotting functions, which are also common features of insulin resistance syndrome observed in hypertensive patients. Recent study has shown that acute hyperinsulinemia can lower plasma homocysteine concentrations in nondiabetic but not in type 2 diabetic individuals, indicating that insulin may regulate homocysteine metabolism. To investigate the relationships between plasma homocysteine concentration and insulin sensitivity, we studied 90 Chinese hypertensive patients and a group of control subjects (n = 86) matched for age, gender, and body mass index. Fasting plasma homocysteine levels, plasma lipoprotein concentrations, plasma glucose, and insulin responses to oral glucose tolerance tests (OGTT) were determined. The results showed that fasting plasma homocysteine concentrations were significantly higher in subjects with hypertension than in those with normotension (mean +/- SEM, 8.1 +/- 0.6 v 6.8 +/- 0.2 micromol/L; P < .05). Fasting plasma homocysteine levels correlated significantly with insulin secretion in response to OGTT even after adjustment for body mass index (P < .05) in hypertensive patients but not in normotensive individuals. However, fasting plasma homocysteine concentrations showed no correlations with steady-state plasma glucose concentration, a measurement of insulin sensitivity, during an insulin suppression test in groups of hypertensive (n = 42) and normotensive (n = 37) subjects. When the steady-state plasma glucose concentrations were divided into three tertiles, fasting plasma homocysteine concentrations showed no difference across these three groups in either hypertensive patients (8.6 +/- 0.5 v 7.2 +/- 0.5 v 8.4 +/- 0.6 micromol/L; P = .148) or normotensive subjects (6.3 +/- 0.4 v 8.0 +/- 0.8 v 7.0 +/- 0.8 micromol/L; P = .199). In conclusion, hypertensive Chinese subjects had higher fasting plasma homocysteine concentrations and a higher degree of insulin resistance when compared to a group of age-, gender-, and body mass index-matched normotensive individuals. Fasting plasma homocysteine levels were associated with insulin response to OGTT in hypertensives but not in normotensives. No correlation was observed between the degree of insulin resistance and plasma homocysteine levels in either the hypertensive or the normotensive group. The role of insulin in homocysteine metabolism deserves further investigation.

Endothelial dysfunction in type 2 diabetes mellitus subjects with peripheral artery disease

We strived to characterize the endothelial function status in type 2 diabetic patients with peripheral artery disease which was detected by ankle-brachial index by utilizing high frequency ultrasounds. Predictors of endothelial dysfunction were investigated. We chose 23 type 2 diabetic patients had ankle-brachial index <0.97 (0.15-0.95; mean=0.74+/-0.20), 31 diabetic patients had ankle-brachial index >/=1.0 and 28 non-diabetic subjects for study. Older age, a longer duration of diabetes, higher systolic blood pressure, higher prevalence of history of hypertension were observed in patients with peripheral vascular disease. Type 2 diabetic patients showed impaired flow-mediated dilatation than non-diabetic and it showed more impaired in patients with peripheral vascular disease. Nitroglyerin-induced dilatation showed a trend of impairment in patients with peripheral vascular disease but did not reach statistical significance. Age (r=-0.259, P=0.019), baseline brachial artery diameter (r=-0.321, P=0.003), ankle-brachial index (r=0.259, P=0.002) and hypertension history (P=0.01) were significantly associated with flow-mediated dilatation. However, after adjusting for age, only baseline diameter and ankle-brachial index were independent predictors of flow-mediated dilatation. In conclusion, we demonstrated flow-mediated dilatation was impaired in type 2 diabetic patients and it was further impaired in patients with peripheral vascular disease. Nitroglycerin-induced dilatation showed a trend of impairment but did not reach statistical significance.

Coronary Artery Disease Risk Predicted by Insulin Resistance, Plasma Lipids, and Hypertension In People without Diabetes

BACKGROUND It has been shown that insulin resistance syndrome, including glucose intolerance, dyslipidemia, and hypertension, is frequently associated with coronary artery disease (CAD). However, their relative contributions and predictive power in the development of CAD are still unclear, particularly in persons without diabetes. METHOD We examined these risk factors between 96 patients without diabetes but with angiographically documented CAD and 96 age-, sex-, and body mass index-matched healthy control subjects. Fasting plasma lipoprotein, glucose, and insulin concentrations in response to a 75-g oral glucose tolerance test were determined, and insulin sensitivity was measured by the insulin suppression test. RESULTS Patients with CAD had significantly higher values of fasting glucose, glucose and insulin responses to oral glucose tolerance test, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride and decreased high-density lipoprotein (HDL) cholesterol concentrations compared with those of healthy people (P < 0.02-0.001). Although the steady-state plasma insulin values were similar in both groups, the steady-state plasma glucose (SSPG) concentrations were significantly higher in patients with CAD (12.2+/-0.4 versus 8.1+/-0.4 mmol/L, P < 0.001) compared with healthy subjects. When HDL < 0.9 mmol/L, LDL cholesterol > or = 4.1 mmol/L, triglyceride > or = 2.3 mmol/L, SSPG > or = 10.5 mmol/L, and presence of hypertension were defined as separate risk factors for CAD, significantly higher odds-ratio values were observed in patients with CAD compared with healthy people. From logistic multiple regression analysis, SSPG was the strongest risk, followed by lowered HDL cholesterol, elevated triglyceride and LDL cholesterol, and hypertension, to predict CAD. These 5 factors accounted for 36% of total risk for development of CAD in persons without diabetes. CONCLUSIONS Patients without diabetes with CAD have abnormal glucose metabolism, hyperinsulinemia, and insulin resistance. Degree of insulin resistance (SSPG values), plasma lipid values, and history of hypertension together accounted for one third of all risk for CAD, although degree of insulin resistance was the strongest risk factor.

PLASMA TUMOR NECROSIS FACTOR α LEVELS AND INSULIN SENSITIVITY IN HYPERTENSIVE SUBJECTS

Recent studies have shown that tumor necrosis factor-alpha (TNFα), secreted by macrophage, adipocyte and muscle cells, are associated with insulin resistance syndrome i.e., hyperinsulinemia, hypertriglyceridemia and decreased high density lipoprotein (HDL) cholesterol levels. However, it is unclear whether plasma TNFα levels relate to insulin resistance syndrome in subjects with essential hypertension who are also characterized by an insulin resistance state. We recruited 85 nondiabetic subjects (45 men and 40 women) with essential hypertension and 85 nondiabetic subjects who were matched for age, sex and body mass index (BMI) to determine their fasting plasma glucose, insulin and lipoprotein concentrations, their glucose and insulin responses to an oral glucose challenge, and their degrees of insulin resistance. Fasting plasma leptin and TNFα levels were measured by radioimmunoassay and chemiluminescent enzyme immunometric assay respectively. Total body fat mass was assessed by the bioelectrical impedance method. The results showed that fasting plasma leptin levels were similar between hypertensive and normotensive subjects (7.9±0.6 vs 7.4±0.7 ng/ml, p=0.190). Fasting plasma TNFα concentrations were not different between subjects with hypertension and normotension (10.5±0.5 vs 9.8±0.4 pg/ml, p=0.360). Fasting plasma TNFα concentrations were not different across three subgroups of the insulin resistance both in hypertensive patients (8.4±0.4 vs. 10.9±1.6 vs. 9.9±1.0 pg/ml, p=0.297) and normotensive subjects (9.2±0.7 vs. 9.3±0.9 vs. 9.7±0.9 pg/ml, p=0.875). Fasting plasma TNFα values showed significantly positive correlations with triglyceride concentrations (p<0.03) but negative correlation with HDL cholesterol concentrations (p<0.04) in normotensive but not in hypertensive individuals. These relations persisted even after adjustment for BMI and total fat mass. In conclusion, our data indicated that circulating levels of TNFα did not differ between hypertensive subjects and normotensive controls. Plasma TNFα concentrations correlated positively with fasting plasma triglyceride levels and negatively with HDL cholesterol concentrations in normotensive but not in hypertensive subjects. The influence of TNFα on carbohydrate and lipoprotein metabolism in hypertensive patients deserves further investigations.

Lack of association between genetic variation in the β3-adrenergic receptor gene and insulin resistance in patients with coronary heart disease☆

Abstract The β-adrenergic system plays a critical role in regulating lipolysis and thermogenesis. Recent studies have suggested that a missense Trp64Arg mutation in the β3-adrenergic receptor gene is involved in visceral obesity and insulin resistance. We investigated the effect of this mutation on insulin resistance in patients with angiographically documented coronary heart disease ([CHD] n = 137) and normal subjects (n = 188). Plasma glucose and insulin responses to a 75-g oral glucose tolerance test and insulin resistance measured by the insulin suppression test, were determined in 58 (42%) patients with CHD and 121 (64%) controls. The genotype and allele frequency of the β3-adrenergic receptor did not differ between patients with CHD and controls. The blood pressure, body mass index (BMI), waist to hip ratio, fasting plasma glucose, insulin, and lipid, and plasma glucose and insulin responses to the glucose load were relatively similar in subjects with and without the mutation in CHD and normal groups. The degree of insulin sensitivity, ie, the steady-state plasma glucose concentration, was not significantly different between subjects with and without the mutation in the CHD group (11.3 ± 1.2, n = 11 v 11.9 ± 0.6 mmol/L, n = 47, P = NS) and control group (8.4 ± 0.7, n = 30 v 8.2 ± 0.4 mmol/L, n = 91, P = NS). We conclude that Trp64Arg polymorphism of the β3-adrenergic receptor gene does not likely play a major role in the development of CHD in the Chinese population. In addition, it appears to have no association with the insulin resistance syndrome in either CHD or non-CHD subjects.

Comparison of Brachial Artery Flow-Mediated Vasodilatation in Symptomatic and Asymptomatic Patients With Carotid Arterial Stenosis

T is a strong association between severity of extracranial carotid arterial stenosis and cerebral ischemia, but the natural histories of symptomatic and asymptomatic carotid stenoses are different. The mechanism of this dichotomy is complex and not fully understood. Plaque morphology might contribute to variations in clinical course. However, overall morphologic differences are inconsistent predictors of symptomatic plaque. Dysfunction of the endothelium is a critical factor in the pathogenesis of several vascular diseases and thrombus formation. Endothelial dysfunction may contribute to cerebral ischemic events in patients with carotid stenosis, but the association has not been clinically evaluated. Noninvasive evaluation of brachial artery reactivity using B-mode ultrasound is a useful surrogate for detecting systemic endothelial dysfunction in several diseases. We hypothesized that in addition to a stenotic lesion of the carotid artery, impairment of systemic endothelial function plays a role in acute cerebral ischemic events. This study investigates the extent and characteristics of endothelial dysfunction in patients with asymptomatic and acute symptomatic carotid stenoses.

Metabolic syndrome and its contribution to coronary artery disease in non-diabetic subjects.

BACKGROUND AND PURPOSE People with the metabolic syndrome are at increased risk for developing diabetes mellitus and coronary artery disease (CAD). This study assessed the 5 risk factors of metabolic syndrome in non-diabetic individuals with angiographically-documented CAD. METHODS To estimate the CAD risk associated with metabolic syndrome, we examined the 5 components of metabolic syndrome, defined by the National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) III, including blood pressure (> or = 130/85 mm Hg), fasting glucose (> or = 110 mg/dL), fasting triglycerides (> or = 150 mg/dL), high-density lipoprotein (HDL) cholesterol level (men < 40 mg/dL; women < 50 mg/dL), and abdominal obesity (waist circumference defined by the Department of Health, Taiwan: men > 90 cm; women > 80 cm) among 139 non-diabetic patients with angiographically-documented CAD and 139 age- and gender-matched non-diabetic control subjects. RESULTS Metabolic syndrome was found to be more prevalent in subjects with CAD than subjects without CAD (51.8% vs 18.7%; p < 0.001). Multiple logistic regression analysis showed that hypertension was the strongest predictor of CAD, followed by higher fasting glucose and lowered HDL cholesterol. These 5 factors accounted for 41.3% of total risk for CAD without diabetes. CONCLUSIONS Our data revealed that the prevalence of metabolic syndrome was higher in this group of patients with angiographically-diagnosed CAD without diabetes than in controls.

Changes in Flow-Mediated Dilatation, Cytokines and Carotid Arterial Stenosis During Aggressive Atorvastatin Treatment in Normocholesterolemic Patients

Background: Aggressive statin therapy to reduce low‐density lipoprotein (LDL) cholesterol in patients with normal LDL‐cholesterol levels reduces the incidence of future cardiovascular events and enhances atherosclerotic regression in the common carotid artery. We tried to quantify changes in flow‐mediated dilatation (FMD), inflammatory cytokines, and the severity of carotid arterial stenosis, after aggressive statin administration to patients with normal LDL‐cholesterol levels, and stroke or transient ischemic attack ipsilateral to carotid arterial stenosis. Methods: Twenty patients with at least a 50% reduction in the diameter of the carotid artery were studied. Atorvastatin 10 mg daily was prescribed for 4 months. Serial changes in the severity of carotid arterial stenosis, and brachial‐artery FMD were evaluated by high‐resolution ultrasound. Tumor necrosis factor‐alpha (TNF‐α), interleukin‐1beta (IL‐1β), interleukin‐6 (IL‐6), vascular cell adhesion molecule (VCAM), intracellular adhesion molecule (ICAM), soluble endothelin‐1 (ET‐1), and high‐sensitivity C‐reactive protein (hs‐CRP), were measured before, and after 2 and 4 months of, atorvastatin treatment. Results: Atorvastatin significantly decreased plasma levels of total cholesterol and LDL‐cholesterol after 1, 2 and 4 months of treatment (p < 0.01). FMD showed significant improvement after only 4 months (10.0% vs 6.8% at baseline; p = 0.019). The overall severity of carotid arterial lesions was not significantly reduced by atorvastatin. Changes in TNF‐α, IL‐1β, IL‐6 and ET‐1 showed trends towards a progressive decline after atorvastatin, but none of the cytokines was reduced significantly. FMD did not correlate with the severity of carotid arterial stenosis, lipid profile, or cytokine levels. Conclusion: Atorvastatin effectively reduced plasma concentrations of total cholesterol and LDL‐cholesterol, and had beneficial effects on endothelial function, in Chinese patients with carotid arterial stenosis and normal LDL‐cholesterol levels.

Relationship between several surrogate estimates of insulin sensitivity in non-diabetic patients with coronary artery disease.

BACKGROUND AND PURPOSE Insulin resistance plays an important role in the pathogenesis of coronary artery disease (CAD). Thus, there is a need for accurate and accessible tools for measurement of insulin sensitivity in patients with this disease. This study explored the relationship between several surrogate estimates of insulin sensitivity in non-diabetic patients with angiographic evidence of CAD. METHODS The study population consisted of 1363 non-diabetic subjects with angiography results which revealed evidence of CAD in 660 and no evidence of CAD in 703 subjects. After overnight fasting, blood samples were drawn for determination of glucose and insulin concentrations in order to determine the homeostasis model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). In addition, steady-state plasma glucose (SSPG) concentrations obtained from insulin suppression tests were carried out in 54 subjects with and 194 subjects without CAD. The correlation of QUICKI with other surrogate estimates of insulin sensitivity in obese and non-obese subjects was also evaluated. RESULTS The QUICKI correlated significantly with other methods for estimating insulin sensitivity in the CAD and non-CAD groups. The QUICKI also had a closer correlation with SSPG and log fasting plasma insulin (log FPI) in subjects with CAD (r = -0.573 and -0.869, respectively) than HOMA-IR (r = 0.508 and 0.777, respectively). QUICKI had a closer correlation with SSPG in the obese subjects than in the non-obese subjects, irrespective of the presence of CAD. CONCLUSIONS The QUICKI was more closely related with SSPG, insulin area, and log FPI than other measurements of insulin sensitivity. These findings suggest that the QUICKI may provide a convenient, efficient method to measure insulin sensitivity in non-diabetic patients with CAD.