Weiqiong Gu

Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics

A comprehensive metabonomic method, in combination with fingerprint analysis and target analysis, was performed to reveal potential mechanisms of berberine action in the treatment of patients with type 2 diabetes and dyslipidemia. Serum samples of 60 patients before and after treatment with either berberine or placebo were collected. Ultra-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS) coupled with pattern recognition analysis were used to identify changes in global serum metabolites. Compared with placebo, patients before and after berberine treatment could be separated into distinct clusters as displayed by the orthogonal signal correction filtered partial least-squares discriminant analysis (OSC-PLS-DA) score plot, which indicated changes in circulating metabolites after berberine treatment. Among them, free fatty acids changed markedly. These were further quantified by UPLC combined with single quadrupole mass spectrometry (UPLC SQ MS). There was a highly significant decrease in the concentrations of 13 fatty acids following berberine administration. 10 fatty acids also differed statistically from placebo. These results suggest that berberine might play a pivotal role in the treatment of type 2 diabetes through down-regulating the high level of free fatty acids and that comprehensive metabonomic measurements are potentially very useful for studying the mechanisms of action of traditional Chinese medicines.

Brown Adipose Tissue in Humans Is Activated by Elevated Plasma Catecholamines Levels and Is Inversely Related to Central Obesity

Background Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity. Methodology/Principal Findings We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007–2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = −0.47, p = 0.010), visceral fat areas (R = −0.39, p = 0.044), visceral/total fat areas (R = −0.52, p = 0.0043) and waist circumferences (R = −0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = −0.009, p = 0.009) were the two independent predictors of BAT activities. Conclusions/Significance Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity.

Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention

Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.

Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch

Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), specialized for energy expenditure through thermogenesis, potently counteracts obesity. Factors that induce brown adipocyte commitment and energy expenditure would be a promising defence against adiposity. Here, we show that Lgr4 homozygous mutant (Lgr4m/m) mice show reduced adiposity and resist dietary and leptin mutant-induced obesity with improved glucose metabolism. Lgr4m/m mice show a striking increase in energy expenditure, and exhibit brown-like adipocytes in WAT depots with higher expression of BAT and beige cell markers. Furthermore, Lgr4 ablation potentiates brown adipocyte differentiation from the stromal vascular fraction of epididymal WAT, partially through retinoblastoma 1 gene (Rb1) reduction. A functional low-frequency human LGR4 variant (A750T) has been associated with body mass index in a Chinese obese-versus-control study. Our results identify an important role for LGR4 in energy balance and body weight control through regulating the white-to-brown fat transition.

Relation of Serum Osteocalcin Level to Risk of Coronary Heart Disease in Chinese Adults

Osteocalcin, a bone-derived polypeptide, was recently found to have hormonal function associated with metabolic disorders and atherosclerosis. Few studies have examined the association between circulating osteocalcin and coronary heart disease (CHD) risk. The aim of the present study was to investigate whether serum osteocalcin concentration was associated with CHD risk and metabolic profiles in Chinese adults. A total of 461 subjects (243 with CHD and 218 without CHD) who underwent coronary angiography were included. Serum osteocalcin, glucose, lipid profiles, and other biochemical markers were measured. Severity of coronary atherosclerosis was estimated by number of diseased vessels. Results showed that serum osteocalcin levels were significantly lower in the CHD group (12.2 ng/ml, 9.5 to 15.1) than in the non-CHD group (13.6 ng/ml, 10.7 to 18.0, p = 0.001) and were significantly decreased with the increasing of number of diseased vessels (p = 0.005). Serum osteocalcin concentration was inversely correlated with fasting and post load 2 hour plasma glucose and hemoglobin A(1c) (p = 0.044, 0.043, and 0.011, respectively), adjusting for CHD status. Odds ratios (95% confidence intervals) of CHD across increasing quartiles of serum osteocalcin were 0.68 (0.42 to 1.12), 0.59 (0.36 to 0.98), and 0.40 (0.23 to 0.69). The test for trend was significant (p = 0.0007). Adjusting for age, body mass index, and other conventional risk factors for CHD did not appreciably change the results. Spline regression analyses indicated a linear relation between serum osteocalcin level and CHD risk. In conclusion, our data indicate that serum osteocalcin level was associated with decreased risk of CHD and protective metabolic changes in Chinese adults.

Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas - a meta-analysis from randomized clinical trials.

Dipeptidyl peptidase‐IV (DPP‐4) inhibitors and sulfonylureas are two important second‐line anti‐diabetic agents. The objective of this research was to evaluate the efficacy and safety of DPP‐4 inhibitors compared with sulfonylureas by meta‐analytic approach of available randomized studies.

Diabetic Ketoacidosis at Diagnosis Influences Complete Remission After Treatment With Hematopoietic Stem Cell Transplantation in Adolescents With Type 1 Diabetes

OBJECTIVE To determine if autologous nonmyeloablative hematopoietic stem cell transplantation (AHSCT) was beneficial for type 1 diabetic adolescents with diabetic ketoacidosis (DKA) at diagnosis. RESEARCH DESIGN AND METHODS We enrolled 28 patients with type 1 diabetes, aged 14–30 years, in a prospective AHSCT phase II clinical trial. HSCs were harvested from the peripheral blood after pretreatment consisting of a combination of cyclophosphamide and antithymocyte globulin. Changes in the exogenous insulin requirement were observed and serum levels of HbA1c, C-peptide, and anti-glutamic acid decarboxylase antibody were measured before and after the AHSCT. RESULTS After transplantation, complete remission (CR), defined as insulin independence, was observed in 15 of 28 patients (53.6%) over a mean period of 19.3 months during a follow-up ranging from 4 to 42 months. The non-DKA patients achieved a greater CR rate than the DKA patients (70.6% in non-DKA vs. 27.3% in DKA, P = 0.051). In the non-DKA group, the levels of fasting C-peptide, peak value during oral glucose tolerance test (Cmax), and area under C-peptide release curve during oral glucose tolerance test were enhanced significantly 1 month after transplantation and remained high during the 24-month follow-up (all P < 0.05). In the DKA group, significant elevation of fasting C-peptide levels and Cmax levels was observed only at 18 and 6 months, respectively. There was no mortality. CONCLUSIONS We have performed AHSCT in 28 patients with type 1 diabetes. The data show AHSCT to be an effective long-term treatment for insulin dependence that achieved a greater efficacy in patients without DKA at diagnosis.

Elevated circulating microRNA-122 is associated with obesity and insulin resistance in young adults

OBJECTIVE MicroRNAs (miRNAs) are involved in the regulation of adiposity, but functional studies have yielded inconclusive results. Examining the associations of circulating miRNAs levels with obesity and insulin sensitivity in humans may lead to improved insights. DESIGN AND METHODS Serum samples collected from 112 obese and control subjects (50.0% men) were randomly divided and combined into four pools (28 samples in each obese or control pool). The genome-wide circulating miRNA profiles were detected via microarray. Elevated miR-122 was selected and validated in individual serum samples from 123 obese (46.7% men) and 107 control (50.0% men) young adults. Associations between circulating miR-122 levels and parameters related to adiposity, insulin resistance, lipid profiles and hepatic enzymes were further assessed. RESULTS Thirty-four miRNAs were found to be expressed differently in the sera of obese patients compared with control subjects (P<0.001). Further analyses confirmed that obese patients had 3.07-fold higher circulating miR-122 levels than controls (P<0.001). Serum miR-122 levels were correlated with BMI (r=0.469), alanine aminotransferase (r=0.634), triglycerides (r=0.448), HDL-cholesterol (r=-0.351) and homeostasis model assessment of insulin resistance (r=0.401, all P<0.01). After controlling for confounding factors, miR-122 remained as an independent risk factor for insulin resistance (OR=3.379, 95% CI=1.141-10.007, P=0.028). CONCLUSIONS Elevated circulating miR-122 is positively associated with obesity and insulin resistance in young adults. These findings provide a better understanding regarding the role of miRNAs in adiposity and insulin sensitivity.

Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome.

Overproduction of proinflammatory factors is associated with obesity and diabetes. Interleukin (IL)-18 as a member of IL-1 cytokine family is increased in obese, in diabetic, and even in polycystic ovary syndrome (PCOS) patients. In the present study we evaluated the association of serum IL-18 levels with insulin resistance in PCOS women. Forty-two PCOS women and 38 control subjects were enrolled in this study and matched with respect to age and body mass index (BMI). Serum IL-18 levels and hormones were measured for all subjects. Furthermore, euglycemic hyperinsulinemic clamp test was performed in selected 30 PCOS women and 11 control subjects. Serum IL-18 levels were elevated in PCOS women compared with the control (p=0.003). IL-18 levels were positively correlated with homeostasis model assessment index (HOMA) β index, which assesses β cell function (p=0.035), but were inversely correlated with clamp indices, which best-represent insulin resistance status: M, Clamp ISIS100, and MCRg values (p=0.006, 0.010, and 0.009 respectively). No correlation was found between IL-18 and age, BMI, waist-to-hip ratio (WHR), lipid profile, dehydroepiandrosterone-sulfate (DHEAS), sex hormone-binding globulin (SHBG), or fasting insulin levels. In conclusion, in the present study, serum IL-18 levels were significantly increased in PCOS women and firmly associated with insulin resistance displayed by euglycemic hyperinsulinemic clamp test. It indicates that IL-18 may be a contributing factor linking inflammation and insulin resistance in PCOS women.

Globular adiponectin augments insulin secretion from pancreatic Islet β cells at high glucose concentrations

Adiponectin plays an important role in improving insulin resistance and preventing atherosclerosis. However it has been rarely reported that adiponectin influences insulin secretion because its receptor was identified in human islet β cells. In order to investigate the direct effect of adiponectin on pancreatic islet β cells, we performed an insulin secretion test in purified rat islets, which were incubated with adiponectin (100 ng/mL) at low (3.3 mM) and high (16.7 mM) glucose concentrations. Furthermore, cell lysates were extracted from the adiponectin-treated islets for p-AMPKα assay. RTPCR and immunohistochemical examination showed both adiponectin receptor 1 (AdipoR1) and receptor 2 (A dipoR2) were expressed in islet cells and AdipoR1 was predominantly expressed. Insulin secretion was significantly increased in the presence of adiponectin for 6 h at high glucose concentration. Meanwhile, the levels of phosphorylated AMPK increased with adiponectin treatment at high glucose concentrations. It is concluded that adiponectin augments insulin secretion from pancreatic islet β cells at high glucose concentration through AMPK activation.