Low plasma adiponectin levels are associated with increased hepatic lipase activity in vivo

OBJECTIVE: Hepatic lipase plays a key role in hydrolyzing triglycerides and phospholipids present in circulating plasma lipoproteins. Plasma hepatic lipase activity is known to be regulated by several hormonal and metabolic factors, but hepatic lipase responsiveness to insulin is still controversial. Hypoadiponectinemia is known to be associated with insulin resistance, diabetes, and obesity. These conditions are often characterized by high plasma triglyceride and low HDL cholesterol levels, and they have been shown to be associated with high plasma hepatic lipase activity. We therefore raised the question whether adiponectin may be associated with plasma hepatic lipase activity in vivo. RESEARCH DESIGN AND METHODS: We measured plasma adiponectin and postheparin hepatic lipase activity in 206 nondiabetic men and in a second group of 110 patients with type 2 diabetes. The correlation of these parameters with markers of insulin resistance and systemic inflammation was investigated. RESULTS: In nondiabetic patients, adiponectin levels were significantly inversely correlated with plasma hepatic lipase activity (r = -0.4, P < 0.01). These results were confirmed in the group of patients with type 2 diabetes (r = -0.32, P = 0.004). Multivariate analysis revealed that adiponectin was the strongest factor influencing hepatic lipase activity. The association was independent of age, sex, BMI, plasma triglycerides, insulin, HDL cholesterol, and high-sensitivity C-reactive protein and accounted for approximately 10 and 12% of the variation in hepatic lipase activity in the two different patient cohorts, respectively. CONCLUSIONS: These results demonstrate for the first time a significant inverse association between adiponectin and postheparin plasma hepatic lipase activity that is independent of other factors such as markers of insulin resistance or inflammation. Therefore, adiponectin, rather than insulin, may represent an important factor contributing to the regulation of hepatic lipase activity in both nondiabetic individuals and patients with type 2 diabetes. The effect of adiponectin on hepatic lipase activity may also help to explain the HDL cholesterol-elevating action of adiponectin.     

Post-heparin plasma lipoprotein lipase, but not hepatic lipase activity, is related to plasma adiponectin in type 2 diabetic patients and healthy subjects

The aim of this study was to determine the relationships of plasma adiponectin with post-heparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities, and to evaluate whether plasma adiponectin contributes to diabetes-associated dyslipidaemia. Plasma adiponectin, post-heparin plasma lipase activities, lipoproteins and insulin sensitivity (hyperinsulinaemic euglycaemic clamp) were measured in 24 male type 2 diabetic patients and 24 age-matched healthy men. Plasma triglycerides (P < 0.01) and apolipoprotein B levels (P < 0.01) were higher, and HDL cholesterol was lower (P < 0.05) in type 2 diabetic patients. Plasma adiponectin, as well as LPL and HL activities were not significantly different between diabetic and healthy subjects. Multiple regression analysis showed that LPL activity was positively related with plasma adiponectin (P < 0.05). In contrast, HL activity was positively related with body mass index (P < 0.02) and waist/hip ratio (P < 0.05, multiple r = 0.74), but not with plasma adiponectin. Plasma adiponectin was positively associated with insulin sensitivity (P = 0.001), age (P < 0.02) and LPL activity (P < 0.05, multiple r = 0.64), but not with the presence of diabetes and HL activity. Plasma triglycerides were negatively related with LPL activity (P = 0.002) and positively with the diabetic state (P = 0.001, multiple r = 0.58). HDL cholesterol was positively related with plasma adiponectin (P = 0.003) and negatively with HL activity (P < 0.02) as well as with the presence of diabetes (P = 0.05, multiple r = 0.59). We conclude that post-heparin plasma LPL activity, but not HL activity, is related with plasma adiponectin. Plasma adiponectin appears to be a determinant of plasma triglycerides via an effect on LPL activity. It seems unlikely that plasma adiponectin predicts the effects of the diabetic state as such on high plasma triglycerides and low HDL cholesterol.     

Plasma adiponectin plays an important role in improving insulin resistance with glimepiride in elderly type 2 diabetic subjects

OBJECTIVE: We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2alpha (8-epi-PGF2alpha), an oxidative stress marker. RESEARCH DESIGN AND METHODS: A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of beta-cell function, HbA(1c), C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2alpha, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp. RESULTS: After 8 weeks of glimepiride treatment, significant reductions were observed in HbA(1c) (from 8.4 +/- 1.9 to 6.9 +/- 1.0%), HOMA-IR (from 2.54 +/- 2.25 to 1.69 +/- 0.95%), and plasma TNF-alpha concentrations (from 4.0 +/- 2.0 to 2.6 +/- 2.5 pg/ml). MCR-g was significantly increased from 3.92 +/- 1.09 to 5.73 +/- 1.47 mg. kg(-1). min(-1). Plasma adiponectin increased from 6.61 +/- 3.06 to 10.2 +/- 7.14 micro g/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers. CONCLUSIONS: Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA(1c) without changing extrapancreatic beta-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-alpha may underlie the improvement of insulin resistance with glimepiride.     

Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus

OBJECTIVE: Women with prior gestational diabetes mellitus (pGDM) are at increased risk of developing type 2 diabetes and associated vasculopathy. Because increased fat mass and inflammatory processes are angiopathic risk factors, the relationship between insulin sensitivity, parameters of subclinical inflammation, and plasma concentrations of adipocytokines was investigated in pGDM both at 3 months and 12 months after delivery. RESEARCH DESIGN AND METHODS: Insulin sensitivity (through a frequently sampled intravenous glucose tolerance test) and plasma concentrations of ultrasensitive C-reactive protein (CRP), adiponectin, plasminogen activator inhibitor (PAI)-1, tumor necrosis factor-alpha, leptin, and interleukin-6 were measured in 89 pGDM (BMI 26.9 +/- 0.5 kg/m(2), age 32 +/- 0.5 years) and in 19 women with normal glucose tolerance during pregnancy (NGT) (23.7 +/- 0.9 kg/m(2), 31 +/- 1.3 years). RESULTS: pGDM showed lower (P < 0.0001) plasma adiponectin (6.7 +/- 0.2 microg/ml) than NGT (9.8 +/- 0.6 microg/ml) and a decreased (P < 0.003) insulin sensitivity index (S(i)) and disposition index (P < 0.03), but increased plasma leptin (P < 0.003), PAI-1 (P < 0.002), and CRP (P < 0.03). After adjustment for body fat mass, plasma adiponectin remained lower in pGDM (P < 0.004) and correlated positively with S(i) (P < 0.003) and HDL cholesterol (P < 0.0001) but negatively with plasma glucose (2-h oral glucose tolerance test [OGTT]) (P < 0.0001), leptin (P < 0.01), CRP (P < 0.007), and PAI-1 (P < 0.0001). On regression analysis, only HDL cholesterol, postload (2-h OGTT) plasma glucose, and S(i) remained significant predictors of plasma adiponectin, explaining 42% of its variability. Of note, adiponectin further decreased (P < 0.05) only in insulin-resistant pGDM despite unchanged body fat content and distribution after a 1-year follow-up. CONCLUSIONS: Lower plasma adiponectin concentrations characterize women with previous GDM independently of the prevailing insulin sensitivity or the degree of obesity and are associated with subclinical inflammation and atherogenic parameters.     

Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus

Dyslipidaemia, hallmarked by low HDL cholesterol and high plasma triglycerides, is a feature of insulin resistance and type 2 diabetes mellitus. These lipoprotein abnormalities represent major cardiovascular risk factors in these conditions. Among other factors, lipoprotein lipase (LPL), hepatic lipase (HL), lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) play an important role in an abnormal HDL metabolism in insulin resistance and type 2 diabetes mellitus. LPL hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. In insulin resistant states, a decreased post-heparin plasma LPL activity contributes to a low HDL cholesterol, whereas an increased activity of HL reduces HDL particle size by hydrolysing its triglycerides and phospholipids. High HL activity coincides with low HDL cholesterol. The esterification of free cholesterol by LCAT increases HDL particle size. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins. This cholesteryl ester transfer process results in lower HDL cholesterol and indirectly decreases HDL size. Plasma cholesterol esterification is unaltered or increased, whereas cholesteryl ester transfer is enhanced in type 2 diabetes mellitus, abnormalities which are probably related to the degree of hypertriglyceridaemia. It is plausible that a low LPL activity contributes to premature atherosclerosis as observed in insulin resistance and type 2 diabetes mellitus, but the effects of high HL activity and altered plasma cholesterol esterification on atherosclerosis development are uncertain. Since the cholesteryl ester transfer process between lipoproteins provides a metabolic intermediate between low HDL cholesterol and high plasma triglycerides, hypertriglyceridaemia-associated accelerated transfer of cholesteryl ester out of HDL may be pathogenetically involved in the development of cardiovascular disease in insulin resistance and type 2 diabetes mellitus.     

Variability in postheparin hepatic lipase activity is associated with plasma adiponectin levels in African Americans.

BACKGROUND: African Americans commonly have normal high-density lipoprotein cholesterol (HDL-C) and low triglyceride levels despite having insulin resistance and obesity. The higher than expected HDL-C levels are usually attributed to low levels of hepatic triglyceride lipase (HTGL) activity. Factors that regulate HTGL in African Americans are not well delineated. METHODS: In the current study, HTGL activity was examined in relation to indices of body fat (body mass index [BMI] and waist circumference [WC]), insulin resistance (fasting plasma insulin and homeostasis model assessment of insulin resistance [HOMA-IR] index), and adipokines (adiponectin and leptin). Sixty-three African Americans (33 men, 30 women; median age 31 years, range 20-50 years; median BMI 28.6 kg/m2, range 19.7-54.7 kg/m2) had anthropometry and measurement of postheparin lipase activities (HTGL), plasma HDL-C, triglycerides, and plasma adiponectin. RESULTS: HTGL correlated strongly with HDL-C (r = -.52, p < .0001) and adiponectin (r = -.49, p < .001). HTGL increased with BMI and WC (r = .297, p = .018 and r = .301, p = .016, respectively). Adiponectin correlated strongly with HDL-C (r = .50, p < .0001) and triglycerides (r = -.493, p < .001). From multiple regression models, 28% of HTGL variability among African Americans can be explained by adiponectin levels in combination with gender and 35% of HTGL is explained with HDL-C included in the model. CONCLUSION: The data suggest that adiponectin is a significant metabolic concomitant of HTGL activity in African Americans.     

Adiponectin in a native Canadian population experiencing rapid epidemiological transition

OBJECTIVE: Adiponectin is emerging as an important protein in the etiology of obesity and related metabolic disorders. The objectives of this study were to determine cross-sectional and prospective associations of adiponectin concentration with adiposity, type 2 diabetes, and cardiovascular disease (CVD) risk factors in a population-based study of Native Canadians, a group experiencing dramatic increases in diabetes and CVD. RESEARCH DESIGN AND METHODS: During the 1993-1995 baseline survey, samples for glucose, insulin, adiponectin, and lipids were collected after an overnight fast. Waist circumference and percent body fat were measured, and a 75-g oral glucose tolerance test was administered: n = 505 with normal glucose tolerance (NGT), 74 with impaired glucose tolerance (IGT), and 149 with diabetes. In 1998, 95 high-risk subjects, defined as those who, at baseline, had either IGT or NGT with an elevated 2-h glucose concentration (>/==" BORDER="0">7.0 mmol/l), participated in a follow-up examination using the protocol used at baseline. RESULTS: After adjustment for covariates including percent body fat and homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin concentrations were significantly lower among men versus women (10.8 vs. 15.0 micro g/ml, P < 0.0001) and among diabetic versus NGT subjects (11.1 vs. 13.1 micro g/ml, P < 0.05). Adiponectin was inversely correlated with percent body fat, waist circumference, HOMA-IR, and triglyceride and positively correlated with HDL (r = |0.30|-|0.44|, all P < 0.0001). In multivariate linear regression analysis in nondiabetic subjects, HDL and percent body fat were significantly related to adiponectin variation among both men and women (R(2) = 28-29%). Factor analysis returned three underlying factors among these variables, with adiponectin loading on the second factor along with insulin, waist circumference, triglyceride, and HDL. In the follow-up study, higher adiponectin at baseline was significantly associated with increases in HDL (r = 0.24, P = 0.03) and decreases in HOMA-IR (r = -0.29, P = 0.009) after adjustment for covariates, including age, adiposity, and diabetes status at baseline and follow-up. CONCLUSIONS: These population-based findings support the hypothesis that low circulating levels of adiponectin are an important determinant of risk of CVD.     

Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins

Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling. Lipoprotein lipase hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. Hepatic lipase reduces HDL particle size by hydrolysing its triglycerides and phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low HDL2 cholesterol in insulin resistance. The esterification of free cholesterol by LCAT increases HDL particle size. Plasma cholesterol esterification is unaltered or increased in type 2 diabetes mellitus, probably depending on the extent of triglyceride elevation. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins, and is involved in decreasing HDL size. An increased plasma cholesteryl ester transfer is frequently observed in insulin-resistant conditions, and is considered to be a determinant of low HDL cholesterol. Phospholipid transfer protein generates small pre beta-HDL particles that are initial acceptors of cell-derived cholesterol. Its activity in plasma is elevated in insulin resistance and type 2 diabetes mellitus in association with high plasma triglycerides and obesity. In insulin resistance, the ability of plasma to promote cellular cholesterol efflux may be maintained consequent to increases in PLTP activity and pre beta-HDL. However, cellular cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of ATP binding cassette transporter 1 and scavenger receptor class B type I are likely to result in diminished cellular cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived cholesterol and subsequent hepatobiliary transport is altered in insulin resistance and type 2 diabetes mellitus is unknown. Specific CETP inhibitors have been developed that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animals. As an increased CETP-mediated cholesteryl ester transfer represents a plausible metabolic intermediate between high triglycerides and low HDL cholesterol, studies are warranted to evaluate the effects of these agents in insulin resistance- and diabetes-associated dyslipidaemia.     

Preheparin lipoprotein lipase mass is a practical marker of insulin resistance in ambulatory type 2 diabetic patients treated with oral hypoglycemic agents

BACKGROUND: Lipoprotein lipase (LPL) is a key enzyme in the metabolism of triglyceride (TG)-rich lipoproteins. LPL in the preheparin serum (Pr-LPL) mass reflects the insulin sensitivity of diabetic patients (DM) receiving neither insulin nor hypoglycemic agents. METHODS: To determine whether Pr-LPL mass is a marker of insulin resistance in ambulatory type 2 DM receiving oral hypoglycemic agents, we measured Pr-LPL mass using an enzyme immunoassay in 107 ambulatory DM aged 64.9+/-11.5 y. RESULTS: Pr-LPL mass was inversely correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) (-0.363, p<0.001), insulin (-0.351, p<0.001), and lnTG (-0.402, p<0.001), and was positively correlated with HDL-C (0.471, p<0.001). The correlation between Pr-LPL mass and HOMA-IR was equally strong in men and women. Despite medications, hypertension, dyslipidemia, and metabolic syndrome were associated with low Pr-LPL mass. Multiple regression analysis revealed that HOMA-IR was the strongest predictor of Pr-LPL mass. Pr-LPL mass remained constant from 07:30 to 17:30 h. CONCLUSIONS: Pr-LPL mass is a marker of insulin resistance in ambulatory type 2 DM receiving oral hypoglycemic agents, and Pr-LPL mass is stable during the daytime. Therefore, Pr-LPL mass may be more useful than HOMA-IR at diabetes clinics, especially for patients in the postprandial state.     

Possible impairment of transcardiac utilization of adiponectin in patients with type 2 diabetes

OBJECTIVE: Adiponectin, an adipocyte-derived protein, has been suggested to enhance insulin sensitivity and prevent atherosclerosis. Circulating adiponecin levels are reduced in states of insulin resistance such as type 2 diabetes. We examined transcardiac utilization of adiponectin in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 17 male type 2 diabetic patients and 17 male nondiabetic patients were investigated. Venous blood samples were taken to measure glucose and lipid variables. Blood samples for the measurement of adiponectin were collected simultaneously from the aortic root and coronary sinus. Angiographic semiquantitative stenosis score of coronary artery was also evaluated. RESULTS: The adiponectin levels in both the aortic root and coronary sinus in the diabetic patients were significantly lower than those in the nondiabetic patients. The adiponectin level was significantly lower in the coronary sinus than in the aortic root in the nondiabetic patients, but there was no significant difference between adiponectin levels in the aortic root and coronary sinus in the diabetic patients. The total stenosis score, as an index of severity of coronary artery stenosis, was significantly higher in the diabetic patients than in the nondiabetic patients. The stenosis score was correlated with the degree of transcardiac utilization of adiponectin from the aortic root to coronary sinus in the nondiabetic patients but not in the diabetic patients. CONCLUSIONS: Diabetic patients not only have a decreased adiponectin level in the basal state compared with nondiabetic patients but also have impaired utilization of adiponectin in the coronary artery and/or the heart, which may promote the development of atherosclerosis.     

Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease

BACKGROUND: Adiponectin, an adipocyte-derived hormone, appears to be a modulator of lipid metabolism and systemic inflammation and is present in particularly low concentrations in patients with coronary heart disease (CHD). However, the clinical importance of adiponectin in individuals at markedly high risk for future cardiovascular morbidity and mortality has not been fully elucidated. We examined the associations between serum adiponectin and several biomarkers related to cardiovascular disease and heart failure in a large high-risk population comprising patients with prevalent CHD. METHODS: We measured fasting adiponectin, interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and markers of lipoprotein metabolism in 1174 patients with CHD. RESULTS: After adjustment for age and sex, adiponectin was associated with HDL-cholesterol (HDL-C; r = 0.25; P <0.0001), NT-proBNP (r = 0.17; P <0.0001), and plasma triglyceride (r = -0.21; P <0.0001) concentrations. There was, however, no statistically significant association between adiponectin and markers of systemic inflammation. In partial correlation analyses further adjusted for body mass index, alcohol intake, smoking status, presence of diabetes and/or hypertension, lipid-lowering drug therapy, and fasting plasma glucose, adiponectin remained significantly associated with HDL-C (r = 0.21; P <0.0001), NT-proBNP (r = 0.15; P <0.0001), and plasma triglycerides (r = -0.16; P <0.0001). CONCLUSIONS: Serum adiponectin is associated with the presence of atherogenic dyslipidemia and with NT-proBNP concentration but not with markers of systemic inflammation in patients with manifest CHD. Thus, atherogenic dyslipidemia may link adiponectin with the progression of atherosclerosis. Moreover, serum adiponectin may be related to BNP in patients with CHD.     

Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes

OBJECTIVE: To investigate the usefulness of the homeostasis model assessment as an index of insulin resistance (HOMA-IR) for evaluating the clinical course of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The usefulness of HOMA-IR and its relationship with insulin resistance assessed by the hyperinsulinemic-euglycemic clamp study (clamp IR) were evaluated in 55 Japanese patients with type 2 diabetes before and after treatment. The patients were subjected to diet (approximately 1,440-1,720 kcal/day) and exercise therapy (walking 10,000 steps daily) for 6 weeks during their hospitalization. RESULTS: Univariate regression analysis disclosed a significant correlation between log-transformed HOMA-IR and log-transformed clamp IR before (r = -0.613, P < 0.0001) and after ( = -0.734, P < 0.0001) treatment. Neither the slopes (-0.71 +/- 0.12 vs. -0.79 +/- 0.09, F = 0.25, P = 0.61) nor the intercepts (y-intercept = 1.67 vs. 1.70, x-intercept = 2.36 vs. 2.15, F = 0.02, P = 0.88) of the regression lines between HOMA-IR and clamp IR were significantly different before and after treatment. There was a significant correlation between the decrease in log-transformed HOMA-IR and the increase in clamp IR during treatment (r = -0.617, P < 0.0001). CONCLUSIONS: HOMA-IR may constitute a useful method not only for diagnosing insulin resistance, but also for follow-up during the treatment of patients with type 2 diabetes.     

Insulin resistance in early untreated rheumatoid arthritis patients

ObjectivesTo assess insulin resistance in early untreated rheumatoid arthritis patients and its relation to the clinical, inflammatory and biochemical characteristics of these patients.Patients and methodsSixty-six untreated rheumatoid arthritis (RA) patients with disease duration less than 1 year along with age and sex matched controls were studied. Disease activity score (DAS28) was used to assess disease activity. Plasma levels of C- reactive protein (CRP), glucose, insulin and complete lipid profile were measured. Insulin resistance (IR) was estimated by the homeostasis model assessment for insulin resistance (HOMA-IR).ResultsRA patients revealed high grade systemic inflammation compared to control group p < 0.0001. Patients with high disease activity were more insulin resistant than patients with moderate disease activity P < 0.0001.ConclusionThe findings of the present study showed that early untreated RA patients are characterized by a severe insulin resistant state that is driven primarily by disease activity and systemic inflammation.     

The mushroom Agaricus Blazei Murill in combination with metformin and gliclazide improves insulin resistance in type 2 diabetes: a randomized, double-blinded, and placebo-controlled clinical trial

BACKGROUND: Complementary and alternative medicine use in adults with type 2 diabetes is popular. Although most of the herbs and supplements appear to be safe, there is still insufficient evidence that demonstrates their definitive beneficial effects. This study was done to determine whether the supplement of Agaricus blazei Murill extract improves insulin resistance in type 2 diabetes. MATERIALS AND METHODS: This study was a clinical randomized, double-blind, placebo-controlled trial. Of a population of 536 registered diabetes patients with 72 subjects (1) aged between 20 and 75 years, (2) being Chinese, (3) having type 2 diabetes for more than 1 year, and (4) having been taking gliclazide and metformin for more than 6 months were enrolled in this study. The enrolled patients were randomly assigned to either receiving supplement of Agaricus blazei Murill (ABM) extract or placebo (cellulose) 1500 mg daily for 12 weeks. Homeostasis model assessment for insulin resistance (HOMA-IR) was used as the major outcome measurement. RESULTS: At the end of the study, subjects who received supplement of ABM extract (n = 29) showed significantly lower HOMA-IR index (3.6[standard deviation, 2.5] versus 6.6[standard deviation, 7.4], p = 0.04) than the control group (n = 31). The plasma adiponectin concentration increased 20.0(standard deviation, 40.7)% in the ABM group after 12 weeks of treatment, but decreased 12.0(20.0)% among those taking the placebo (p < 0.001). CONCLUSIONS: Supplement of ABM extract improves insulin resistance among subjects with type 2 diabetes. The increase in adiponectin concentration after taking AMB extract for 12 weeks might be the mechanism that brings the beneficial effect. Studies with longer periods of follow-up should be conducted in the future.     

Birth weight, type 2 diabetes, and insulin resistance in Pima Indian children and young adults.

OBJECTIVE: To investigate the mechanisms underlying the association between birth weight and type 2 diabetes in a population-based study of 3,061 Pima Indians aged 5-29 years. RESEARCH DESIGN AND METHODS: Glucose and insulin concentrations were measured during a 75-g oral glucose tolerance test, and insulin resistance was estimated according to the homeostatic model (homeostasis model assessment-insulin resistance [HOMA-IR]). Relationships between birth weight, height, weight, fasting and postload concentrations of glucose and insulin, and HOMA-IR were examined with multiple regression analyses. RESULTS: Birth weight was positively related to current weight and height (P < 0.0001, controlled for age and sex, in each age-group). The 2-h glucose concentrations showed a U-shaped relationship with birth weight in subjects > 10 years of age, and this relation was independent of current body size. In 2,272 nondiabetic subjects, after adjustment for weight and height, fasting and 2-h insulin concentrations and HOMA-IR were negatively correlated with birth weight. CONCLUSIONS: Low-birth-weight Pimas are thinner at ages 5-29 years, yet they are more insulin resistant relative to their body size than those of normal birth weight. By contrast, those with high birth weight are more obese but less insulin resistant relative to their body size. The insulin resistance of low-birth-weight Pima Indians may explain their increased risk for type 2 diabetes.     

罗格列酮对2型糖尿病患者血浆C反应蛋白和纤溶酶原激活剂抑制剂(PAI1)活性的影响

血清C反应蛋白(CRP)是机体受到各种损伤或发生炎症反应后的一种急性期反应蛋白。近年来研究发现其本身还具有促进炎症反应及动脉粥样斑块破裂,促发局部血栓形成的作用。CRP还与肥胖、2型糖尿病及冠心病有关,对这组疾病的未来风险预测及临床治疗有效性的评估具有一定价值[1]。研     

Impact of physical inactivity on adipose tissue low-grade inflammation in first-degree relatives of type 2 diabetic patients

OBJECTIVE

First-degree relatives (FDRs) of patients with type 2 diabetes may exhibit a disproportionately elevated risk of developing insulin resistance, obesity, and type 2 diabetes when exposed to physical inactivity, which to some unknown extent may involve low-grade inflammation. We investigated whether subjects who are nonobese FDRs show signs of low-grade inflammation before or after exposure to short-term physical inactivity.

RESEARCH DESIGN AND METHODS

We studied 13 healthy FDR subjects and 20 control (CON) subjects matched for age, sex, and BMI before and after 10 days of bed rest (BR). Insulin sensitivity was measured by the hyperinsulinemic euglycemic clamp. Key low-grade inflammation mediators were measured in arterial blood and microdialysate from subcutaneous abdominal (SCAAT) and femoral adipose tissue. Adipokine mRNA expression was determined in SCAAT.

RESULTS

Before BR, FDR subjects displayed insulin resistance, elevated plasma C-reactive protein, leptin, and monocyte chemoattractant protein (MCP)-1, high interleukin (IL)-6, and MCP-1 expressions, as well as low adiponectin and leptin expressions. FDR subjects responded to BR by decreasing plasma adiponectin and IL-10 expression and increasing plasma expression of IL-10 and tumor necrosis factor-α. In contrast, CON subjects responded to BR by increasing plasma adiponectin and adiponectin expression and by decreasing SCAAT microdialysate leptin.

CONCLUSIONS

Young and nonobese FDR of patients with type 2 diabetes exhibit low-grade inflammation, which is further and disproportionately aggravated when exposed to physical inactivity. The study provides support for the notion that people at increased risk of type 2 diabetes should avoid even short periods of physical inactivity.Human adipose tissue produces a variety of inflammatory mediators that act locally in the adipose tissue and systemically, leading to obesity-associated low-grade inflammation. Many of the inflammatory mediators can regulate insulin action in skeletal muscle and adipose tissue (1,2) and form putative links between adipose tissue and systemic metabolism (3). Chronic low-grade inflammation is pathophysiologically related to the development of type 2 diabetes and atherosclerosis.Physical inactivity contributes to a positive energy balance and the induction of obesity, but the relation between physical inactivity and low-grade inflammation may be independent of obesity. In a cross-sectional design, a low level of physical activity was associated with elevated plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) independently of obesity (4). A review by Hamer (5) found an inverse association between the level of physical activity and one or more inflammatory markers in 27 of 40 observational studies after adjusting for measures of fatness. Furthermore, physically active individuals consistently demonstrated low concentrations of CRP. Recent intervention studies found that exercise training downregulated markers of chronic inflammation such as IL-6 and alanine aminotransferase (6,7). However, it is not known if physical inactivity per se in a longitudinal design upregulates inflammatory markers and changes molecular mechanisms relevant to the development of type 2 diabetes.First-degree relatives (FDRs) of type 2 diabetic patients bear a high lifetime risk of developing insulin resistance and represent a genetic model for studies into the cause of type 2 diabetes. Individuals who progress to type 2 diabetes display features of low-grade inflammation years before onset of the disease, suggesting that low-grade inflammation is involved in the pathogenetic processes (6,8). The objective of the current study was to investigate adipose tissue and systemic markers of low-grade inflammation in healthy, nonobese FDR and control (CON) subjects and in a longitudinal design to explore the effect of physical inactivity on these markers.     

2型糖尿病及合并冠心病糖尿病患者脂联素水平观察

目的：观察脂联索(adiponectin)在2型糖尿病(DM)及DM合并冠心病时的浓度变化．并探讨影响2型糖尿病患血浆脂联索水平的因素。方法：用ELISA方法在2型糖尿病组(无或合并冠心病)、非糖尿病正常对照组测定血浆脂联索水平。结果：无冠心病的糖尿病组血浆脂联索水平较非糖尿病正常对照组明显降低．合并冠心病的糖尿病组更低。结论：2型糖尿病中血浆脂联索水平的明显下降可作为冠心病的危险标志。     

脂联素与肝源性糖尿病的相关研究

目的检测肝源性糖尿病患者血清脂联素浓度,探讨脂联素与肝源性糖尿病的关系。方法筛选住院的肝源性糖尿病患者30例,同期门诊确诊的初发单纯2型糖尿病29例,查体正常人员（正常对照组）31例为研究对象,分别检测血清脂联素、空腹血糖（FBG）、空腹胰岛素（FINS）、：丙氨酸转移酶（ALT）、天冬氨酸转移酶（AST）、总胆红素（TBLL）和白蛋白（ALB）水平、并计算胰岛素敏感指数（ISI）和胰岛素抵抗指数（HOMA—IR）。结果肝源性糖尿病组和初发2型糖尿病组脂联素水平明显低于正常对照组（P〈0．01）;肝源性糖尿病组脂联素水平明显高于初发2型糖尿病组（P〈0．05）。肝源性糖尿病组和初发2型糖尿病组ISI水平明显低于正常对照组（P〈0．01）;肝源性糖尿病组FBG、FINS、HOMA—IR和初发2型糖尿病组FBG、HOMA-IR水平明显高于正常对照组（P〉0．01）;肝源性糖尿病组FINS水平明显高于初发2型糖尿病组（P〉0．05）,而FBG、ISI水平明显低于初发2型糖尿病组（P〉0．05）。脂联素与FBG、HOMA-IR呈显著负相关;与ISI呈显著正相关;与肝功能指标无相关性。结论肝源性糖尿病患者存在明显胰岛素抵抗且脂联素代谢发生异常,两者可能共同影响肝源性糖尿病的发生和发展。     

Genetic Architecture of Plasma Adiponectin Overlaps With the Genetics of Metabolic Syndrome�CRelated Traits

OBJECTIVE

Adiponectin, a hormone secreted by adipose tissue, is of particular interest in metabolic syndrome, because it is inversely correlated with obesity and insulin sensitivity. However, it is not known to what extent the genetics of plasma adiponectin and the genetics of obesity and insulin sensitivity are interrelated. We aimed to evaluate the heritability of plasma adiponectin and its genetic correlation with the metabolic syndrome and metabolic syndrome–related traits and the association between these traits and 10 ADIPOQ single nucleotide polymorphisms (SNPs).

RESEARCH DESIGN AND METHODS

We made use of a family-based population, the Erasmus Rucphen Family study (1,258 women and 967 men). Heritability analysis was performed using a polygenic model. Genetic correlations were estimated using bivariate heritability analyses. Genetic association analysis was performed using a mixed model.

RESULTS

Plasma adiponectin showed a heritability of 55.1%. Genetic correlations between plasma adiponectin HDL cholesterol and plasma insulin ranged from 15 to 24% but were not significant for fasting glucose, triglycerides, blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR), and C-reactive protein. A significant association with plasma adiponectin was found for ADIPOQ variants rs17300539 and rs182052. A nominally significant association was found with plasma insulin and HOMA-IR and ADIPOQ variant rs17300539 after adjustment for plasma adiponectin.

CONCLUSIONS

The significant genetic correlation between plasma adiponectin and HDL cholesterol and plasma insulin should be taken into account in the interpretation of genome-wide association studies. Association of ADIPOQ SNPs with plasma adiponectin was replicated, and we showed association between one ADIPOQ SNP and plasma insulin and HOMA-IR.The dramatic increase in the prevalence of the metabolic syndrome in countries with a western lifestyle is precipitated by environmental variables. However, the individual susceptibility to the obesogenic environment is largely determined by genetic susceptibility (1). Central obesity, dyslipidemia, impaired glucose metabolism, and hypertension are the key elements determining the expression of the metabolic syndrome (2), which is associated with an increased risk for type 2 diabetes and cardiovascular disease (2).Adipose tissue is an active endocrine tissue that can respond to changes in metabolic conditions by secreting biologically active substances (adipokines). The adipokine family can be divided into two overlapping sets of signaling molecules, namely those with metabolic/immunological function, which include interleukins 1β, 6, 8, 10, or 18, tumor necrosis factor-α and transforming growth factor-β, and those with endocrine function, which include leptin, retinol-binding protein 4, adiponectin, and resistin (3). Human adiponectin is a protein of 247 amino acids (30-kDa), encoded by a gene (ADIPOQ) located on chromosome 3q27 (4). Adiponectin is secreted and present in plasma in various multimeric forms, for which the biological significance remains to be determined. Rasmussen-Torvik et al. (5) showed that binding of adiponectin to adiponectin receptors (ADIPOR1 and ADIPOR2) in mice results in increased AMP-activated protein kinase activity and peroxisome proliferator–activated receptor-α activity. In humans, both receptors are expressed mainly in skeletal muscle and adiponectin could thus play a role in energy metabolism.The role of adiponectin in energy metabolism is confirmed by its inverse correlation with body weight, metabolic syndrome, metabolic syndrome–related traits, and type 2 diabetes (6). In mouse models, adiponectin has been shown to play a role in energy homeostasis by regulating insulin sensitivity of the liver (7). In addition, adiponectin is suggested to exhibit anti-inflammatory properties (8). Thus, adiponectin could play a role in obesity–induced impairment of the metabolic state, systemic inflammation, and the corresponding risk for cardiovascular disease.Limited data on the overall heritability of plasma adiponectin are available. Furthermore, it is not known whether the genetics of plasma adiponectin overlap with the genetics of body weight and insulin sensitivity/diabetes or other individual components of the metabolic syndrome. Several studies showed convincing association of genetic variants near and in the promoter region of the ADIPOQ gene with plasma adiponectin and type 2 diabetes or type 2 diabetes–related traits (5,9,10).In the present study, we set out to evaluate the heritability of plasma adiponectin and its genetic correlation with the metabolic syndrome and metabolic syndrome–related traits (BMI, insulin, homeostasis model assessment of insulin resistance [HOMA-IR], and plasma C-reactive protein [CRP]).