Weiping Jia

Prevalence of Diabetes among Men and Women in China

BACKGROUND Because of the rapid change in lifestyle in China, there is concern that diabetes may become epidemic. We conducted a national study from June 2007 through May 2008 to estimate the prevalence of diabetes among Chinese adults. METHODS A nationally representative sample of 46,239 adults, 20 years of age or older, from 14 provinces and municipalities participated in the study. After an overnight fast, participants underwent an oral glucose-tolerance test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance). Previously diagnosed diabetes was determined on the basis of self-report. RESULTS The age-standardized prevalences of total diabetes (which included both previously diagnosed diabetes and previously undiagnosed diabetes) and prediabetes were 9.7% (10.6% among men and 8.8% among women) and 15.5% (16.1% among men and 14.9% among women), respectively, accounting for 92.4 million adults with diabetes (50.2 million men and 42.2 million women) and 148.2 million adults with prediabetes (76.1 million men and 72.1 million women). The prevalence of diabetes increased with increasing age (3.2%, 11.5%, and 20.4% among persons who were 20 to 39, 40 to 59, and > or = 60 years of age, respectively) and with increasing weight (4.5%, 7.6%, 12.8%, and 18.5% among persons with a body-mass index [the weight in kilograms divided by the square of the height in meters] of < 18.5, 18.5 to 24.9, 25.0 to 29.9, and > or = 30.0, respectively). The prevalence of diabetes was higher among urban residents than among rural residents (11.4% vs. 8.2%). The prevalence of isolated impaired glucose tolerance was higher than that of isolated impaired fasting glucose (11.0% vs. 3.2% among men and 10.9% vs. 2.2% among women). CONCLUSIONS These results indicate that diabetes has become a major public health problem in China and that strategies aimed at the prevention and treatment of diabetes are needed.

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride

BACKGROUND & AIMS Fibroblast growth factor 21 (FGF21), a hormone primarily secreted by the liver in response to peroxisome proliferator-activated receptor-α (PPARα) activation, has recently been shown to possess beneficial effects on lipid metabolism and hepatic steatosis in animal models. This study investigated the association of FGF21 with nonalcoholic fatty liver disease (NAFLD) in Chinese patients. METHODS Serum FGF21 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 224 NAFLD and 124 control subjects, and their association with parameters of adiposity, glucose, and lipid profiles and levels of liver injury markers was studied. Besides serum concentrations, the mRNA expression of FGF21 in the liver tissue was also quantified by real-time PCR in 17 subjects with different degrees of steatosis, and was correlated with the levels of intrahepatic lipid. The protein levels of FGF21 were determined by quantitative ELISA. RESULTS Serum FGF21 levels in patients with NAFLD (402.38 pg/ml [242.03, 618.25]) were significantly higher than those in control subjects (198.62 pg/ml [134.96, 412.62]) (p<0.01). In human liver tissues, FGF21 mRNA expression increased with the degree of steatosis. Both FGF21 mRNA expression and serum FGF21 concentrations were positively correlated with intrahepatic triglyceride (TG) having r = 0.692 and r = 0.662, respectively, at p<0.01. Furthermore, the increased expression of FGF21 was accompanied by elevated protein levels in liver tissues. CONCLUSIONS These results support the role of FGF21 as a key regulator of hepatic lipid metabolism in humans, and suggest that serum FGF21 can be potentially used as a biomarker for NAFLD.

Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.

Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance

Insulin resistance, a hallmark of type 2 diabetes, is a defect of insulin in stimulating insulin receptor signalling, which has become one of the most serious public health threats. Upon stimulation by insulin, insulin receptor recruits and phosphorylates insulin receptor substrate proteins, leading to activation of the phosphatidylinositol-3-OH kinase (PI(3)K)–Akt pathway. Activated Akt phosphorylates downstream kinases and transcription factors, thus mediating most of the metabolic actions of insulin. β-arrestins mediate biological functions of G-protein-coupled receptors by linking activated receptors with distinct sets of accessory and effecter proteins, thereby determining the specificity, efficiency and capacity of signals. Here we show that in diabetic mouse models, β-arrestin-2 is severely downregulated. Knockdown of β-arrestin-2 exacerbates insulin resistance, whereas administration of β-arrestin-2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a new β-arrestin-2 signal complex, in which β-arrestin-2 scaffolds Akt and Src to insulin receptor. Loss or dysfunction of β-arrestin-2 results in deficiency of this signal complex and disturbance of insulin signalling in vivo, thereby contributing to the development of insulin resistance and progression of type 2 diabetes. Our findings provide new insight into the molecular pathogenesis of insulin resistance, and implicate new preventive and therapeutic strategies against insulin resistance and type 2 diabetes.

Serum osteocalcin concentrations in relation to glucose and lipid metabolism in Chinese individuals.

OBJECTIVES Osteocalcin, a bone-derived protein, has recently been reported to affect energy metabolism. We investigated the relationship between serum osteocalcin and parameters of adiposity, glucose tolerance, and lipid profile in Chinese subjects. METHODS Serum osteocalcin was measured by electrochemiluminescence immunoassay in 254 men (128 with newly diagnosed type 2 diabetes mellitus (T2DM) and 126 with normal glucose tolerance (NGT)), 66 premenopausal women (33 with T2DM and 33 with NGT) as well as 180 postmenopausal women (92 with T2DM and 88 with NGT). Their associations with parameters of adiposity, glucose tolerance, and lipid profile were examined. RESULTS Serum osteocalcin concentrations in diabetic patients were significantly lower than those in NGT subjects after adjusted for age, gender, and body mass index (P=0.003). Postmenopausal women had higher osteocalcin concentrations than premenopausal women and men (both P<0.001). Multiple stepwise regression analysis showed that age, %fat, high-density lipoprotein cholesterol, fasting plasma glucose, and fasting serum insulin were independently associated with osteocalcin in men (P<0.05). Age and HbA1c were independently correlated with osteocalcin in postmenopausal women. Besides age and HbA1c, serum triglyceride was also an independent factor influencing osteocalcin in premenopausal women. In addition, osteocalcin was also positively associated with homeostasis model assessment of beta-cell function. Furthermore, multiple logistic regression analysis demonstrated that osteocalcin was independently associated with T2DM. CONCLUSIONS Serum osteocalcin was closely associated with not only fat and glucose metabolism but also with lipid metabolism.

Prevalence of Hypertension in China: A Cross-Sectional Study

Aims The present study aimed to assess the prevalence of hypertension among Chinese adults. Methods Data were obtained from sphygmomanometer measurements and a questionnaire administered to 46239 Chinese adults ≥20 years of age who participated in the 2007–2008 China National Diabetes and Metabolic Disorders Study. Hypertension was defined as blood pressure ≥140/90 mm Hg or use of antihypertensive medication. Results A total of 26.6% of Chinese adults had hypertension, and a significantly greater number of men were hypertensive than women (29.2% vs 24.1%, p<0.001). The age-specific prevalence of hypertension was 13.0%, 36.7%, and 56.5% among persons aged 20 to 44 years (young people), 45 to 64 years (middle-aged people), and ≥65 years (elderly people), respectively. In economically developed regions, the prevalence of hypertension was significantly higher among rural residents than among urban residents (31.3% vs 29.2%, p = 0.001). Among women or individuals who lived in the northern region, the disparity in the prevalence of hypertension between urban and rural areas disappeared (women: 24.0% vs. 24.0%, p = 0.942; northern region: 31.6% vs. 31.2%, p = 0.505). Among hypertensive patients, 45.0% were aware of their condition, 36.2% were treated, and 11.1% were adequately controlled. Conclusions The prevalence of hypertension in China is increasing. The trend of an increase in prevalence is striking in young people and rural populations. Hypertension awareness, treatment, and control are poor. Public health efforts for further improving awareness and enhancing effective control are urgently needed in China, especially in emerging populations.

Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways

The binding of the adaptor protein APPL1 to adiponectin receptors is necessary for adiponectin-induced AMP-activated protein kinase (AMPK) activation in muscle, yet the underlying molecular mechanism remains unknown. Here we show that in muscle cells adiponectin and metformin induce AMPK activation by promoting APPL1-dependent LKB1 cytosolic translocation. APPL1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances LKB1 cytosolic localization by anchoring this kinase in the cytosol. Adiponectin also activates another AMPK upstream kinase Ca2+/calmodulin-dependent protein kinase kinase by activating phospholipase C and subsequently inducing Ca2+ release from the endoplasmic reticulum, which plays a minor role in AMPK activation. Our results show that in muscle cells adiponectin is able to activate AMPK via two distinct mechanisms as follows: a major pathway (the APPL1/LKB1-dependent pathway) that promotes the cytosolic localization of LKB1 and a minor pathway (the phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathway) that stimulates Ca2+ release from intracellular stores.

PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population.

Background Recent advance in genetic studies added the confirmed susceptible loci for type 2 diabetes to eighteen. In this study, we attempt to analyze the independent and joint effect of variants from these loci on type 2 diabetes and clinical phenotypes related to glucose metabolism. Methods/Principal Findings Twenty-one single nucleotide polymorphisms (SNPs) from fourteen loci were successfully genotyped in 1,849 subjects with type 2 diabetes and 1,785 subjects with normal glucose regulation. We analyzed the allele and genotype distribution between the cases and controls of these SNPs as well as the joint effects of the susceptible loci on type 2 diabetes risk. The associations between SNPs and type 2 diabetes were examined by logistic regression. The associations between SNPs and quantitative traits were examined by linear regression. The discriminative accuracy of the prediction models was assessed by area under the receiver operating characteristic curves. We confirmed the effects of SNPs from PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 on risk for type 2 diabetes, with odds ratios ranging from 1.114 to 1.406 (P value range from 0.0335 to 1.37E-12). But no significant association was detected between SNPs from WFS1, FTO, JAZF1, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2-ADAM30 and type 2 diabetes. Analyses on the quantitative traits in the control subjects showed that THADA SNP rs7578597 was association with 2-h insulin during oral glucose tolerance tests (P = 0.0005, empirical P = 0.0090). The joint effect analysis of SNPs from eleven loci showed the individual carrying more risk alleles had a significantly higher risk for type 2 diabetes. And the type 2 diabetes patients with more risk allele tended to have earlier diagnostic ages (P = 0.0006). Conclusions/Significance The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes. These type 2 diabetes risk loci contributed to the disease additively.

Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice

Background Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. Objective Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation. Methods ApoE−/−/TLR4mut mice and ApoE−/−/TLR4 wild-type mice (ApoE−/−/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE−/−) strain with TLR4-mutant (TLR4mut) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity. Results ApoE−/−/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE−/−/TLR4mut mice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE−/−/TLR4-WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE−/−/TLR4mut mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-κB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice. Conclusions These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.