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Abstract Glucagon-like peptide-1 (GLP-1) analogs are important therapeutics for type 2 diabetes and obesity. Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog. We conducted a Phase 2, randomized, double-blind, placebo-controlled study enrolling 145 adults with T2DM. Participants were randomized to 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once-weekly injections for 20 weeks. The primary objective was to evaluate the efficacy of ecnoglutide, as measured by HbA1c change from baseline at Week 20. Secondary endpoints included body weight, glucose and lipid parameters, as well as safety. We show that, at end of treatment, the 0.4, 0.8, and 1.2 mg groups had statistically significant HbA1c reductions from baseline of −1.81%, −1.90%, and −2.39%, respectively, compared to −0.55% for placebo (P

Abstract Background With the fast pace of modern life, people have less time for meals, but few studies have examined the association between the habit of fast eating and metabolic diseases. Objective Combining the results of the current study and the prior ones, we aimed to investigate the possible relationship between fast eating and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods This is a sub-analysis of a multicenter cross-sectional study of 1965 participants investigated the association between fast eating and MASLD in Chinese. Fast eating was defined as meal time less than five minutes and participants were divided into three categories based on their self-reported frequency of fast eating: ≤1 time/month, ≤1 time/week and ≥2 times/week. We further conducted a literature search for available studies published before November, 2023 as well as a meta-analysis to investigate the association between fast eating and MASLD. Results The proportion of MASLD was 59.3%, 50.5%, and 46.2% in participants with fast eating ≥2 times/week, ≤1 time/week and ≤1 time/month, respectively (P for trend

BackgroundChronic kidney disease (CKD) is a significant long-term complication of diabetes and is a primary contributor to end-stage kidney disease. ObjectiveThis study aimed to report comprehensive nationwide data on the prevalence, screening, and awareness rates of CKD in Chinese patients with type 2 diabetes, along with associated risk factors. MethodsBaseline data analysis of the ongoing prospective, observational IMPROVE study was conducted. The study cohort comprised patients who had been diagnosed with type 2 diabetes more than 12 months prior, received at least 1 hypoglycemic medication, and were aged ≥18 years. The participants completed questionnaires and underwent laboratory assessments, including blood and urine samples. The data encompassed patient demographics, medical history, concurrent medications, and comorbidities. Comprehensive evaluations involved physical examinations, urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), glycated hemoglobin (HbA1c), fasting blood glucose, 2-hour postprandial blood glucose, fasting blood lipid profile, and urinalysis. Descriptive statistics were applied for data interpretation, and logistic regression analyses were used to identify the CKD-associated risk factors in patients with type 2 diabetes. ResultsA national study from December 2021 to September 2022 enlisted 9672 participants with type 2 diabetes from 45 hospitals that had endocrinology departments. The enrollees were from diverse regions in China, as follows: central (n=1221), east (n=3269), south (n=1474), north (n=2219), and west (n=1489). The prevalence, screening, and awareness rates of CKD among patients with type 2 diabetes were 31% (2997/9672), 27% (810/2997), and 54.8% (5295/9672), respectively. Multivariate binary regression analysis revealed that the CKD risk factors were screening, awareness, smoking, age, diabetes duration, concurrent antihypertensive and microcirculation medications, diabetic complications (foot, retinopathy, and neuropathy), hypertension, elevated low-density lipoprotein (LDL) cholesterol, and suboptimal glycemic control. Subgroup analysis highlighted an increased CKD prevalence among older individuals, those with prolonged diabetes durations, and residents of fourth-tier cities. Residents of urban areas that had robust educational and economic development exhibited relatively high awareness and screening rates. Notably, 24.2% (1717/7107) of patients with an eGFR ≥90 mL/min/1.73 m2 had proteinuria, whereas 3.4% (234/6909) who had a UACR 5.18 μmol/L, LDL cholesterol >3.37 μmol/L, BMI ≥30 kg/m2, and hypertension. ConclusionsIn a Chinese population of adults with type 2 diabetes, the CKD prevalence was notable, at 31%, coupled with low screening and awareness rates. Multiple risk factors for CKD have been identified. Trial RegistrationClinicalTrials.gov NCT05047471; https://clinicaltrials.gov/study/NCT05047471

Intrahepatic cholangiocarcinoma (iCCA) is a prevalent liver tumor that presents a diagnostic challenge due to its nonspecific symptoms, necessitating reliance on imaging techniques for accurate diagnosis. The similarity of imaging features with other liver diseases, such as hepatocellular carcinoma (HCC) and hepatic alveolar echinococcosis, often leads to confusion and misdiagnosis. In contrast, the distinct characteristics of hepatic cystic echinococcosis (HCE) result in fewer reported misdiagnoses. A case involving a 53-year-old female from Changji (Xinjiang, China) diagnosed with iCCA, who was hospitalized for symptoms of upper abdominal distension and pain, along with nausea and vomiting, is presented. The patient underwent a partial hepatectomy in 1990 for hepatic echinococcosis. Abdominal computed tomography revealed multiple, quasicircular, low-density masses in the hilar region and right anterior lobe of the liver, with the largest measuring 5.61 cm × 4.84 cm. Enhanced computed tomography did not reveal significant enhancement of the lesion. Considering epidemiological factors, medical history, and imaging findings, the initial diagnosis was HCE, which prompted surgical intervention. The diagnosis of iCCA with necrosis was confirmed via pathological examination. The literature and relevant sources were consulted to establish that biliary tract tumors with necrosis or mucin production typically do not exhibit significant enhancement in enhanced scans, maintaining a consistently low density across all phases, resembling the presentation of HCE. When making diagnoses based on imaging data, it is essential to have knowledge of both the typical features and unique manifestations of the disease. In specific instances, relying solely on epidemiology and medical history may lead to incorrect conclusions. Therefore, comprehensive consideration of all aspects is necessary to prevent missed diagnoses and misdiagnoses.

ContextFew studies have directly compared the cognitive characteristics of patients with mild autonomous cortisol secretion (MACS) and Cushing’s syndrome (CS). The effect of surgical or conservative treatment on cognitive function in patients with MACS is still unclear.ObjectiveTo compare the differences in cognitive function between patients with MACS and CS and evaluate the effect of surgery or conservative treatment on cognitive function.MethodsWe prospectively recruited 59 patients with nonfunctional adrenal adenoma (NFA), 36 patients with MACS, and 20 patients with adrenal CS who completed the global cognition and cognitive subdomains assessments. Seventeen MACS patients were re-evaluated for cognitive function after a 12-month follow-up period; of these, eleven underwent laparoscopic adrenalectomy and six received conservative treatment.ResultsPatients with MACS and CS performed worse in the global cognition and multiple cognitive domains than those with NFA (all P

Abstract As a sensor, glucokinase (GK) controls glucose homeostasis, which progressively declines in patients with diabetes. GK maintains the equilibrium of glucose levels and regulates the homeostatic system set points. Endocrine and hepatic cells can both respond to glucose cooperatively when GK is activated. GK has been under study as a therapeutic target for decades due to the possibility that cellular GK expression and function can be recovered, hence restoring glucose homeostasis in patients with type 2 diabetes. Five therapeutic compounds targeting GK are being investigated globally at the moment. They all have distinctive molecular structures and have been clinically shown to have strong antihyperglycemia effects. The mechanics, classification, and clinical development of GK activators are illustrated in this review. With the recent approval and marketing of the first GK activator (GKA), dorzagliatin, GKA's critical role in treating glucose homeostasis disorder and its long‐term benefits in diabetes will eventually become clear.

Abstract Background This retrospective multicenter study evaluated the efficacy and safety of bariatric surgery in Chinese patients with obesity. Methods Patients with obesity who underwent laparoscopic sleeve gastrectomy or laparoscopic Roux‐en‐Y gastric bypass and completed a 12‐month follow‐up between February 2011 and November 2019 were enrolled. Weight loss, glycemic and metabolic control, insulin resistance, cardiovascular risk, and surgery‐related complications at 12 months were analyzed. Results We enrolled 356 patients aged 34.3 ± 0.6 years with a mean body mass index of 39.4 ± 0.4 kg/m2. Successful weight loss occurred in 54.6%, 86.8%, and 92.7% of patients at 3, 6, and 12 months, respectively, with no difference in percent excess weight loss between the laparoscopic sleeve gastrectomy and laparoscopic Roux‐en‐Y gastric bypass surgery groups. The average percentage of total weight loss was 29.5% ± 0.6% at 12 months; 99.4%, 86.8%, and 43.5% of patients achieved at least 10%, 20%, and 30% weight loss, respectively, at 12 months. Significant improvements in metabolic indices, insulin resistance, and inflammation biomarkers were observed at 12 months. Conclusions Bariatric surgery resulted in successful weight loss and improved metabolic control, insulin resistance, and cardiovascular risk in Chinese patients with obesity. Both laparoscopic sleeve gastrectomy and laparoscopic Roux‐en‐Y gastric bypass are suitable approaches for such patients.

Background: This prespecified subgroup analysis of the FIDELIO-DKD trial aimed to evaluate the efficacy and safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in China. Methods: 372 participants were recruited from 67 centers in China and randomized 1:1 to oral finerenone or placebo with standard therapy for T2DM. The primary composite outcome included kidney failure, sustained decrease of estimated glomerular filtration rate ≥40% from baseline over at least 4 weeks, or renal death. The key secondary composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Results: After a median follow-up of 30 months, the finerenone group showed a relative risk reduction (RRR) of 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI], 0.39–0.88; p = 0.009) for the primary composite outcome compared with placebo, consistent across its components with treatment benefits with finerenone. Based on an absolute between-group difference of 12.2% after 30 months, the number of patients who needed to be treated with finerenone to prevent one primary outcome event was eight (95% CI: 4–84). For the key secondary composite outcome, the finerenone group showed a RRR of 25% (HR = 0.75, 95% CI, 0.38–1.48; p = 0.408). Adverse events were similar between the two groups. The effects of finerenone on blood pressure were modest. No gynecomastia events were reported in the study. Hyperkalemia leading to discontinuation occurred in eight (4.3%) and two (1.1%) participants in the finerenone and control groups, respectively. The incidence of acute kidney injury was comparable between the two groups (1.6% vs. 1.6%). Conclusions: Finerenone resulted in lower risks of CKD progression than placebo and a balanced safety profile in Chinese patients with CKD and T2DM.

Abstract The current epidemic status of diabetic retinopathy in China is unclear. A national prevalence survey of diabetic complications was conducted. 50,564 participants with gradable non-mydriatic fundus photographs were enrolled. The prevalence rates (95% confidence intervals) of diabetic retinopathy and vision-threatening diabetic retinopathy were 16.3% (15.3%–17.2%) and 3.2% (2.9%–3.5%), significantly higher in the northern than in the southern regions. The differences in prevalence between those who had not attained a given metabolic goal and those who had were more pronounced for Hemoglobin A1c than for blood pressure and low-density lipoprotein cholesterol. The participants with vision-threatening diabetic retinopathy had significantly higher proportions of visual impairment and blindness than those with non-vision-threatening diabetic retinopathy. The likelihoods of diabetic retinopathy and vision-threatening diabetic retinopathy were also associated with education levels, household income, and multiple dietary intakes. Here, we show multi-level factors associated with the presence and the severity of diabetic retinopathy.

Recent studies have shown placenta-derived exosome (pdE) acts as an important mediator of organ-to-organ interplay regulating maternal metabolic alterations, however, the function and mechanisms of placental exosomes on pancreatic β-cell maladaptation in gestational diabetes mellitus (GDM) remain unclear. The purpose of this investigation was to ascertain how placental exosomes affected the β-cell dysfunction associated with the onset of GDM. Exosomes were isolated from chorionic villi explants of pregnant mice and humans with normal glucose tolerance (NGT) and GDM. The effects of pdE from GDM on glucose tolerance in vivo and islets function in vitro were determined. Isolated islets from mice fed on the chow diet displayed an increase in apoptosis and observed their glucose-stimulated insulin secretion (GSIS) greatly diminished by PdE from GDM mice. Mice that accepted PdE from mice with GDM possessed glucose intolerance.Based on miRNA microarray assay and bioinformatics analysis from human placental exosomes, we identified miR-320b selectively enriched in PdE secreted in GDM compared with NGT. Importantly, the level of placental miR-320b was positively correlated with the 1h-glucose and 2-h glucose of a 75 g oral glucose tolerance test (OGTT) during human pregnancies. Furthermore, miR-320 overexpression attributed to impaired insulin secretion and increased apoptosis in MIN6 cells and islets obtained from mice with normal insulin sensitivity. This study firstly proposed that altered miRNAs in pdE contribute to defective adaptation of β cells during pregnancy, which expands the knowledge of GDM pathogenesis. Exosomes from the placenta may be an emerging therapeutic target for GDM.

Abstract Aims/Introduction To explore whether carotid atherosclerosis is an independent risk factor for small fiber nerve dysfunction in type 2 diabetes mellitus patients. Materials and Methods A total of 247 type 2 diabetes patients from Nanjing Drum Tower Hospital received carotid ultrasonography and quantitative sensory testing, including cold and warm detection thresholds, and some patients received cold and heat pain detection thresholds, respectively. According to the results of quantitative sensory testing, patients were divided into normal small fiber nerve function (NSF) and small fiber nerve dysfunction (SFD) group. Meanwhile, patients were divided into the non‐carotid atherosclerosis group, carotid intimal thickening, unilateral carotid atherosclerosis and bilateral carotid atherosclerosis group. The correlation between carotid ultrasonography with quantitative sensory testing parameters was analyzed by SPSS 26.0. Results First, the incidence rate of SFD increased significantly in patients with carotid atherosclerosis (72.2%, P

Abstract Liver dysfunction is a common complication of Graves’ disease (GD) that may be caused by excessive thyroid hormone (TH) or anti-thyroid drugs (ATDs). Radioactive iodine (RAI) therapy is one of the first-line treatments for GD, but it is unclear whether it is safe and effective in patients with liver dysfunction. 510 consecutive patients with GD receiving first RAI were enrolled in the study, and followed up at 3-, 6- and 12-month. Liver dysfunction was recorded in 222 (43.5%) patients. GD patients with liver dysfunction had higher serum levels of free triiodothyronine (FT3) (median 27.6 vs. 20.6 pmol/L, p

Thyroid eye disease (TED) is the major extrathyroidal manifesta tion of Graves’ disease (GD). Treatment choice is based on clinical activity and severi ty of TED, as evaluated with clinical activity score (CAS) and magnetic resonance (MR) imagi ng. We aimed to determine the relationship between neutrophil-to-lymphocyte ratio (NLR), a readily available indicator of systemic inflammation, and clinical and MR imaging parameters in TED patients. Eighty-seven consecutive TED patients were included. The average signa l intensity ratio (SIR), average extraocular muscle (EOM) diameter, and proptosis of the study eye were extracted from MR images. A baseline NLR ≥ 2.0 was recorded in 37 (42.5%) patients and NLR < 2.0 in 50 (57.5%) patients. TED patients with NLR ≥ 2.0 were older, had a higher CAS, average SIR, average EOM diameter and proptosis, and a lower serum thyrotrop hin receptor antibody level than patients with NLR < 2.0 (all P < 0.05). All MR parameters showed significant correlation with CAS (P < 0.05). NLR correlated significantly with CAS (P = 0.001), average SIR (P = 0.004), average EOM diameter (P = 0.007), and proptosis (P = 0.007). Multiple regression revealed a significant correlation between NLR and CAS (P = 0.001), average SIR (P = 0.029), and proptosis (P = 0.037). Cox regression analysis showed that a high NLR at baseline was associated with a worse clinical outcome of TED (hazard rat io 3.7, 95% CI 1.22–11.2, P = 0.02), at a median follow-up of 25 months. In conclusion, NLR was correlated with CAS and MR imaging parameters and was associated with a worse clini cal outcome of TED at follow-up in patients with TED. Additional prospective studies are needed to validate our findings.

Abstract Background The therapeutic potential of mesenchymal stem cells (MSCs) in type 1 diabetes (T1D) has been demonstrated in both preclinical and clinical studies. MSCs that have been used in research on T1D are derived from various tissue sources, with bone marrow (BM) and umbilical cord (UC) tissues being the most commonly used. However, the influence of tissue origin on the functional properties and therapeutic effects of MSCs in T1D remains unclear. This study aimed to compare the therapeutic efficacy of UC-MSCs and BM-MSCs in a mouse model of T1D as well as in patients with T1D. Methods In non-obese diabetic (NOD) mice, the development of diabetes was accelerated by streptozotocin injections. Thereafter, diabetic mice were randomized and treated intravenously with UC-MSCs, BM-MSCs or phosphate-buffered saline as a control. Blood glucose and serum insulin were measured longitudinally after transplantation. At 14 days post-transplantation, pancreatic tissues were collected to assess insulitis and the β-cell mass. Flow cytometry was performed to evaluate the composition of T lymphocytes in the spleen and pancreatic lymph nodes of the NOD mice. In our retrospective study of patients with T1D, 28 recipients who received insulin therapy alone or a single transplantation of UC-MSCs or BM-MSCs were enrolled. The glycaemic control and β-cell function of the patients during the first year of follow-up were compared. Results In NOD mice, UC-MSC and BM-MSC transplantation showed similar effects on decreasing blood glucose levels and preserving β cells. The regulation of islet autoimmunity was examined, and no significant difference between UC-MSCs and BM-MSCs was observed in the attenuation of insulitis, the decrease in T helper 17 cells or the increase in regulatory T cells. In patients with T1D, MSC transplantation markedly lowered haemoglobin A1c (HbA1c) levels and reduced insulin doses compared to conventional insulin therapy. However, the therapeutic effects were comparable between UC-MSCs and BM-MSCs, and they also exerted similar effects on the endogenous β-cell function in the patients. Conclusion In conclusion, both UC-MSCs and BM-MSCs exhibited comparable therapeutic effects on improving glycaemic control and preserving β-cell function in T1D. Considering their abundance and higher cell yields, UC-MSCs appear to be more promising than BM-MSCs in clinical applications. Trial registration NCT02763423. Registered on May 5, 2016—Retrospectively registered, https://www.clinicaltrials.gov/ .

Abstract Background Although type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged. However, the pivotal disease-relevant B cell subset and its contribution to islet autoimmunity remain elusive. Methods The frequencies and phenotypic characteristics of circulating B cell subsets were analyzed using flow cytometry in individuals with new-onset T1D, long-term T1D, type 2 diabetes, and nondiabetic controls, and also in a prospective cohort of patients receiving mesenchymal stromal cell (MSC) transplantation. NOD mice and adoptive transfer assay were used to dissect the role of the certain B cell subset in disease progression. An in-vitro coculture system of islets with immune cells was established to examine the response against islets and the underlying mechanisms. Results We identified that plasmablasts, a B cell subset at the antibody-secreting stage, were significantly increased and correlated with the deterioration of beta cell function in patients with new-onset T1D. Further, a fall of plasmablast number was associated with the preservation of beta cell function in patients who received MSC transplantation after 3 months of follow-up. Meanwhile, a gradual increase of plasmablasts in pancreatic lymph nodes during the natural progression of insulitis was observed in non-obese diabetic (NOD) mice; adoptive transfer of plasmablasts together with T cells from NOD mice accelerated diabetes onset in NOD/SCID recipients. Conclusions Our study revealed that plasmablasts may function as antigen-presenting cells and promote the activation and proinflammatory response of CD4+ T cells, further contributing to the T cell-mediated beta cell destruction. Our results provide insights into the pathogenic role of plasmablasts in islet autoimmunity and may offer new translational strategies for inhibiting T1D development.

Abstract Background We aimed to report pregnancy outcomes of women with type 1 diabetes (T1D) in China, on which data were sparse. Methods This is a nationwide retrospective study conducted in 11 general medical centers in 8 cities across China. We investigated the clinical data of all women who attended these centers with a singleton pregnancy and whose pregnancy ended between 1 January 2004 and 31 December 2014. Pregnancies of women with pregestational T1D were ascertained and compared with those of women without T1D. Results From over 300 000 pregnancies over the 11‐year study period, we identified 265 singleton pregnancies of women with T1D. One maternal death was documented among 265 (0.37%) women with T1D and 83 among 318 486 (0.03%) women without T1D. Women with T1D suffered from higher rates of pregnancy loss (13.21% vs 2.92%, crude risk ratio [cRR] 5.08 [95% CI, 3.56‐7.26]) and preeclampsia (17.74% vs 4.20%, cRR 4.94 [95% CI, 3.60‐6.77]) compared with those without T1D. Infants of these women with T1D had elevated rates of neonatal death (5.65% vs 0.16%, cRR 37.36 [95% CI, 21.21‐65.82]) and congenital malformation(s) (8.26% vs 3.53%, cRR 2.46 [95% CI, 1.54‐3.93]) compared with those of women without T1D. No significant improvement in pregnancy outcomes in women with T1D was observed over the period 2004 to 2014. Conclusions Pregnancy outcomes were persistently poor in women with T1D during 2004 to 2014 in China. Pregnancy care needs to be improved to reduce adverse pregnancy outcomes among Chinese women with T1D.

Abstract Aim To investigate the diagnostic utility of corneal confocal microscopy (CCM) for small fiber neuropathy in type 2 diabetes. Materials and Methods There were 186 participants with type 2 diabetes enrolled in this cross‐sectional research. Pure small fiber neuropathy and mixed fiber neuropathy were defined using clinical examination, electromyography, and quantitative sensory testing. Demographics and clinical data, corneal confocal microscopy parameters, and other neuropathy measures were compared among the groups. The diagnostic utility of corneal confocal microscopy for small fiber neuropathy was assessed by the receiver operating curve. Results Of the 186 patients, 24.7% had a pure small fiber neuropathy and 17.2% of patients were diagnosed with mixed fiber neuropathy. The corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), and corneal nerve fiber length (CNFL) were significantly lower in subjects with pure small fiber neuropathy compared with those without diabetic peripheral neuropathy (all P

Thyroid nodules (TNs) represent a common scenario. More accurate pre-operative diagnosis of malignancy has become an overriding concern. This study incorporated demographic, serological, ultrasound, and biopsy data and aimed to compare a new diagnostic prediction model based on Back Propagation Neural Network (BPNN) with multivariate logistic regression model, to guide the decision of surgery. Records of 2,090 patients with TNs who underwent thyroid surgery were retrospectively reviewed. Multivariate logistic regression analysis indicated that Bethesda category (OR=1.90, P

BackgroundGlycemic control remains suboptimal in developing countries due to critical system deficiencies. An innovative mobile health (mHealth)-enabled hierarchical diabetes management intervention was introduced and evaluated in China with the purpose of achieving better control of type 2 diabetes in primary care.Methods and findingsA community-based cluster randomized controlled trial was conducted among registered patients with type 2 diabetes in primary care from June 2017 to July 2019. A total of 19,601 participants were recruited from 864 communities (clusters) across 25 provinces in China, and 19,546 completed baseline assessment. Moreover, 576 communities (13,037 participants) were centrally randomized to the intervention and 288 communities (6,509 participants) to usual care. The intervention was centered on a tiered care team-delivered mHealth-mediated service package, initiated by monthly blood glucose monitoring at each structured clinic visit. Capacity building and quarterly performance review strategies upheld the quality of delivered primary care. The primary outcome was control of glycated hemoglobin (HbA1c; ConclusionsThe mHealth-enabled hierarchical diabetes management intervention effectively improved diabetes control in primary care and has the potential to be transferred to other chronic conditions management in similar contexts.Trial registrationChinese Clinical Trial Registry (ChiCTR) IOC-17011325.

Background and objectiveClinical characteristics of obesity are heterogenous, but current classification for diagnosis is simply based on BMI or metabolic healthiness. The purpose of this study was to use machine learning to explore a more precise classification of obesity subgroups towards informing individualized therapy.Subjects and MethodsIn a multi-center study (n=2495), we used unsupervised machine learning to cluster patients with obesity from Shanghai Tenth People’s hospital (n=882, main cohort) based on three clinical variables (AUCs of glucose and of insulin during OGTT, and uric acid). Verification of the clustering was performed in three independent cohorts from external hospitals in China (n = 130, 137, and 289, respectively). Statistics of a healthy normal-weight cohort (n=1057) were measured as controls.ResultsMachine learning revealed four stable metabolic different obese clusters on each cohort. Metabolic healthy obesity (MHO, 44% patients) was characterized by a relatively healthy-metabolic status with lowest incidents of comorbidities. Hypermetabolic obesity-hyperuricemia (HMO-U, 33% patients) was characterized by extremely high uric acid and a large increased incidence of hyperuricemia (adjusted odds ratio [AOR] 73.67 to MHO, 95%CI 35.46-153.06). Hypermetabolic obesity-hyperinsulinemia (HMO-I, 8% patients) was distinguished by overcompensated insulin secretion and a large increased incidence of polycystic ovary syndrome (AOR 14.44 to MHO, 95%CI 1.75-118.99). Hypometabolic obesity (LMO, 15% patients) was characterized by extremely high glucose, decompensated insulin secretion, and the worst glucolipid metabolism (diabetes: AOR 105.85 to MHO, 95%CI 42.00-266.74; metabolic syndrome: AOR 13.50 to MHO, 95%CI 7.34-24.83). The assignment of patients in the verification cohorts to the main model showed a mean accuracy of 0.941 in all clusters.ConclusionMachine learning automatically identified four subtypes of obesity in terms of clinical characteristics on four independent patient cohorts. This proof-of-concept study provided evidence that precise diagnosis of obesity is feasible to potentially guide therapeutic planning and decisions for different subtypes of obesity.Clinical Trial Registrationwww.ClinicalTrials.gov, NCT04282837.

Abstract Backgrounds To investigate the value of prolactin (PRL) in diagnosing non-alcoholic fatty liver disease (NAFLD). Methods Metabolic parameters and serum PRL levels were measured in 452 males and 421 females, who were randomized to the estimation or the validation group as a 1:1 ratio. Hepatic steatosis was diagnosed via abdominal ultrasound. Variables that significantly associated with NAFLD in univariate analysis were included in multiple logistic regression. We used the receiver operator characteristic (ROC) curves to test the model performance. Besides, 147 patients underwent metabolic and liver biopsy were analyzed to validate the diagnostic value of this model. Results Body mass index, alanine aminotransferase, prolactin, high density lipoprotein cholesterol and HbA1c were included into models. In males, the area under ROC curve (AUC) was 0.86 (95%CI: 0.82–0.91) for the validation group. With two cut-off points (− 0.79 and 1.71), the sensitivity and specificity for predicting NALFD was 95.2 and 91.1% in the validation group, respectively. In females, the AUC was 0.82 (95%CI: 0.76–0.88) for the validation group. With two cut-off points (− 0.68 and 2.16), the sensitivity and specificity for predicting NALFD was 97.1 and 91.4% in the validation group, respectively. In subjects with liver pathology, the AUC was higher than that of fatty liver index. A positive correlation between the scores of the model and the severities of NAFLD was observed. Importantly, we demonstrated a potential value of this model in predicting nonalcoholic steatohepatitis. Conclusion We established a mathematic model that can conveniently and effectively diagnose the existence and severities of NAFLD.

Whether adipose ILC1s regulate adipose tissue fibrogenesis is unknown. Here, the authors report a direct role of adipose ILC1s in adipose tissue fibrogenesis and provide insights into the mechanisms of local immune dysfunction in obesity-associated metabolic disorders.

Abstract Aims/Introduction Type 2 diabetes mellitus is frequently accompanied by fatty liver disease. Lipid accumulation within the liver is considered as one of the risk factors for insulin resistance. Hepatocyte growth factor (HGF) is used to treat liver dysfunction; however, the effect and mechanism of HGF on hepatic lipid metabolism are still not fully understood. Materials and Methods Male C57BL/6 mice were induced with a high‐fat diet for 12 weeks, followed by a 4‐week treatment of HGF or vehicle saline. The levels of fasting blood glucose, fasting insulin and homeostatic model assessment of insulin resistance were calculated for insulin sensitivity. Biochemical plasma parameters were also measured to assess the effect of HGF on lipid accumulation. Additionally, genes in the lipid metabolism pathway were evaluated in palmitic acid‐treated HepG2 cells and high‐fat diet mice. Results HGF treatment significantly decreased the levels of fasting blood glucose, hepatic triglyceride and cholesterol contents. Additionally, HGF‐regulated expression levels of sterol regulatory element‐binding protein‐1c/fatty acid synthase, peroxidase proliferator‐activated receptor‐α, and upstream nuclear receptors, such as farnesoid X receptor and small heterodimer partner. Furthermore, c‐Met inhibitor could partially reverse the effects of HGF. Conclusions HGF treatment can ameliorate hepatic insulin resistance and steatosis through regulation of lipid metabolism. These effects might occur through farnesoid X receptor–small heterodimer partner axis‐dependent transcriptional activity.

Abstract Aims/Introduction To investigate the direct medical costs for patients with type 2 diabetes in China and to examine the influencing factors. Materials and Methods In the present multicenter study, 1,070 patients with type 2 diabetes from 16 tertiary hospitals in 14 major cities of China were enrolled. Patient data and direct medical costs were collected during a follow‐up period of 6 months at intervals of 1 month. The log‐transformed direct medical costs were fitted by a generalized estimation equation to indicator variables for demographics, metabolic control, treatments, complications and comorbidities. Results Data of 871 participants were included in the analysis. The mean annual total direct medical costs and outpatient medical costs were $1,990.20 and $1,687.20 respectively. The average costs per inpatient per admission were $2,127.10. The share of out‐of‐pocket for total medical costs, outpatient costs and cost per inpatient per admission were 45.4, 46.3 and 26.0% respectively. Independent determinants of total medical costs were diabetes duration, dyslipidemia and diabetic complications, such as neuropathy and nephropathy, as well as diabetes treatment, such as the use of glucagon‐like peptide‐1 receptor agonists. Costs showed prominent variation across centers. Conclusions Diabetes is imposing a growing economic burden in patients with type 2 diabetes in China. Diabetes‐related complications and comorbidities have a great impact on the medical costs. As different health policies, economic development and regional health inequalities also have an important influence on the direct medical cost, healthcare reform needs to optimize resource allocation in health service delivery systems, and provide more equitable and affordable healthcare.

Aims. Epidemiological data on diabetic retinopathy (DR) in Chinese population is still rather scarce, and risk factors for diabetic retinopathy are inconsistent because of study designs, grading standards, and population samples. Materials and Methods. This hospital-based retrospective study included 1052 type 2 diabetes patients. Diabetic retinopathy was diagnosed by nonmydriatic fundus photography and/or fundus examination apparatus. Logistic regression analysis was performed to evaluate the risk of diabetic retinopathy. Results. A total of 352 (33.5% prevalence) subjects were diagnosed with diabetic retinopathy based on our population. The patients in the DR group not only had significantly higher hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), urinary microalbumin-creatinine ratio (ACR), and systolic blood pressure but also had higher follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin (SHBG) levels compared to those in the non-DR group. Moreover, we confirmed that diabetes duration and HbA1c are strongly associated with DR risk. We also found that serum LH was an independent risk factor in male diabetic retinopathy patients (OR=1.086, 95% CI 1.024–1.152), and the levels of LH were significantly associated with diabetic retinopathy prevalence (P=0.018). Conclusions. Our study strengthens the argument that diabetes duration and HbA1c are risk factors for patients with DR. Additionally; we firstly confirmed that serum LH was an independent risk factor in male diabetic retinopathy patients.

Purpose. Targeting white adipose tissue (WAT) beiging has been proposed as an effective way to increase thermogenesis and improve glucose metabolism. Neuromedin U (NMU) is a neuropeptide that could increase energy expenditure, while its effects on WAT beiging and glucose homeostasis remain to be investigated. Methods. Male C57BL/6 mice were fed with high fat diet (HFD) to induce obesity and hyperglycemia and then treated with chronic subcutaneous injection of NMU. Body weight and food intake were recorded daily. After 14 days of injection, intraperitoneal glucose tolerance tests and 18F-fluorodeoxyglucose micro-positron emission tomography/computed tomography (18F-FDG micro-PET/CT) scans were conducted. Subcutaneous WAT (sWAT) and interscapular brown adipose tissue were collected for the evaluation of adipocyte size, expression of uncoupling protein 1 (Ucp1), and other thermogenic-related genes. Stromal vascular fraction of subcutaneous WAT was extracted for the measurement of type 2 innate lymphocytes (ILC2s) proportions. Results. Glucose tolerance was markedly improved by peripherally administered NMU. Micro-PET/CT suggested that NMU promoted WAT beiging, which was further confirmed by haematoxylin and eosin (H&E) staining and immunohistochemistry. In diet-induced-obese (DIO) mice, NMU activated thermogenic-related genes in WAT. In addition, NMU stimulated ILC2s in the stromal vascular fraction of WAT. Conclusion. Taken together, our study indicates that peripheral administration of NMU is a potential therapeutic strategy for the promotion of WAT beiging and the improvement of impaired glucose tolerance.

Metabolic surgery (MS) is one of the most effective therapies for treating obesity. Due to the lack of multicenter cohort research on nutritional evaluations after surgery in Chinese patients, we explored the changes in nutritional status following MS in Chinese patients. This was a retrospective study of patients (n = 903) who underwent sleeve gastrectomy (SG) (n = 640) or Roux-en-Y gastric bypass (RYGB) (n = 263) for obesity at five different hospitals in China between 17 February 2011, and 20 December 2019. Major nutrients were evaluated at baseline and 1, 3, 6, and 12 months postoperatively. Hb levels decreased, and anemia prevalence increased at 12 months after MS in the premenopausal female group. Moreover, patients with preoperative anemia had an increased risk of postoperative anemia. The ferritin levels (p < 0.001) decreased and iron deficiency increased (p < 0.001) at 12 months after MS among premenopausal females. No significant changes in folate deficiency and vitamin B12 deficiency were found throughout the study. The bone mineral density (BMD) of the femoral neck, lumbar spine, and total hip significantly decreased from baseline to 12 months after MS; however, no new patients developed osteopenia or osteoporosis after MS. Based on 12 months of follow-up, premenopausal females presented a high incidence of anemia after MS. Although we found no differences in osteopenia and osteoporosis prevalence after MS, the BMD did decrease significantly, which suggests that nutrient supplements and long-term follow-up are especially necessary postoperation.

Abstract Background Efficacy trials showed that glucagon-like peptide–1 receptor (GLP1R) agonists reduced metabolic risk factors in addition to glucose lowering, but the cardiovascular and microvascular efficacy of this drug class remains to be determined. We aimed to evaluate the overall cardiovascular and microvascular efficacy of GLP1R agonists by performing a meta-analysis with trial sequential analysis. Methods Randomized controlled, cardiovascular outcomes trials including at least 2000 patient-years’ follow-up and 100 composite cardiovascular events were included. Trial sequential analysis (TSA) was performed and the quality of evidence was graded. Results Thirty-three thousand four hundred fifty-seven patients and 4105 cardiovascular events from 4 large trials were included. GLP1R agonists were associated with a statistically significant reduction in risks for all-cause mortality (hazard ratio [HR]: 0.88, 95% CI: 0.81 to 0.95; number needed to treat [NNT]: 286 person-years), cardiovascular mortality (HR: 0.87, 95% CI: 0.79 to 0.96; NNT: 412 person-years), stroke (HR: 0.87, 95% CI: 0.76 to 0.98; NNT: 209 person-years) and the composite adverse cardiovascular outcome (MACE; HR: 0.91, 95% CI: 0.85 to 0.96; NNT: 241 person-years). The magnitude of benefit on MACE was attenuated in patients with a history of congestive heart failure (HR: 0.96, 95% CI: 0.85 to 1.08 with; HR: 0.87, 95% CI: 0.77 to 1.00 without). The risks for hospitalization for heart failure and myocardial infarction were not significantly different. The quality of the evidence was deemed as moderate to high based on GRADE approach. TSA provided firm evidence for a 10% reduction in all-cause mortality, a 15% reduction in MACE, and lack of a 15% reduction in hospitalization for heart failure, but evidence remains inconclusive for cardiovascular mortality and myocardial infarction. GLP1R agonists numerically reduced the rates for nephropathy but the risk for retinopathy was similar. Conclusions Meta-analysis with trial sequential analysis suggested that GLP1R agonists significantly reduced the risk for all-cause mortality and composite cardiovascular outcomes, but the reduction of cardiovascular mortality remains to be confirmed.

The management of patients with adrenocorticotropic hormone-independent Cushing’s syndrome and bilateral adrenal masses is challenging. Adrenal venous sampling (AVS) has been used to identify functional lesions in previous studies, but it is not always reliable. The present study aims to address the variability of cortisol in the adrenal veins of patients without excessive cortisol secretion and investigate the use of adrenal androgens to correct the cortisol lateralization ratio in AVS. Thirty-seven patients with primary aldosteronism underwent successful AVS. Patients with normal cortisol secretion exhibited a wide range of cortisol concentrations in the right (601-89, 400 nmol/l) and left (331-35, 300 nmol/l) adrenal veins. The median cortisol gradients between adrenal venous and peripheral venous samples were 15.25 and 10.14 in the right and left sides, respectively, and the cortisol lateralization ratio (high side to low side) was as high as 9.49 (median 1.54). The mean plasma levels of cortisol in the adrenal venous and peripheral venous samples decreased from t-15 to t0. Significant positive correlations were observed between the cortisol concentrations and both androstenedione and dehydroepiandrosterone concentrations in the right and left adrenal veins. After correcting for androstenedione or dehydroepiandrosterone levels, the cortisol lateralization ratio was less than 2 in most adrenal venous samples. The present study demonstrated the wide variation in cortisol concentrations in the adrenal veins of patients with normal cortisol secretion. The adrenal androgens might be ideal analytes used as normalizers when assessing the cortisol lateralization of AVS in normal or hypercortisolism cases.

Following publication of the original article [1], we have been notified that the given name of one of the authors was spelled incorrectly.

Different studies have produced conflicting results regarding the association between smoking and diabetes mellitus, and detailed analysis of this issue in Chinese males based on nationwide samples is lacking. We explored the association between cigarette smoking and newly-diagnosed diabetes mellitus (NDM) in Chinese males using a population-based case-control analysis; 16,286 male participants without previously diagnosed diabetes were included. Prediabetes and NDM were diagnosed using the oral glucose tolerance test. The cohort included 6,913 non-smokers (42.4%), 1,479 ex-smokers (9.1%) and 7,894 current smokers (48.5%). Age-adjusted glucose concentrations (mmol/L) were significantly lower at fasting and 120 min in current smokers than non-smokers (5.25 vs. 5.30, 6.46 vs. 6.55, respectively, both P < 0.01). After adjustment for demographic and behavioral variables (age, region, alcohol consumption status, physical activity, education, and family history of diabetes), logistic regression revealed significant negative associations between smoking and NDM in males of a normal weight (BMI < 25 kg/m2: adjusted odds ratio [AOR] = 0.75, P = 0.007; waist circumference < 90 cm: AOR = 0.71, P = 0.001) and males living in southern China (AOR = 0.75, P = 0.009), but not in males who were overweight/obese, males with central obesity, or males living in northern China. Compared to non-smokers, current smokers were less likely to be centrally obese or have elevated BP (AOR: 0.82 and 0.74, both P < 0.05), and heavy smokers (≥ 20 pack-years) were less likely to have elevated TG (AOR = 0.84, P = 0.012) among males of a normal weight. There were no significant associations between quitting smoking and metabolic disorders either among males of a normal weight or males who were overweight/obese. In conclusion, smokers have a lower likelihood of NDM than non-smokers among Chinese males with a lower BMI/smaller waist.

AIM:To investigate the association between different family history risk categories and prevalence of diabetes in the Chinese population. METHODS:The family history of diabetes was obtained from each subject, and an oral glucose tolerance test was performed for measuring the fasting and postload glucose and insulin levels based on a national representative cross-sectional survey of 46,239 individuals (age ≥ 20 years) in the 2007-2008 China National Diabetes and Metabolism Disorders Study. The family history risk categories of diabetes were high, moderate, and average (FH2 and FH1: at least two generations and one generation of first-degree relatives with diabetes, respectively; FH0: no first-degree relatives with diabetes). RESULTS:The age- and gender-adjusted prevalence rates of diabetes were 32.7% (95% confidence interval (CI): 26.4-39.7%) in FH2, 20.1% (95% CI: 18.2-22.1%) in FH1, and 8.4% (95% CI: 7.9-8.9%) in FH0 (P < 0.0001). The calculated homeostatic model assessment-estimated insulin resistance (HOMA-IR), Matsuda insulin sensitivity index (ISI), and insulinogenic index (ΔI30/ΔG30) values showed significant trending changes among the three risk categories, with the most negative effects in FH2. Multivariate logistic regression analysis showed that the odds ratios of having diabetes were 6.16 (95% CI: 4.46-8.50) and 2.86 (95% CI: 2.41-3.39) times higher in FH2 and FH1, respectively, than in FH0 after adjustment for classical risk factors for diabetes. CONCLUSIONS:Family history risk categories of diabetes have a significant, independent, and graded association with the prevalence of this disease in the Chinese population.

ObjectiveTo investigate the association of hyperglycemia with blood pressure control goal in the patients with type 2 diabetes (T2D) cared by tertiary hospitals in China.Study design and methodsA cross sectional survey of 29442 patients was conducted in 77 tertiary hospitals in 4 major cities in China in 2011 and 18350 of them without known hypertension were used in the analysis. Univariable and multivariable logistic regression analysis stratified on cities and hospitals was performed to obtain odds ratio of factors of interest for achievement of the blood pressure treatment goal, i.e., 140/80 mmHg as recommended by American Diabetes Association (ADA). Sensitivity analysis was performed after re-inclusion of 11902 patients with diagnosed hypertension. Findings from were further replicated in patients with T2D recruited using the same protocol from tertiary hospitals located in other central cities in China.ResultsThe mean age was 58.2 (SD: 11.3) years and 53.3% were male, with a median of 4 years of disease duration. A total of 12129 patients (58.2%) did not achieve the ADA recommended goal for BP control. After adjusting for covariables, hyperglycemia was associated with failure to achieve the BP goal (OR of HbA1c at 6.5%-6.9% vs. ConclusionsHyperglycemia defined as HbA1c ≥ 6.5% increased the risk of failure to achieve the BP goal in T2D patients.

Obesity is a well-known risk factor for type 2 diabetes. Genome-wide association studies have identified a number of genetic loci associated with obesity. The aim of this study is to examine the contribution of obesity-related genomic loci to type 2 diabetes in a Chinese population.We successfully genotyped 18 obesity-related single nucleotide polymorphisms among 5338 type 2 diabetic patients and 4663 controls. Both individual and joint effects of these single nucleotide polymorphisms on type 2 diabetes and quantitative glycemic traits (assessing β-cell function and insulin resistance) were analyzed using logistic and linear regression models, respectively.Two single nucleotide polymorphisms near MC4R and GNPDA2 genes were significantly associated with type 2 diabetes before adjusting for body mass index and waist circumference (OR (95% CI) = 1.14 (1.06, 1.22) for the A allele of rs12970134, P = 4.75×10(-4); OR (95% CI) = 1.10 (1.03, 1.17) for the G allele of rs10938397, P = 4.54×10(-3)). When body mass index and waist circumference were further adjusted, the association of MC4R with type 2 diabetes remained significant (P = 1.81×10(-2)) and that of GNPDA2 was attenuated (P = 1.26×10(-1)), suggesting the effect of the locus including GNPDA2 on type 2 diabetes may be mediated through obesity. Single nucleotide polymorphism rs2260000 within BAT2 was significantly associated with type 2 diabetes after adjusting for body mass index and waist circumference (P = 1.04×10(-2)). In addition, four single nucleotide polymorphisms (near or within SEC16B, BDNF, MAF and PRL genes) showed significant associations with quantitative glycemic traits in controls even after adjusting for body mass index and waist circumference (all P values

BACKGROUND: We updated the prevalence of obesity and evaluated the clinical utility of separate and combined waist circumference (WC) or body mass index (BMI) category increments in identifying cardiometabolic disorder (CMD) and cardiovascular disease (CVD) risk in Chinese adults. METHODS AND FINDINGS: 46,024 participants aged ≥20 years, a nationally representative sample surveyed in 2007-2008, were included in this analysis. Taking the cutoffs recommended by the Chinese Joint Committee for Developing Chinese Guidelines (JCDCG) and the Working Group on Obesity in China (WGOC) into account, the participants were divided into four WC and four BMI groups in 0.5-SD increments around the mean, and 16 cross-tabulated combination groups of WC and BMI. 27.1%, 31.4%, and 12.2% of Chinese adults are centrally obese, overweight, or obese according to JCDCG and WGOC criteria. After adjustment for confounders, after a 1-SD increment, WC is associated with a 1.7-fold or 2.2-fold greater risk of having DM or DM plus dyslipidemia than BMI, while BMI was associated with a 2.3-fold or 1.7-fold higher hypertension or hypertension plus dyslipidemia risk than WC. The combination of WC and BMI categories had stronger association with CMD risk, i.e., the adjusted ORs (95% CI) of having DM, hypertension, and dyslipidemia for the combined and separate highest WC and BMI categories were 2.19 (1.96-2.44) vs 1.88 (1.67-2.12) and 1.12 (0.99-1.26); 5.70 (5.24-6.19) vs 1.51 (1.39-1.65) and 1.69 (1.57-1.82); and 3.73 (3.42-4.07) vs 2.16 (1.98-2.35) and 1.33 (1.25-1.40), respectively. The combination of WC and BMI categories was more likely to identify individuals with lower WC and lower BMI at CVD risk, even after the effects of CMD were controlled (all P

[This corrects the article DOI: 10.1371/journal.pone.0071399.].

Erythropoietin (EPO) has multiple biological functions, including the modulation of glucose metabolism. However, the mechanisms underlying the action of EPO are still obscure. This study is aimed at investigating the potential mechanisms by which EPO improves glucose tolerance in an animal model of type 2 diabetes. Male C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks and then treated with EPO (HFD-EPO) or vehicle saline (HFD-Con) for two week. The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. Therefore, our data indicated that EPO treatment improved glucose intolerance by inhibiting gluconeogenesis and inflammation in the livers of HFD-fed mice.

Though multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes have been identified, the genetic bases of isolated fasting hyperglycaemia (IFH) and isolated postprandial hyperglycaemia (IPH) were still unclear. In present study, we aimed to investigate the association of genome-wide association study-validated genetic variants and IFH or IPH in Han Chinese.We genotyped 27 validated SNPs in 6,663 unrelated individuals comprising 341 IFH, 865 IPH, 1,203 combined fasting hyperglycaemia and postprandial hyperglycaemia, and 4,254 normal glycaemic subjects of Han ancestry. The distributions of genotype frequencies of FTO, CDKAL1 and GCKR were significant different between individuals with IFH and those with IPH (SNP(ptrend ): rs8050136(0.0024), rs9939609(0.0049), rs7756992(0.0122), rs780094(0.0037)). Risk allele of FTO specifically increased the risk of IFH (rs8050136: OR 1.403 [95% CI 1.125-1.750], p = 0.0027; rs9939609: 1.398 [1.120-1.744], p = 0.0030). G allele of CDKAL1 specifically increased the risk of IPH (1.217 [1.092-1.355], p = 0.0004). G allele of GCKR increased the risk of IFH (1.167 [0.999-1.362], p = 0.0513), but decreased the risk of IPH (0.891 [0.801-0.991], p = 0.0331). In addition, TCF7L2 and KCNQ1 increased the risk of both IFH and IPH. When combined, each additional risk allele associated with IFH increased the risk for IFH by 1.246-fold (p

BACKGROUND: Genome-wide association study (GWAS) has identified more than 30 loci associated with type 2 diabetes (T2D) in Caucasians. However, genomic understanding of T2D in Asians, especially Han Chinese, is still limited. METHODS AND PRINCIPAL FINDINGS: A two-stage GWAS was performed in Han Chinese from Mainland China. The discovery stage included 793 T2D cases and 806 healthy controls genotyped using Illumina Human 660- and 610-Quad BeadChips; and the replication stage included two independent case-control populations (a total of 4445 T2D cases and 4458 controls) genotyped using TaqMan assay. We validated the associations of KCNQ1 (rs163182, p = 2.085×10(-17), OR 1.28) and C2CD4A/B (rs1370176, p = 3.677×10(-4), OR 1.124; rs1436953, p = 7.753×10(-6), OR 1.141; rs7172432, p = 4.001×10(-5), OR 1.134) in Han Chinese. CONCLUSIONS AND SIGNIFICANCE: Our study represents the first GWAS of T2D with both discovery and replication sample sets recruited from Han Chinese men and women residing in Mainland China. We confirmed the associations of KCNQ1 and C2CD4A/B with T2D, with the latter for the first time being examined in Han Chinese. Arguably, eight more independent loci were replicated in our GWAS.