Guoyue Yuan

Increased Circulating Levels of Betatrophin in Newly Diagnosed Type 2 Diabetic Patients

OBJECTIVE Betatrophin, a newly identified hormone, has been recently characterized as a potent stimulator that increases the production and expansion of insulin-secreting β-cells in mice, but the physiological role of betatrophin remains poorly understood. This study measured for the first time serum betatrophin levels in newly diagnosed patients with type 2 diabetes (T2DM) and explored the correlations between its serum levels and various metabolic parameters in T2DM. RESEARCH DESIGN AND METHODS We analyzed the concentrations of betatrophin by ELISA in blood samples of 166 well-characterized individuals in whom anthropometric parameters, oral glucose tolerance test (OGTT), glycosylated hemoglobin, blood lipids, insulin sensitivity (1/homeostasis model assesment of insulin resistance [1/HOMA-IR] and Matsuda index [ISIM]), and insulin secretion were measured. The participants were divided into newly diagnosed T2DM patients (n = 83) and age-, sex- and BMI-matched healthy control subjects (n = 83). RESULTS Serum betatrophin levels were significantly higher in T2DM patients than in healthy control subjects (613.08 [422.19–813.08] vs. 296.57 [196.53–509.46] pg/mL; P < 0.01). Serum betatrophin positively correlated with age, 2-h post-OGTT glucose (2hPG), and postprandial serum insulin (PSI), but negatively with 1/HOMA-IR and ISIM in T2DM patients. In the control group, betatrophin was only positively associated with age. In T2DM subjects, multivariate regression analyses showed that age, 2hPG, and PSI were independent factors influencing serum betatrophin levels. CONCLUSIONS Circulating concentrations of betatrophin are significantly increased in T2DM patients. Our results suggest that betatrophin may play a role in the pathogenesis of T2DM.

Decreased circulating levels of oxytocin in obesity and newly diagnosed type 2 diabetic patients.

CONTEXT AND OBJECTIVE Oxytocin can affect energy homeostasis and has interesting potential as a metabolic disease therapeutic. We detected serum oxytocin levels in obese (OB) and type 2 diabetes mellitus (T2DM) subjects and investigated the relationships between serum oxytocin levels and glycolipid metabolism, insulin resistance, pancreatic β-cell function, and inflammation. PATIENTS AND METHODS A total of 176 subjects were enrolled in the study, including 88 patients with newly diagnosed T2DM and 88 subjects with normal glucose tolerance (NGT). NGT and T2DM groups were divided into normal-weight (NW) and OB subgroups. We analyzed the concentrations of oxytocin by ELISA. Oral glucose tolerance testing was done, and hemoglobin A1c (HbA1c), blood lipids, and highly sensitive C-reactive protein (hs-CRP) were also measured. Insulin resistance and pancreatic β-cell function were assessed by homeostasis model assessment (HOMA). RESULTS Serum oxytocin levels were lower in the T2DM group than in the NGT group (P < .01). The levels of serum oxytocin in OB subjects were also lower than those in NW subjects (P < .01). Serum oxytocin levels were negatively correlated with body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), HbA1c, fasting plasma glucose (FPG), 2-hour plasma glucose, fasting insulin (FINS), 2-h insulin, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), HOMA of insulin resistance (HOMA-IR), and hs-CRP and positively correlated with HOMA of β-cell function (HOMA-β) (P < .05). Multiple stepwise regression analysis showed that 2-hour plasma glucose, BMI, and TC were associated with serum oxytocin levels (P < .05). Logistic regression analyses demonstrated that serum oxytocin was significantly associated with T2DM (P < .01). CONCLUSIONS Serum oxytocin levels were decreased in T2DM as well as OB subjects.

Circulating adiponectin levels and the risk of breast cancer: a meta-analysis

Adiponectin is an important adipokine exclusively secreted from adipose tissue. Growing evidence suggests that adiponectin inhibits the growth of cancer cells and reduces cancer risk. Many studies have examined the association between circulating adiponectin levels and the risk of breast cancer. However, the results of numerous epidemiological studies have been inconsistent. The aim of the present study was to conduct a systematic review and a meta-analysis on the association between circulating adiponectin levels and the risk of breast cancer. PubMed, MEDLINE, EMBASE, and ISI Web of Science were searched to identify all observational studies that examined the relationship between circulating adiponectin and breast cancer. Standard mean difference (SMD) values and 95% confidence intervals (CIs) were estimated and pooled using the meta-analysis methodology. Summary effect estimates were derived using a random effects meta-analysis model. The analysis included eight studies that met the study criteria and described the relationship between circulating adiponectin levels and breast cancer. A total of 1803 participants and 885 cases of breast cancer were included in this meta-analysis. Serum total adiponectin concentrations were lower in patients with breast cancer, with a pooled SMD of −0.39 &mgr;g/ml (95% CI −0.618 to −0.161, P=0.001). However, adiponectin levels were not associated with the risk of breast cancer in premenopausal women [four studies, random effects SMD=0.02 &mgr;g/ml (95% CI −0.164 to 0.204, P=0.829)]. These results collectively suggest that lower adiponectin levels are associated with a higher risk of breast cancer in postmenopausal women.

Effects of C-reactive protein on adipokines genes expression in 3T3-L1 adipocytes

Adipose tissue is now recognized to be an important endocrine organ, secreting a variety of adipokines that are involved in the regulation of energy metabolism, insulin resistance and metabolic syndrome. C-reactive protein (CRP) is considered as one of the most sensitive markers of inflammation. A number of studies have shown that elevation of CRP concentrations is an independent predictive parameter of type 2 diabetes mellitus, which is also strongly associated with various components of the metabolic syndrome. The aim of the present study is to investigate the effects of CRP on adipokines genes expression in 3T3-L1 adipocytes. Quantitative real-time PCR analysis revealed that CRP inhibited adiponectin, leptin and peroxisome proliferator-activated receptor-gamma (PPAR-γ) genes expression and raised tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA levels in matured 3T3-L1 adipocytes in a dose and time-dependent manner. Pharmacological inhibition of phosphatidylinositol (PI)-3 kinase by wortmannin partially reversed the effects of CRP on adiponectin, TNF-α and leptin genes expression. These results collectively suggest that CRP regulates adiponectin, TNF-α, leptin, IL-6 and PPAR-γ genes expression, and that might represent a mechanism by which CRP regulates insulin resistance, obesity and metabolic syndrome.

Fibroblast growth factor 1 levels are elevated in newly diagnosed type 2 diabetes compared to normal glucose tolerance controls

Fibroblast growth factor 1 (FGF1) has been recently characterized as a potent insulin sensitizer that regulates adipose tissue remodeling, but the physiological role of FGF1 remains unclear. This study measured serum FGF1 levels for the first time in patients with newly diagnosed type 2 diabetes mellitus (T2DM), and further explored the correlations between FGF1 levels and various metabolic parameters in T2DM. Serum FGF1 levels were determined using ELISA in age-, sex- and BMI- matched subjects with normal glucose tolerance (NGT) (n=80) and newly diagnosed T2DM (n=80). Oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1C), blood lipids, and insulin secretion were also measured. Insulin resistance and pancreatic β-cell function were assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta cell function (HOMA-β), respectively. Serum FGF1 levels were significantly higher in T2DM patients than in normal glucose tolerance subjects (74.52 [55.91∼101.34] vs. 60.31 [48.99∼83.91] pg/mL; P<0.05). In addition, serum FGF1 level positively correlated with body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), fasting plasma glucose (FPG), 2-h post-OGTT glucose (2h PG), and HbA1C (all P values <0.05) in T2DM subjects. Multivariate regression analyses showed that BMI and HbA1C were the independent factors influencing serum FGF1 levels. Logistic regression analyses demonstrated that serum FGF1 was significantly associated with type 2 diabetes (P<0.01). Circulating concentrations of FGF1 are significantly increased in T2DM patients. Our results suggest that FGF1 may play a role in the pathogenesis of T2DM.

Reduced circulating oxytocin and High-Molecular-Weight adiponectin are risk factors for metabolic syndrome

The neurohypophysial hormone, oxytocin, is involved in the regulation of energy metabolism. Adiponectin (APN) is an adipose tissue-specific serum protein that inversely associates with metabolic syndrome (MetS). High-molecular-weight adiponectin (HMW APN) is considered the active form. In the present study, we aimed to determine the relationships of oxytocin and HMW APN to MetS and investigate whether or not the combination of oxytocin and HMW APN is associated with further metabolic abnormalities compared to each of them alone. A total of 170 subjects (75 with MetS and 95 non-MetS) were enrolled. Anthropometric parameters, oral glucose tolerance test (OGTT), blood lipids, hs-CRP, oxytocin and HMW APN levels were measured. Compared with non-MetS subjects, serum oxytocin and HMW APN levels were significantly lower in subjects with MetS (P<0.01). We then classified the subjects into three groups: high oxytocin and high HMW APN levels (high score group), low oxytocin and low HMW APN levels (low score group) and others. Participants in low score group showed the worst metabolic profiles and were more likely to have MetS compared to the other two group. In Spearman rank correlation coefficient, the classification by the combination of oxytocin and HMW APN was significantly correlated with a larger number of metabolic risk factors compared with classification by each of them alone. Individuals with low circulating oxytocin levels coupled with low HMW APN levels were at significantly increased risk of MetS. The combination of both markers would be useful for identifying MetS high risk patients.

Improvement of β-cell function ameliorated glycemic variability in patients with newly diagnosed type 2 diabetes after short-term continuous subcutaneous insulin infusion or in combination with sitagliptin treatment: a randomized control trial

Glycemic variability (GV) has been proposed as contributor to diabetes-related macrovascular complications. This randomized control trial evaluated a new combination therapy with continuous subcutaneous insulin infusion (CSII) plus sitagliptin (CSII + sitagliptin) vs. CSII only in terms of metabolic control, GV and β-cell function in patients with newly diagnosed type 2 diabetes (T2DM). 217 patients were randomized to two weeks of CSII (n = 108) or CSII + sitagliptin (n = 109) therapy. As a measure of GV, the coefficient of variation (CV) was computed from capillary blood glucose during the first and second week, respectively. β-cell function before and after treatment was determined with the Insulin Secretion-Sensitivity Index-2 (ISSI-2). Good metabolic controls were established with both therapies. CSII + sitagliptin therapy resulted in greater improvements in CV and ISSI-2 than CSII alone (all P = 0.000). For each group, change in CV was inversely correlated with change in ISSI-2 (r = -0.529, P = 0.000 and r = -0.433, P = 0.000, respectively). The multivariate regression analysis demonstrated that improved ISSI-2 was the only independent contributor to reduced CV in both groups (standardized β = -0.388, P = 0.004 and standardized β = -0.472, P = 0.000, respectively). Correction of β-cell function in newly diagnosed T2DM patients via use of either CSII or CSII + sitagliptin therapy was feasible in controlling GV to prevent secondary complications of T2DM. Moreover, CSII + sitagliptin therapy was superior to CSII monotherapy in terms of GV.

C-reactive protein inhibits high-molecular-weight adiponectin expression in 3T3-L1 adipocytes via PI3K/Akt pathway

Adiponectin, an adipose-specific protein hormone, is secreted from white adipose tissue and involved in glucose and lipid metabolism. It is assembled into low-molecular-weight trimer (LMW), middle-molecular-weight hexameric (MMW) and high-molecular-weight (HMW), among which HMW exhibits higher activity. In this study, we proved that C-reactive protein (CRP), an inflammatory marker, inhibited adiponectin expression, especially HMW in time-and dose-dependent manners. Furthermore, CRP decreased the HMW/total adiponectin ration and reduced adiponectin assembly by increasing ERp44, and decreasing Ero1-α and DsbA-L. CRP activated pAkt, the downstream of PI3K. Inhibition of PI3K or pAkt abolished the effect of CRP. Our study suggested that CRP decreased adiponectin expression and multimerization, while CRP-induced decline in adiponectin might be mediated through the PI3K/Akt pathway.

Increased Interleukin-23 in Hashimoto’s Thyroiditis Disease Induces Autophagy Suppression and Reactive Oxygen Species Accumulation

Hashimoto’s thyroiditis (HT) represents the most common organ-specific autoimmune disease. Inflammatory factors and reactive oxygen species (ROS) play detrimental roles during the pathogenesis of HT. In this study, we found that thyroid follicular cells (TFCs) from HT patients expressed an elevated level of interleukin-23 (IL-23), which contributed to autophagy suppression and ROS accumulation. Additionally, IL-23-induced autophagy suppression and ROS accumulation in human TFCs was attributed to AKT/mTOR/NF-κB signaling pathway activation. Inhibition of either IL-23 by a specific neutralization antibody, or mTOR by rapamycin, or NF-κB by IKK-16, significantly reversed the autophagy suppression and ROS accumulation. These results demonstrate a key role for IL-23 in HT pathogenesis and provide a potential therapeutic strategy against IL-23 or its signaling pathway in HT.

LDL cholesterol/HDL cholesterol ratio in newly diagnosed type 2 diabetic patients complicated with metabolic syndrome

Objective To investigate the change of low-density lipoprotein cholesterol(LDL-C)/high-density lipoprotein cholesterol(HDL-C)ratio in newly diagnosed patients with type 2diabetes mellitus(T2DM)and metabolic syndrome(MS),and to discuss its relationship with the clinical parameters.Methods Totally 140 newly diagnosed T2 DM patients were selected for this study,and they were divided into MS group(n=73)and non-MS group(n=67)according to the presence of MS;the normal control group included 73participants(NC group).All participants underwent an oral glucose tolerance test(OGTT)and insulin releasing test;meanwhile,the blood glucose,insulin,blood lipid and other items were measured.The LDL-C/HDL-C ratios of each group were calculated.Clinical parameters and LDL-C/HDL-C ratios were compared among different groups,and correlation analysis was made between LDL-C/HDL-C ratios and clinical indices.Furthermore,all participants were divided into three groups according to LDL-C/HDL-C levels and the prevalence rates of MS were compared.Results The LDL-C/HDL-C ratios of MS group(3.18±0.85)and non-MS group(2.61±0.93)were significantly higher than that in NCgroup(2.26±0.70,P0.05),and the LDL-C/HDL-C ratio of MS group was significantly higher than that in non-MS group(P0.05).The prevalence rates of MS were significantly increased in the patients with the elevation of LDL-C/HDL-C(11.27%,35.21%,and 56.34%,P0.05).Correlation analysis showed that LDL-C/HDL-C ratio was positively correlated with the body mass index(BMI),waist circumference(WC),waist-hip ratio(WHR),systolic blood pressure(SBP),diastolic blood pressure(DBP),postprandial plasma glucose(PPG),fasting insulin(FINS),postprandial insulin(PSI),homeostasis model assessment of insulin resistance(HOMA-IR),triglyceride(TG),cholesterol(CHOL)and LDL-C(P0.05),and negatively correlated with HDL-C(P0.01).When LDL-C/HDL-C was taken as the dependent variable,multiple regression analysis showed that HDL-C,LDL-C and FINS entered the equation(P0.01).Conclusion The LDL-C/HDL-C ratio is increased in T2 DM patients complicated with MS,and the prevalence rate of MS is higher in patients with high LDL-C/HDL-C value.The ratio of LDL-C/HDL-C may be a better index for the early detection of MS compared with LDL-C,which provides a simple,feasible strategy for the prevention and treatment of MS.