Association between HMW adiponectin,HMW-total adiponectin ratio and early-onset coronary artery disease in Chinese population

Objective

Adiponectin is an adipose-secreting protein that shows atheroprotective property and has inverse relation with coronary artery disease (CAD). High-molecular weight (HMW) adiponectin is reported as the active form of adiponectin. In the present study, we aimed to investigate the association between total adiponectin, HMW adiponectin, HMW-total adiponectin ratio and the severity of coronary atherosclerosis, and to compare their evaluative power for the risk of CAD.

Methods

Serum levels of total and HMW adiponectin were measured in 382 early-onset CAD (EOCAD) patients and 305 matched controls undergoing coronary angiography by enzyme-linked immunosorbent assay (ELISA). Gensini score was used to evaluate the severity of coronary atherosclerosis.

Results

CAD onset age was positively correlated with HMW adiponectin (r = 0.383, P < 0.001) and HMW-total adiponectin ratio (r = 0.429, P < 0.001) in EOCAD patients. Total and HMW adiponectin and HMW-total adiponectin ratio were all inversely correlated with Gensini score (r = −0.417, r = −0.637, r = −0.578, respectively; all P < 0.001). Multivariate binary logistic regression analysis demonstrated that HMW adiponectin and HMW-total adiponectin ratio were both inversely correlated with the risk of CAD (P < 0.05). ROC analysis indicated that areas under the ROC curves of HMW adiponectin and HMW-total adiponectin ratio were larger than that of total adiponectin (P < 0.05).

Conclusions

Adiponectin is cardioprotective against coronary atherosclerosis onset in EOCAD patients. HMW adiponectin and HMW-total adiponectin ratio show stronger negative associations with the severity of coronary atherosclerosis than total adiponectin does. HMW adiponectin and HMW-total adiponectin ratio are effective biomarkers for the risk of CAD in Chinese population.     

High molecular weight multimer form of adiponectin as a useful marker to evaluate insulin resistance and metabolic syndrome in Japanese men

Adiponectin is an adipocyte-specific secretory protein that possesses antidiabetic and antiatherosclerotic properties. Recent studies have demonstrated that the high molecular weight (HMW) multimer form is the active form of this protein. In patients with type 2 diabetes mellitus, HMW-total adiponectin ratio was reported to be a more useful marker than total adiponectin in the prediction of insulin resistance and metabolic syndrome. In the present study of healthy Japanese male subjects without any medication, we investigated the hypothesis that measuring only HMW adiponectin may be as effective as HMW-total ratio to predict insulin resistance and/or metabolic syndrome. This was a working community-based cross-sectional study of 637 male subjects aged 30 to 65 years. Total and HMW adiponectin concentrations in serum were measured by enzyme-linked immunosorbent assay using commercially available kits. Serum HMW adiponectin level was inversely correlated with homeostasis model assessment of insulin resistance (HOMA-IR) (r = -0.375, P < .0001) even after adjustment for age and body mass index (r' = -0.245, P < .0001). When we divided the study subjects into quartile groups with equal numbers of subjects, HOMA-IR in the 4 groups based on serum HMW adiponectin level was significantly different (P < .01). Metabolic syndrome score in the 4 groups based on serum HMW adiponectin level was also significantly different (P < .01). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.73) to evaluate the presence of insulin resistance (HOMA-IR >2.5) was larger than that of total adiponectin (0.68) or HMW-total ratio (0.70). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.70) to evaluate the presence of metabolic syndrome (body mass index-based modified criteria) was also larger than that of total adiponectin (0.65), but equal to that of HMW-total ratio (0.70). These results suggest that simply measuring HMW adiponectin may be as effective as HMW-total ratio to evaluate the presence of insulin resistance and metabolic syndrome, at least in nondiabetic subjects who are not receiving any medication.     

Alterations in total and high-molecular-weight adiponectin after 3 weeks of moderate alcohol consumption in premenopausal women

Moderate alcohol consumption is associated with increased concentrations of adiponectin. Whether this is the case for both total and high-molecular-weight (HMW) adiponectin is uncertain. Furthermore, the rate at which this increase occurs is unclear. Therefore, we examined the effect of moderate alcohol consumption on total and HMW adiponectin. In a randomized, crossover trial, 24 premenopausal women who were regular alcohol consumers received beer (∼26 g alcohol) or alcohol-free beer daily for 3 weeks preceded by a 1-week washout. Blood samples were collected weekly after an overnight fast for measurement of total and HMW adiponectin and markers of glucose and lipid metabolism. There was a significant interaction (P < .05) between the 2 treatments over time for both plasma HMW and total adiponectin concentrations. Within 3 weeks, plasma total (8.2%, P = .01) and HMW (8.2%, P = .02) adiponectin levels were higher after moderate alcohol consumption compared with abstention. Changes over time in total adiponectin were positively associated with changes in HMW adiponectin during the nonalcoholic beer (r = 0.80; 95% confidence interval, 0.55-0.92) and beer (r = 0.82; 0.58-0.93) intervention. Alcohol consumption did not affect the ratio of HMW to total adiponectin or the serum glucose, insulin, hemoglobin A_1c, or triglyceride levels compared with abstention during the intervention periods. Both total and HMW adiponectin concentrations are higher after moderate alcohol consumption compared with abstention in premenopausal women. These effects were evident after at least 3 weeks of consumption and occurred concomitantly.     

Bone stiffness in men with type 2 diabetes mellitus

Osteoporosis in elderly men as well as women is increasingly recognized, and patients with type 2 diabetes mellitus have higher risk of fracture than nondiabetic subjects. The aim of the present study was to investigate the relationship between bone stiffness and serum testosterone concentration as well as other variables in men with type 2 diabetes mellitus. The relationships between bone stiffness and serum bioavailable testosterone concentrations as well as other variables including age, duration of diabetes, glycemic control (hemoglobin A_1c), or body mass index were evaluated in 294 men with type 2 diabetes mellitus. An inverse correlation was found between stiffness index and age. A positive correlation was found between stiffness index and serum bioavailable testosterone concentration (r = 0.231, P = .0005). Stiffness index was significantly less in current smokers (81.6 ± 17.7) than in past smokers (86.6 ± 17.8, P = .0396) or nonsmokers (87.7 ± 15.2, P = .0426). Multiple regression analysis demonstrated that serum bioavailable testosterone concentration (β = .271, P = .0006) and smoking status (β = −0.147, P = .0408) were independent determinants of stiffness index. In conclusion, bone stiffness was associated with serum bioavailable testosterone concentration but not associated with hemoglobin A_1c or duration of diabetes in men with type 2 diabetes mellitus.     

High-molecular-weight adiponectin is a predictor of progression to metabolic syndrome: a population-based 6-year follow-up study in Japanese men

Adiponectin is an adipocyte-specific secretory protein, which possesses antidiabetic and antiatherosclerotic properties. Adiponectin exists as multimers in serum, and high-molecular-weight (HMW) adiponectin is particularly considered to be the active form of the protein. The objective of the present study was to examine whether decreased HMW adiponectin is a predictor of progression to metabolic syndrome during a 6-year follow-up period in Japanese men. The study subjects were 416 Japanese men without metabolic syndrome, aged 30 to 59 years at baseline, who had participated in annual health checkups in both 2000 and 2006. Low concentration of HMW adiponectin (≤2.65 μg/mL) was associated with substantially higher hazard ratio of the progression to metabolic syndrome after adjustment for age and body mass index (hazard ratio, 1.561; 95% confidence interval, 1.051-2.292; P = .028). The number of subjects with the progression to metabolic syndrome in each tertile based on baseline HMW adiponectin concentration was significantly different among the 3 groups (HMW adiponectin: χ² = 7.473, P = .0238; total adiponectin: χ² = 4.477, P = .1066; HMW-total adiponectin ratio: χ² = 1.676, P = .4325). It was suggested that decreased HMW adiponectin is a predictor of the progression to metabolic syndrome in a 6-year follow-up study of Japanese men. Furthermore, it was suggested longitudinally that measuring HMW adiponectin is efficient to predict the progression to metabolic syndrome compared with measuring total adiponectin or HMW-total adiponectin ratio.     

Serum high-molecular weight adiponectin decreases abruptly after an oral glucose load in subjects with normal glucose tolerance or impaired fasting glucose, but not those with impaired glucose tolerance or diabetes mellitus

Adiponectin exists in the blood as 3 forms, which are a trimer, a hexamer, and a high-molecular weight (HMW) form. We investigated whether circulating HMW adiponectin levels were altered by oral glucose or fat ingestion. Forty male subjects underwent a 75-g oral glucose loading test (OGTT), and 11 healthy subjects (5 women and 6 men) received a fat loading test. Serum levels of HMW and total adiponectin were measured during the OGTT and the fat loading test. The fat loading test was performed for at least 8 hours. Among the 40 male subjects, 11 had normal glucose tolerance (NGT), 9 had impaired fasting glucose (IFG), 11 had impaired glucose tolerance, and 9 had diabetes mellitus (DM). In all 40 subjects, the serum total adiponectin level did not change significantly, whereas serum HMW adiponectin decreased significantly after a glucose load and reached 92.2% of the basal level at 120 minutes after the OGTT (P < .01). The HMW to total adiponectin ratio decreased significantly from 0.47 ± 0.15 at baseline to 0.43 ± 0.13 at 120 minutes after a glucose load (P < .05). Serum HMW adiponectin measured at 120 minutes after the OGTT decreased significantly to 86.0% and 85.6% of the basal level in subjects with NGT or IFG, respectively (both P < .01). In subjects with impaired glucose tolerance or DM, however, serum HMW adiponectin did not change. The area under the curve for insulin at 30 minutes after a glucose load during the OGTT was significantly larger in subjects with NGT or IFG than in those with DM (P < .05). In addition, the insulinogenic index (ΔI_0-30/ΔG_0-30) was significantly higher in subjects with NGT or IFG than in those with DM (P < .001). Percentage changes in serum HMW adiponectin of the baseline at 120 minutes correlated negatively with those in serum insulin (r = −0.468, P = .0023), but not plasma glucose, of the baseline at 30 minutes in 40 subjects. On the other hand, serum triglycerides increased significantly after an oral fat load in 11 healthy subjects; but neither serum total nor HMW adiponectin changed. In conclusion, serum HMW adiponectin (but not total adiponectin) decreased rapidly after glucose loading in subjects with NGT or IFG; and the decrease of HMW adiponectin may be associated with an increase of serum insulin at 30 minutes.     

Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males

Aims/hypothesis It is well established that total systemic adiponectin is reduced in type 2 diabetic subjects. To date most studies have been concerned with the singular full-length protein or proteolytically cleaved globular domain. It is, however, apparent that the native protein circulates in serum as a lower molecular weight hexamer and as larger multimeric structures of high molecular weight (HMW). In this study we address the clinical significance of each form of the protein with respect to glucose tolerance.Methods Serum was obtained from 34 Indo-Asian male subjects (BMI 26.5±3.1; age 52.15±10.14 years) who had undertaken a 2-h oral glucose tolerance test. An aliquot of serum was fractionated using velocity sedimentation followed by reducing SDS-PAGE. Western blots were probed for adiponectin, and HMW adiponectin as a percentage of total adiponectin (percentage of higher molecular weight adiponectin [S_A] index) was calculated from densitometry readings. Total adiponectin was measured using ELISA; leptin, insulin and IL-6 were determined using ELISA.Results Analysis of the cohort demonstrated that total adiponectin (r=0.625, p=0.0001), fasting insulin (r=–0.354, p=0.040) and age (r=0.567, p=0.0001) correlated with S_A. S_A showed a tighter, inverse correlation with 2-h glucose levels (r=–0.58, p=0.0003) than total adiponectin (r=–0.38, p=0.0001).Conclusions/interpretation This study demonstrates the importance of the S_A index as a better determinant of glucose intolerance than measurements of total adiponectin. Our findings suggest that HMW adiponectin is the active form of the protein.     

Circulating angiotensin II is associated with body fat accumulation and insulin resistance in obese subjects with type 2 diabetes mellitus

Adipocytes express all components of the renin-angiotensin system, and the renin-angiotensin system is involved in obesity and insulin resistance. Circulating angiotensin II (Ang II) is detectable in blood, but its significance in human obesity remains unknown. The aim of this study was to investigate plasma Ang II in obese patients with type 2 diabetes mellitus (T2D) and the change during weight loss. Fifty Japanese obese subjects with T2D (body weight, 75.0 ± 14.1 kg; body mass index, 29.1 ± 3.7 kg/m²; visceral fat area [VFA], 169.3 ± 54.3 cm²; hemoglobin A_1c, 7.6% ± 1.5%) were enrolled. The subjects were prescribed a diet of daily caloric intake of 20 kcal/kg for 24 weeks. Plasma Ang II was measured by radioimmunoassay. Leptin, adiponectin, and lipoprotein lipase mass in preheparin serum were also measured as adipocyte-derived factors. After 24 weeks of weight reduction diet, the mean body weight, VFA, and hemoglobin A_1c decreased significantly by 2.3%, 7.0%, and 8.3%, respectively. The mean plasma Ang II decreased by 24% (P < .0001) and correlated with body weight both at baseline (r = 0.425, P = .0018) and at 24 weeks (r = 0.332, P = .0181). The change in Ang II correlated with changes in body weight (r = 0.335, P = .0167) and VFA (r = 0.329, P = .0191). The change in Ang II also correlated positively with change in leptin (r = 0.348, P = .0127) and tended to correlate negatively with change in lipoprotein lipase mass in preheparin serum (r = −0.260, P = .0683), which is a marker of insulin sensitivity. Plasma Ang II is associated with body weight, decreases during weight loss, and is associated with markers of insulin resistance in obese subjects with T2D.     

Prevalence of osteoporosis and factors affecting bone mineral density among postmenopausal Turkish women with type 2 diabetes

ObjectivesControversy remains as to the effects of type 2 diabetes on bone metabolism. The aims of this study were to assess the association between type 2 diabetes and bone mineral density (BMD) and to evaluate the possible relationship between chronic diabetic complications and bone density.MethodsBone mineral densities at the lumbar spine, femur, and radius in 206 postmenopausal Turkish women with type 2 diabetes were evaluated by dual-energy X-ray absorptiometry and compared with those in 61 age-matched postmenopausal nondiabetic women. Medical and lifestyle characteristics, body mass index (BMI), hemoglobin A_1c level, and status of microvascular and macrovascular diabetic complications were recorded. Frequency of osteoporosis and that of osteopenia as well as the relationship between microvascular and macrovascular complications and BMD were evaluated.ResultsThe groups did not differ on BMDs and T scores at the hip, lumbar spine, and radius. Patients with radial and/or lumbar and/or hip osteoporosis had a longer duration of diabetes (P=.000), were older (P=.000), and had a lower BMI (P=.000). No correlation was found between osteopenia or osteoporosis and hemoglobin A_1c level, presence of microalbuminuria, retinopathy, neuropathy, peripheral artery disease, cerebrovascular event, and coronary artery disease. Among the three sites, BMD at the hip was positively correlated with BMI (P=.000) but negatively correlated with age (P=.000) and duration of diabetes (P=.000). Presence of microalbuminuria revealed a negative correlation with BMD at the femoral neck (P=.042).ConclusionThere is no evidence that type 2 diabetes influenced BMD in our postmenopausal patient group.     

Leptin is an independent determinant of bone mineral density in men with type 2 diabetes mellitus

To investigate the possible relationship of leptin to bone mineral density (BMD) in men with type 2 diabetes mellitus (T2DM), we screened 168 Belarusian men aged 45–65 years. Plasma total cholesterol (TC), high-density lipoprotein cholesterol, and triglyceride concentrations were assessed, and low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol (LDL-C) were calculated. Hemoglobin A_1c, immune-reactive insulin (IRI), serum total testosterone, and sex hormone-binding globulin were also evaluated. BMD was evaluated using dual-energy X-ray absorptiometry. By univariate linear regression analysis, BMD was significantly correlated with body mass index (r = 0.23, P = 0.002) and leptin (r = 0.21, P = 0.006). By multivariate regression analysis adjusting for confounding factors, log leptin was independently correlated with BMD (β = 0.058, P = 0.001). Our study revealed that leptin is an independent determinant of BMD in patients with T2DM. Further research is necessary to confirm this association and to develop ways to correct abnormalities of bone metabolism in patients with T2DM.     

Distribution and cardiovascular risk correlates of hemoglobin A(1c) in nondiabetic younger adults: the Bogalusa Heart Study

Excess glycated hemoglobin (HbA_1c), an indicator of long-term glucose homeostasis, is recognized as a risk factor for cardiovascular (CV) disease and mortality even among persons without diabetes. However, information is scant regarding its distribution and correlates of CV risk in nondiabetic younger adults. This aspect was examined in a biracial (black-white) community-based sample of 1111 younger adults (mean age: 36.2 years; 71% white, 43% male) enrolled in the Bogalusa Heart Study. Blacks vs whites and women vs men had higher HbA_1c values (P < .0001). In bivariate analysis adjusted for age, race, sex, and smoking status, significant adverse trends were noted for body mass index, waist circumference, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), total cholesterol to HDL-C ratio, insulin, glucose, and homeostasis model assessment of insulin resistance across HbA_1c quartiles; trends were not significant for mean arterial blood pressure, triglycerides, C-reactive protein, adiponectin, and estimated glomerular filtration rate. In multivariate analysis, besides race and sex, total cholesterol to HDL-C ratio and waist circumference were independent correlates of HbA_1c. Furthermore, the prevalence of excess (top decile) HbA_1c was 1.6-fold (P < .05) higher among those with metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel III and 2.1-fold (P < .01) and 1.5-fold (P < .05) higher, respectively, among those with positive parental history of CV disease and type 2 diabetes mellitus. These findings underscore the potential value of HbA_1c in risk assessments of CV disease and type 2 diabetes mellitus in nondiabetic, apparently “healthy” younger adults.     

Glimepiride increases high-density lipoprotein cholesterol via increasing adiponectin levels in type 2 diabetes mellitus

The aims of the present study are to investigate the effect of glimepiride 1 mg/d on plasma adiponectin and to assess the contribution of adiponectin in changing high-density lipoprotein cholesterol (HDL-c) levels after glimepiride treatment. Forty patients with type 2 diabetes mellitus were included. Plasma adiponectin, fasting plasma glucose, insulin, hemoglobin A_1c, and cholesterol were measured at study entry and after 3 months of treatment with glimepiride. Both plasma adiponectin level (7.5 ± 4.5 vs 8.3 ± 4.5 μg/mL, P = .040) and HDL-c level increased significantly (50 ± 11 vs 53 ± 10 mg/dL, P = .041) in the all-subjects group. In the low-adiponectin group (initial plasma adiponectin level <6 μg/mL), both plasma adiponectin level (4.5 ± 0.9 vs 5.9 ± 2.0 μg/mL, P = .004) and HDL-c level increased significantly (44 ± 8 vs 49 ± 9 mg/dL, P = .011). There was no significant change in the high-adiponectin group (initial plasma adiponectin level ≥6 μg/mL). Change in plasma adiponectin level was an independent factor for change in HDL-c level after adjustment for other factors (β = .574, P = .009, R² = 0.524, P = .036). In conclusion, glimepiride improved plasma adiponectin level, especially in the subjects with type 2 diabetes mellitus with low adiponectin level before treatment, and may directly contribute to improving HDL-c level.     

Influence of acute aerobic exercise on adiponectin oligomer concentrations in middle-aged abdominally obese men

Exercise intensity may induce changes in total adiponectin and adiponectin oligomer levels. However, the effects of acute aerobic exercise on total adiponectin and adiponectin oligomers in middle-aged abdominally obese men remain unknown. The purpose of this study was to investigate the influence of aerobic exercise intensity on changes in the concentrations of total adiponectin and adiponectin oligomers (high-molecular weight [HMW] and middle- plus low-molecular weight [MLMW] adiponectin), and the endocrine mechanisms involved in exercise-induced changes in adiponectin oligomer profiles in middle-aged abdominally obese men. Using a crossover design, 9 middle-aged abdominally obese men (age, 54.1 ± 2.4 years; body mass index, 27.9 ± 0.6 kg/m²) underwent 2 trials that consisted of 60 minutes of stationary cycle exercise at either moderate-intensity (ME) or high-intensity (HE) aerobic exercise (50% or 70% of peak oxygen uptake, respectively). Blood samples were collected to measure the concentrations of adiponectin oligomers, hormones (catecholamines, insulin, and growth hormone), metabolites (free fatty acid, glycerol, triglyceride, and glucose), and cytokines (interleukin-6 and tumor necrosis factor-α). After exercise, plasma catecholamine concentrations were higher during HE than during ME (P < .05). Total adiponectin concentration decreased at the end of HE (P < .05), but remained unchanged after ME. The HMW adiponectin concentration did not change at either intensity, whereas the MLMW concentration decreased at the end of HE (P < .05). The ratio of HMW to total adiponectin concentration increased significantly (P < .05), whereas the ratio of MLMW to total adiponectin concentration decreased significantly (P < .05), at the end of HE. The percentage changes in epinephrine concentration from baseline to the end of exercise were correlated with the percentage changes in total adiponectin concentration (r = −0.67, P < .05) and MLMW adiponectin concentration (r = −0.82, P < .05) from baseline to the end of HE. Our results indicate that the change in total adiponectin was mainly due to a change in MLMW adiponectin concentration during high-intensity exercise in middle-aged abdominally obese men. Epinephrine may partially regulate the decrease in total and MLMW adiponectin concentrations during high-intensity exercise.     

Effects of combination of sibutramine and l-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus l-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA_1c] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus l-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA_1c, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus l-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA_1c, fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus l-carnitine compared with sibutramine alone. Sibutramine plus l-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.     

The first and second phase of insulin secretion in naive Chinese type 2 diabetes mellitus

Impaired insulin secretion (ISEC) has been recognized as one of the most important pathophysiologies of type 2 diabetes mellitus. There are 2 phases of ISEC: the first phase (first ISEC) and second phase (second ISEC). This study aimed to evaluate the 2 phases of ISEC in newly diagnosed type 2 diabetes mellitus patients. Fifty-two drug-naive type 2 diabetes mellitus patients were given 2 tests: a modified low-dose graded glucose infusion (M-LDGGI) and frequent sample intravenous glucose tolerance test. The M-LDGGI is a simplified version of the Polonsky method. Two stages of intravenous infusion of glucose with different rates were given, starting from 2 mg/(kg min) and then followed by 6 mg/(kg min). Each stage was maintained for 80 minutes. The results were interpreted as the slope of the changes of plasma insulin against the glucose levels. The slope of these curves was regarded as the second ISEC and used as the criterion for grouping-the responders and nonresponders. The responders are older and had higher body mass index and log (homeostasis model assessment of β-cell function) (log HOMA-β) but lower fasting plasma glucose and hemoglobin A_1c (HbA_1c) than the nonresponders. Significant correlations were only noted between the second ISEC and first ISEC (r = 0.278, P = .046) and between the second ISEC and log HOMA-β (r = 0.533, P = .000). Correlation between different parameters and HbA_1c was also evaluated. Only second ISEC and log HOMA-β were correlated significantly with HbA_1c (r = −0.388, P = .015 and r = −0.357, P = .026, respectively). In type 2 diabetes mellitus, subjects with higher second ISEC are older and have higher body mass index. At the same time, second ISEC is the most important factor for determining glucose levels in naive Chinese type 2 diabetes mellitus patients. The first and second ISECs were only modestly correlated, which indicated that the deterioration of these 2 phases was not synchronized. Finally, we also recommend using the M-LDGGI for quantifying second ISEC. This practical method could be done in many centers without difficulty.     

Diurnal variation and effect of insulin on circulating high molecular weight (HMW) adiponectin and NF-κB activity in human endothelial cells

ObjectiveTo study the diurnal variation and the effect of insulin on adiponectin multimers and nuclear factor-kappaB (NF-κB) activity in human endothelial cells.Methods and resultsWe utilized a prolonged insulin–glucose infusion in six healthy human subjects. HMW and total adiponectin levels were higher in the morning and lower at night; NF-κB activities in serum treated human microvascular endothelial cells (HMEC-1) cells were lower in the morning and higher at night. Hyperinsulinemic induction significantly decreased HMW and total adiponectin levels but increased NF-κB activity in serum treated HMEC-1 cells (P < 0.05, P < 0.01). There were no significant changes to MMW and LMW adiponectin levels (P > 0.05).ConclusionCircadian rhythm of HMW adiponectin and NF-κB activity are altered by hyperinsulinemia providing novel insights adiponectin and NF-κB biology, which may be pertinent to insulin resistant states, e.g. obesity and type 2 diabetes mellitus.     

Effects of gliclazide on platelet aggregation and the plasminogen activator inhibitor type 1 level in patients with type 2 diabetes mellitus

Vascular complications are a common factor determining morbidity and mortality of diabetic patients. In vitro studies have revealed that gliclazide has antiplatelet activities. To clinically assess this action, we measured the effects of gliclazide on platelet activities and abnormal fibrinolysis in patients with type 2 diabetes mellitus. We studied 14 patients aged 38 to 72 years (9 men and 5 women) with type 2 diabetes mellitus who have been treated with glibenclamide in our hospital for more than 6 months. We switched from glibenclamide to gliclazide using the average ratio of the respective doses, 2.5 vs 40 mg. We titrated the dose of gliclazide to keep the glycemic control at the same level as the previous (glibenclamide) treatment. We measured 10 μmol/L serotonin-induced or 0.5 μmol/L adenosine diphosphate (ADP)-induced platelet aggregate formation by particle counting using light scattering at baseline and up to 6 months after the switch. After switching to gliclazide, platelet aggregate formation induced by serotonin was significantly reduced (P < .05, compared with the levels observed after glibenclamide treatment). The body mass index, fasting plasma glucose, immunoreactive insulin, homeostasis model assessment of insulin resistance, hemoglobin A_1c (HbA_1c), total cholesterol, triglycerides, high-density lipoprotein cholesterol, prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin-antithrombin III complex, plasmin-α2-plasmin inhibitor complex, and plasma plasminogen activator inhibitor type 1 (PAI-1) were not changed. In the group with improved HbA_1c (n = 5), ADP-induced platelet aggregate formation and plasma PAI-1 level were significantly reduced (P < .05, compared with the group with aggravated HbA_1c, n = 9). Multiple regression analysis showed that percentage change of ADP-induced platelet aggregate formation (standardized β = 0.540, P < .05) was independently associated with percentage change of plasma PAI-1 level in addition to percentage change of HbA_1c (standardized β = 0.657, P < .05) (R = 0.939, P < .05) after switching to gliclazide. The other independent variants, like the final dose of gliclazide, homeostasis model assessment of insulin resistance, percentage change of prothrombin time, activated partial thromboplastin time, and total cholesterol, were not significantly associated with the percentage change of plasma PAI-1 level. These results indicate that gliclazide inhibits platelet aggregation via the serotonin pathway, independently of the metabolic control per se. Furthermore, in the patients with improved glycemic control, gliclazide could inhibit ADP-induced platelet aggregation and reduce PAI-I level. Taken together, the results show that gliclazide may be more useful for the prevention of diabetic vascular complications than glibenclamide.     

Almond ingestion at mealtime reduces postprandial glycemia and chronic ingestion reduces hemoglobin A(1c) in individuals with well-controlled type 2 diabetes mellitus

Cohort studies are equivocal regarding a relationship between regular nut consumption and reduced risk of type 2 diabetes mellitus. Although acute trials show reductions in postprandial glycemia in healthy individuals ingesting 60 to 90 g almonds, trials have not been conducted using a single serving of almonds (28 g) in individuals with type 2 diabetes mellitus. This randomized crossover trial examined the impact of one serving of almonds at mealtime on postprandial glycemia, insulinemia, and plasma glucagon-like peptide-1 in healthy individuals and individuals with type 2 diabetes mellitus. On 2 occasions separated by at least 1 week, 19 adults (including 7 adults with type 2 diabetes mellitus) consumed a standardized evening meal and fasted overnight before ingesting the test meal (bagel, juice, and butter) with or without almonds. A small pilot study (6-7 subjects per group) was also conducted to observe whether chronic almond ingestion (1 serving 5 d/wk for 12 weeks) lowered hemoglobin A_1c in individuals with type 2 diabetes mellitus. A standard serving of almonds reduced postprandial glycemia significantly in participants with diabetes (−30%, P = .043) but did not influence glycemia in participants without diabetes (−7%, P = .638). Insulinemia and glucagon-like peptide-1 at 30 minutes postmeal were not impacted by almond ingestion for either group. In the pilot study, regular almond ingestion for 12 weeks reduced hemoglobin A_1c by 4% (P = .045 for interaction) but did not influence fasting glucose concentrations. These data show that modest almond consumption favorably improves both short-term and long-term markers of glucose control in individuals with uncomplicated type 2 diabetes mellitus.     

Effect of red wine on urinary protein, 8-hydroxydeoxyguanosine, and liver-type fatty acid-binding protein excretion in patients with diabetic nephropathy

The aim of the present study was to determine whether red or white wine affects urinary protein, 8-hydroxydeoxyguanosine (8-OHdG), and liver-type fatty acid-binding protein (L-FABP) excretion in type 2 diabetic nephropathy patients. Twenty-four type 2 diabetes mellitus patients with nephropathy were randomly allocated to drink a 118-mL (4-oz) glass of red wine (n = 12, group A) or white wine (n = 12, group B) daily for 6 months. Twelve type 2 diabetes mellitus patients with nephropathy who did not drink any wines served as control subjects (group C). Serum creatinine, 24-hour creatinine clearance, hemoglobin A_1c, urinary protein, urinary 8-OHdG, and urinary L-FABP were measured before and 3 and 6 months after the start of the study. In groups A, B, and C, serum creatinine, 24-hour creatinine clearance, and hemoglobin A_1c changed little during the experimental period. However, urinary protein, 8-OHdG, and L-FABP excretions were significantly decreased at 3 (P < .05) and 6 months (P < .01) compared with the baseline values in group A. In contrast, these markers changed little during the experimental period in groups B and C. Thus, these urinary markers were significantly lower in group A than in groups B and C at 3 and 6 months. These results suggest that red wine is renoprotective whereas white wine has no such effect in type 2 diabetes mellitus patients with nephropathy. The renoprotective effect of red wine may be due in part to its ability to reduce oxidative stress.     

Determinants of leukocyte adenosine triphosphate-binding cassette transporter G1 gene expression in type 2 diabetes mellitus

Cellular cholesterol efflux is regulated by cholesterol transporters including adenosine triphosphate–binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B type I (SR-BI). We have investigated whether the expression of these transporters is affected by type 2 diabetes mellitus and the association with glycemic indexes and oxidized low-density lipoprotein (oxLDL). Messenger RNA of ABCA1, ABCG1, and SR-BI in peripheral monocytes was measured in 30 diabetic patients and 30 matched controls. Plasma oxLDL and advanced glycation end products (AGEs) were assayed by enzyme-linked immunosorbent assay. Cellular cholesterol efflux from monocytes to serum was determined in a subgroup chosen randomly. The expression of ABCG1 was decreased in diabetic patients (P < .05), whereas the levels of ABCA1 and SR-BI were comparable between the 2 groups. Fasting glucose, hemoglobin A_1c, AGEs, and oxLDL were all significantly increased in diabetic patients. There was an inverse correlation between serum AGEs and ABCG1 (r = −0.44, P < .05) that remained significant after adjusting for potential confounding factors. No associations between fasting glucose, hemoglobin A_1c, plasma lipids, or oxLDL and the expression of ABCG1, ABCA1, or SR-BI were found. Cholesterol efflux from monocytes to standard serum or autologous serum was significantly impaired in diabetic patients, and the reduction in efflux to autologous serum correlated with the expression of ABCG1 (r = 0.60, P < .05). The expression of ABCG1 in monocytes is reduced in type 2 diabetes mellitus and is partly related to serum AGEs concentration. The reduction in ABCG1 is associated with impairment in cholesterol efflux and may contribute to accelerated foam cell formation in diabetic patients.