Metabolomic profiling reveals decreased serum cysteine levels during gestational diabetes mellitus progression.

Gestational diabetes mellitus (GDM) is a pregnancy-related metabolic disorder associated with short-term and long-term adverse health outcomes, but its pathogenesis has not been clearly elucidated. Investigations of the dynamic changes in metabolomic markers in different trimesters may reveal the underlying pathophysiology of GDM progression. Therefore, in the present study, we analyzed the metabolic profiles of 75 women with GDM and 75 women with normal glucose tolerance (NGT) throughout the three trimesters. We found that the variation trends of 38 metabolites were significantly different during GDM development. Specifically, longitudinal analyses revealed that cysteine (Cys) levels significantly decreased over the course of GDM progression. Further study showed that Cys alleviated GDM in female mice at gestational day 14.5 possibly by inhibiting phosphoenolpyruvate carboxykinase to suppress hepatic gluconeogenesis. Taken together, these findings suggest that the Cys metabolic pathway might play a crucial role in GDM and that Cys supplementation represents a potential new treatment strategy for GDM patients.

The effects of economic status on metabolic control in type 2 diabetes mellitus at 10 metabolic management centers in China.

OBJECTIVE: This study investigated the association of economic status with metabolic index control in type 2 diabetes mellitus (T2DM) patients. METHODS: In total, 37 454 T2DM patients from 10 National Metabolic Management Centers in China were recruited and categorized into two groups: a high-gross domestic product (GDP) group (n = 23 993) and a low-GDP group (n = 13 461). Sociodemographic characteristics, medical histories, and lifestyle factors were recorded. Logistic regression and interaction analysis were performed to evaluate the association of economic status and healthy lifestyle with metabolic control. RESULTS: Compared to the low-GDP group, there were fewer patients with glycated hemoglobin (HbA1c) levels ≥7% in the high-GDP group. Fewer patients with a high GDP had an abnormal metabolic state (HbA1c ≥ 7%, blood pressure [BP] ≥130/80 mm Hg, total cholesterol [TCH] ≥4.5 mmol/L or body mass index [BMI] ≥24 kg/m2 ). The risks of developing HbA1c ≥ 7% (odds ratios [OR] = 0.545 [95% CI: 0.515-0.577], p < .001), BP ≥ 130/80 mm Hg (OR = 0.808 [95% CI: 0.770-0.849], p < .001), BMI ≥ 24 kg/m2 (OR = 0.840 [95% CI: 0.799-0.884], p < .001), and an abnormal metabolic state (OR = 0.533 [95% CI: 0.444-0.636], p < .001) were significantly lower in the high-GDP group even after adjustment for confounding factors. Younger participants; those with a family history of diabetes, normal weight, and a physical activity level up to standard; and those who did not drink alcohol in the high-GDP group were predisposed to better glycemic levels. CONCLUSIONS: T2DM patients in economically developed regions had better metabolic control, especially glycemic control. A healthy lifestyle had an additive effect on achieving glycemic goals, even among high-GDP patients.

Neuronal Hyperactivity in the Hippocampus during the Early Stage of Streptozotocin-Induced Type 1 Diabetes in Mice.

INTRODUCTION: Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. METHODS: Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate were then measured using ultra-performance liquid chromatography with mass spectrometry. RESULTS: CA1 neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third, and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. CONCLUSION: Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention.

Correlation between bone mineral density and bone metabolic markers in postmenopausal women with osteoporotic fractures at different C-terminal telopeptide of type 1 collagen levels: a retrospective analysis study.

OBJECTIVE: This study aimed to analyze the correlation between bone mineral density (BMD) and bone resorption markers in postmenopausal women with osteoporosis fractures and identify risk factors for second fractures. METHODS: This retrospective analysis of 1,239 older women with fractures with a median age of 70 years who attended Shanghai General Hospital from January 2007 to December 2016, included a first fracture group (1,008 cases) and a second fractures group (231 cases). The risk factors for fractures were analyzed by comparing these groups on clinical characteristics, BMD, and bone metabolism markers stratified by quartiles of serum C-terminal telopeptide of type 1 collagen (CTX). Binary logistic regression analysis was used to identify risk factors for second fractures. RESULTS: In the whole sample, BMD was negatively correlated with age and serum osteocalcin and positively correlated with body mass index (BMI). In women with first fractures, those in the highest quartile of serum CTX had the lowest spine and hip BMD. Second fractures were significantly associated with BMI, lower spine and hip BMD, and higher serum osteocalcin but not CTX. Binary logistic regression analysis showed that high BMI (odds ratio [OR], 1.08 [95% CI, 1.03-1.14]; P = 0.001), low lumbar BMD (OR, 0.24 [95% CI, 0.07-0.82]; P = 0.023), low total hip BMD (OR, 0.05 [95% CI, 0.00-0.88]; P = 0.041), and lack of antiosteoporosis treatment (OR, 2.71 [95% CI, 2.71-4.08]; P < 0.001) were independent risk factors for second fractures. CONCLUSIONS: In older women with fractures, BMD was significantly lower in women with second fractures than in those with first fractures. Higher levels of serum CTX and osteocalcin, which indicates increased bone resorption, were negatively correlated with BMD. In women with a first fracture, serum CTX higher than 605 pg/mL was negatively correlated with BMD, whereas no correlation was found between different CTX and BMD in women with second fractures. High BMI and low BMD as well as not receiving antiosteoporosis treatment were independent risk factors for second fractures.

Interrelation between the lipid accumulation product index and diabetic kidney disease in patients with type 2 diabetes mellitus.

Objective: The purpose of this study was to determine the relation between the lipid accumulation product index (LAPI) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: Herein, 931 patients were enrolled and their data were collected. Then the interrelation between LAPI and DKD was assessed using multivariate logistic regression analyses (LRAs) and by a restricted cubic spline (RCS). Results: In total, 931 participants (352 females and 579 males) aged 55 years on average were included in the study. After adjusting for several confounders, the odds ratio for DKD was increased evidently in the third LAPI tertile compared with that in the first LAPI tertile. In addition, the RCS revealed a positive interrelation between LAPI and DKD. In the subgroup analyses, age, sex, hyperlipidemia, hypertension, and HbA1c did not significantly interact with LAPI. Conclusions: LAPI was higher in the DKD group than in the no-DKD group, and LAPI is positively linked with DKD, which may have potential value to diagnose DKD in clinical practice.

Safety Event Outcomes and Glycemic Control with a Hybrid Closed-Loop System Used by Chinese Adolescents and Adults with Type 1 Diabetes Mellitus.

Background: While evidence supports glycemic control benefits for individuals with type 1 diabetes mellitus (T1DM) using hybrid closed-loop (HCL) systems, HCL automated insulin delivery therapy in China has not been assessed. This study evaluated safety events and effectiveness during HCL system use by Chinese adolescents and adults with T1DM. Methods: Sixty-two participants (n = 12 adolescents with a mean ± standard deviation [SD] of 15.5 ± 1.1 years and n = 50 adults [mean ± SD of 37.6 ± 11.1 years]) with T1DM and baseline A1C of 7.1% ± 1.0% underwent a run-in period (∼2 weeks) using open-loop Manual Mode (sensor-augmented pump) insulin delivery with the MiniMed™ 770G system with the Guardian™ Sensor (3) glucose sensor, followed by a study period (4 weeks) with HCL Auto Mode enabled. Analyses compared continuous glucose monitoring data and insulin delivered during the run-in versus study period (Wilcoxon signed-rank test or t-test). Safety events included rates of severe hypoglycemia and diabetic ketoacidosis (DKA). Results: Compared to baseline run-in, overall Auto Mode use increased time in range (TIR, 70-180 mg/dL) from 75.3% to 80.9% (P < 0.001) and reduced time below range (TBR, <70 mg/dL) from 4.7% to 2.2% (P < 0.001). Subgroup analysis demonstrated that participants (n = 29) with baseline A1C <7.0% had TBR that reduced from 5.6% to 2.0%, while participants (n = 21) with baseline A1C ≥7.5% had time above range (TAR, >180 mg/dL) that reduced from 31.6% to 20.8%. Auto Mode use also increased the percentage achieving combined recommendations for time at sensor glucose ranges (i.e., TIR of >70%, TBR of <4% and TAR of <25%) from 24.2% at baseline to 77.4% at study end. Total daily insulin dose reduced from 42.8 ± 19.8 to 40.7 ± 18.9 U (P = 0.013). There were no severe hypoglycemic, DKA, or serious adverse events. Conclusions: Chinese adolescents and adults, some of whom met target A1C at baseline, safely achieved significantly improved glycemia with 1 month of MiniMed 770G system use when compared to open-loop insulin delivery. ClinicalTrials.gov ID: NCT04663295.

Risk factors of primary and recurrent fractures in postmenopausal osteoporotic Chinese patients: A retrospective analysis study.

BACKGROUND: As postmenopausal osteoporotic fractures can cause higher rates of disability and mortality in women; it is essential to analyze the factors associated with primary and recurrent fractures in postmenopausal osteoporosis (PMOP) patients. METHODS: Retrospective analysis of 2478 PMOP patients aged ≥ 50 years who attended the Shanghai General Hospital from January 2007 to December 2016, including 1239 patients with no fractures and 1239 patients with histories of fractures (1008 in the primary fracture group and 231 in the re-fracture group). All patients' basic clinical data, serum biochemical and bone metabolic markers, bone mineral density (BMD), and other indicators were recorded uniformly. Comparing the differences between the clinical characteristics of patients with primary and recurrent fractures, as well as the differences in the clinical characteristics of patients with primary and recurrent fractures in combination with different diseases, further analyses the risk factors for primary and recurrent fractures in PMOP patients. SPSS.26 was used for statistical analysis. RESULTS: Compared to the unfractured group, the fractured group was older and had lower height and bone mineral density (all P < 0.01), with the re-fractured group having lower BMD at each key site than the primary fracture group (all P < 0.01). Analysis of the combined disease subgroups showed that serum BGP levels were lower in the primary and re-fracture patients with diabetes than in the non-diabetic subgroup (P < 0.05), and serum CTX levels were lower in the re-fracture group with diabetes than in the primary fracture group with diabetes (P < 0.05). Patients with recurrent fractures with cardio-vascular diseases had lower BMD than the subgroup without cardio-vascular diseases (P < 0.05) and also had lower BMD than the group with primary fractures with cardio-vascular diseases (P < 0.05). Multiple logistic regression analysis showed that advanced age, overweight, low lumbar spine and total hip BMD were risk factors for primary and recurrent fractures; and comorbid chronic liver and kidney diseases were risk factors for primary fractures. CONCLUSION: PMOP patients with advanced age, overweight, low bone mineral density, and comorbid chronic liver and kidney diseases are at greater risk of fractures and require early intervention to reduce fractures occurrence. Moreover, those who are elderly, overweight, and have low bone density should also be aware of the risk of re-fractures.

Association between use of liraglutide and liver fibrosis in patients with type 2 diabetes.

Objective: Patients with type 2 diabetes have a high risk of non-alcoholic fatty liver disease (NAFLD) and related liver fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated efficacy in improving NAFLD, while their effectiveness on liver fibrosis is limited in type 2 diabetic patients. Materials/Methods: A prospective cohort study was performed in type 2 diabetic patients. The study subjects were divided into two groups based on the use of liraglutide or not, and propensity score matching (PSM) was also conducted. After 12 months follow-up, liver fibrosis was assessed by NAFLD fibrosis score (NFS) fibrosis-4 (FIB-4), and liver stiffness measurement (LSM). The association between liraglutide use and liver fibrosis was analyzed by multivariable linear regression. Results: In the current study, a total of 1,765 type 2 diabetic patients were enrolled. 262 patients were liraglutide user and 1,503 were nouser. After 12 months follow-up, liraglutide use tended to be associated with reduced prevalence of advanced fibrosis (3.1% vs. 6.1%, P = 0.218). After adjustment for confounding factors, multivariable linear regression revealed that liraglutide use was negatively associated with decreased NFS (ß= -0.34, P = 0.043), FIB4 (ß= -0.26, P = 0.044) and LSM (ß= -4.95, P = 0.007) in type 2 diabetics. The results after PSM were similar to those before PSM. Conclusions: Liraglutide treatment is associated with decreased liver fibrosis in type 2 diabetic subjects.

Association between Chinese visceral adiposity index and metabolic-associated fatty liver disease in Chinese adults with type 2 diabetes mellitus.

Objective: The purpose of the study was to determine the correlation of the Chinese visceral adiposity index (CVAI) with metabolic-associated fatty liver disease (MAFLD) in Chinese adults with type 2 diabetes mellitus (T2DM). Materials/methods: In this cross-sectional study, data on sociodemographic characteristics, laboratory test results, coexisting diseases, and medical therapy were collected and analyzed. Multivariate logistic regression analyses were used to examine the correlation between CVAI and MAFLD. In order to investigate the correlation between CVAI on a continuous scale and MAFLD, a restricted cubic spline (RCS) was used. Results: A total of 679 participants were included in this study. There were 251 female participants and 428 male participants, with a median age of 55 years. In the multivariate logistic regression model, diastolic blood pressure, duration of diabetes, glycated hemoglobin, hemoglobin, alanine transaminase, aspartate aminotransferase, gamma -glutamyl transferase, albumin, blood urea nitrogen, total cholesterol, low-density lipoprotein cholesterol, statin use and metformin use were adjusted, and an evident increase in the odds ratios of MAFLD from the lowest to the highest CVAI quartile was found (P value for trend < 0.001). Moreover, the RCS curves revealed a positive correlation between CVAI and MAFLD. Conclusions: The CVAI is positively correlated with MAFLD and may be an indicator with diagnostic value for MAFLD in clinical practice in type 2 diabetic patients.

High Serum FABP4 Levels are Negatively Associated with the Reversion from Prediabetes to Normal Glucose Tolerance: A 2-Year Retrospective Cohort Community Study.

Objective: To explore the relationship between the level of fatty acid-binding protein 4 (FABP4) and reversion from prediabetes to normal glucose tolerance (NGT). Methods: A two-year retrospective cohort study was conducted on 398 participants with complete information. These 398 participants were divided into an NGT group and an abnormal glucose metabolism (AGM) group after 2 years of follow-up. The baseline level of FABP4 was determined, and the role of FABP4 in predicting reversion from prediabetes to NGT was investigated using an unconditional logistic regression model. Results: Over the two-year follow-up period, 37.4% (149/398) of the participants reverted from prediabetes to NGT. The participants with AGM had a higher baseline level of FABP4 than those with NGT. The baseline level of FABP4 was significantly negatively correlated with reversion from prediabetes to NGT. After adjusting for age, sex, body mass index and waist-to-hip ratio, the level of fasting blood glucose (FBG) [odds ratio (OR) 0.336, 95% confidence interval (CI) (0.196-0.576)], 2-h post-challenge blood glucose (2hBG) [OR 0.697, 95% CI (0.581-0.837)], and FABP4 [OR 0.960, 95% CI (0.928-0.993)] at baseline were significant independent predictors of reversion from prediabetes to NGT. The area under the curve (AUC) value of the receiver operating characteristic curve for FABP4 was 0.605 (95% CI: 0.546-0.665), and the AUC for FABP4 combined with FBG and 2hBG was 0.716 (95% CI: 0.663-0.769). Conclusion: A higher baseline level of FABP4 was positively correlated with an adverse profile of diabetes risk factors and negatively correlated with reversion from prediabetes to NGT. FABP4, FBG and 2hBG were predictors of reversion from prediabetes to NGT.

Prevalence of and risk factors for diabetic retinopathy in residents with different types of abnormal glucose metabolism with or without hypertension: A suburban community-based cross-sectional study.

Aims: The present study examined the prevalence and risk factors for diabetic retinopathy (DR) in residents with abnormal glucose metabolism in a community. Methods: 6029 subjects were included and underwent standardized interviews and comprehensive examinations. Residents with diabetes were divided into nondiabetic retinopathy (NDR) and DR groups and non-hypertension and hypertension groups. Unconditional multivariate logistic regression models were used to analyze the risk factors for DR in different groups. Results: The prevalence of DR in diabetes was 9.9%, and the prevalence of retinopathy, which also has the typical signs of DRs, such as retinal microaneurysms, in prediabetes and normal glucose tolerance was 5.2% and 5.3%, respectively. An elevated waist-to-hip ratio (WHR) (female≥0.85, male≥0.9)[OR 1.683, 95% CI (1.016, 2.790)], systolic blood pressure (SBP)≥140 mmHg [OR 1.875, 95% CI (1.158, 3.034)], elevated HbA1c [OR 1.410, 95% CI (1.220, 1.629)], HbA1c ≥6.5% [OR 2.149, 95% CI (1.320, 3.498)], antidiabetic drug use [OR 3.798, 95% CI (2.209, 6.529)], elevated fasting blood glucose [OR 1.176, 95% CI (1.072, 1.289)], elevated postprandial blood glucose [OR 1.090, 95% CI (1.033, 1.150)] and nonspecific ST-T segment changes on electrocardiography [OR 2.555, 95% CI (1.556, 4.196)] were risk factors for DR. Duration of diabetes [OR 1.206, 95% CI (1.028, 1.415)], elevated WHR [OR 3.796, 95% CI (1.144, 12.603)], elevated waist circumference [OR 6.874, 95% CI (1.403, 33.665)], elevated HbA1c [OR 1.435, 95% CI (1.046, 1.970)], HbA1c ≥6.5% [OR 6.850, 95% CI (1.771, 26.501)], and concurrent metabolic syndrome [OR 3.975, 95% CI (1.144, 13.815)] were risk factors for DR in diabetes without hypertension, and elevated HbA1c [OR 1.395, 95% CI (1.183, 1.645)], HbA1c ≥6.5% [OR 1.745, 95% CI (1.027, 2.966)], use of antidiabetic drugs [OR 4.781, 95% CI (2.624, 8.711)], elevated fasting blood glucose [OR 1.146, 95% CI (1.034, 1.270)], elevated postprandial blood glucose [OR 1.083, 95% CI (1.020, 1.151)], and nonspecific ST-T segment changes on electrocardiography [OR 2.616, 95% CI (1.531, 4.469)] were risk factors for DR in diabetes with hypertension. Conclusion: Retinopathy was found in subjects with normal glucose tolerance and prediabetes. There were differences in risk factors for DR in diabetic patients with and without hypertension.

Comparative efficacy and safety of two insulin aspart formulations (Rapilin and NovoRapid) when combined with metformin, for patients with diabetes mellitus: a multicenter, randomized, open-label, controlled clinical trial.

OBJECTIVE: This phase 3 confirmatory diabetes mellitus treatment study compared the safety and efficacy of Rapilin and NovoRapid insulin asparts in combination with metformin. METHODS: This 24-week, open-label, randomized, active-controlled, noninferiority phase 3 confirmatory study conducted across centers in China aimed to enroll patients with type 2 diabetes mellitus and blood sugar glucose inadequately controlled by oral antidiabetic drugs. Randomized patients received subcutaneous mealtime Rapilin or NovoRapid (3:1) injections, with metformin. The primary objectives were to demonstrate noninferiority (margin of 0.4%) in HbA1c change from baseline and compare safety profiles of Rapilin versus NovoRapid after 24 weeks. Secondary outcomes included 2-h postprandial plasma glucose (PPG), fasting plasma glucose (FPG), and patients achieving HbA1c <7.0% and ≤6.5%. RESULTS: 590 patients with type 2 diabetes mellitus were randomized to Rapilin (n = 441) and NovoRapid (n = 149) groups. After 24 weeks, the mean HbA1c change from baseline was -2.20% (Rapilin) and -2.32% (NovoRapid); the estimated treatment difference based on least-square means was 0.04% (95% CI: -0.17, 0.26), meeting the noninferiority criteria for Rapilin versus NovoRapid. Comparable improvements were reported for mean 2-hour PPG (6.14 and 6.29 mmol/L), FPG (2.02 and 1.70 mmol/L), and patients with HbA1c <7.0% (52.6% and 51.0%) and ≤6.5% (34.2% and 30.9%), in the Rapilin and NovoRapid groups, respectively, with no significant safety or immunogenicity outcome differences. CONCLUSIONS: Rapilin demonstrated non-inferior glycemic control, and matching safety and immunogenicity to NovoRapid in patients with type 2 diabetes mellitus also receiving metformin over 24 weeks. TRIAL REGISTRATION: ChiCTR20003129041.

Association Between High-Sensitivity C-Reactive Protein and Diabetic Kidney Disease in Patients With Type 2 Diabetes Mellitus.

Objective: High-sensitivity C-reactive protein (hs-CRP) is an inflammatory marker. This study aimed to identify the correlation between hs-CRP levels and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Materials/Methods: This cross-sectional and observational study included 927 patients with T2DM. We collected the data of patients based on their medical data, including sociodemographic characteristics, concomitant diseases, laboratory results, and medical therapy. Multivariate logistic regression analysis was conducted to assess the relationship between hs-CRP levels and DKD. A restricted cubic spline (RCS) was used to assess the correlation of hs-CRP levels on a continuous scale with the DKD. Results: In total, 927 patients were recruited in our study. The median age of the recruited patients was 55 years, and there were 346 female patients and 581 male patients. The hs-CRP levels were evidently higher in patients with DKD than those without DKD. After adjusting for age, sex, diastolic blood pressure, systolic blood pressure, body mass index, neck circumference, waist circumference, hypertension, duration of diabetes, common carotid artery plaque, fasting plasma glucose, glycated hemoglobin, hemoglobin, erythrocyte, leukocyte, γ-glutamyl transferase, albumin, urea nitrogen, uric acid and triglyceride, a significant increase in the odds ratios (ORs) for DKD in the fourth hs-CRP quartile compared with the first quartile was observed (P value for trend= 0.003), and the ORs (95% confidence intervals) in the fourth quartile of hs-CRP were 1.968 (1.244-3.114) for DKD compared to the first quartile.. Moreover, the RCS curves presented a positive association between hs-CRP and DKD in total subjects, male subjects and female subjects, respectively. Conclusions: The results of our study indicated that hs-CRP levels were significantly and positively correlated with the presence of DKD, which may provide predictive and diagnostic values in clinical practice.

DUAL I China: Improved glycemic control with IDegLira versus its individual components in a randomized trial with Chinese participants with type 2 diabetes uncontrolled on oral antidiabetic drugs.

BACKGROUND: DUAL I China, one of the DUAL trials, assessed efficacy/safety of insulin degludec/liraglutide (IDegLira) in Chinese adults with type 2 diabetes (T2D) not controlled by oral antidiabetic drugs (OADs). METHODS: This phase 3a, treat-to-target multicenter trial randomized participants (glycated hemoglobin [HbA1c] 53.0-85.8 mmol/mol; previous metformin ± another OAD) 2:1:1 to IDegLira (n = 361), degludec (n = 179), or liraglutide (n = 180). Primary endpoint was change in HbA1c after 26 weeks. Secondary endpoints included: HbA1c < 53.0 mmol/mol attainment, weight change, treatment-emergent hypoglycemia, end-of-treatment insulin dose, and safety. RESULTS: At 26 weeks, HbA1c had decreased by a mean 18.12 mmoL/moL (IDegLira), 12.37 mmoL/moL (degludec) (estimated treatment difference [ETD] -6.50 mmoL/moL; 95% confidence interval [CI] -7.96, -5.04; P < .0001), and 11.33 mmoL/moL (liraglutide) (ETD -6.87 mmoL/moL; 95% CI -8.33, -5.41; P < 0.0001), indicating noninferiority for IDegLira vs degludec and superiority vs liraglutide. HbA1c < 53.0 mmoL/moL attainment was 77.0% (IDegLira), 46.4% (degludec), and 48.3% (liraglutide). Mean weight change with IDegLira (0.1 kg) was superior to degludec (1.2 kg) (ETD -1.08 kg; 96% CI -1.55, -0.62; P < 0.0001). Severe or confirmed hypoglycemic event rates were 0.24 (IDegLira) and 0.17 (degludec) episodes/participant-year (estimated rate ratio 1.46; 95% CI 0.71, 3.02; P = .3008, not significant). At the end of treatment, the IDegLira insulin dose was lower (24.5 U/d) vs degludec (30.3 U/d) (ETD -5.49 U; 95% CI -7.77, -3.21; P < 0.0001). No unexpected safety issues occurred. CONCLUSIONS: IDegLira is efficacious and well tolerated in Chinese adults with T2D not controlled by OADs.

Consistently Low Levels of Osteocalcin From Late Pregnancy to Postpartum Are Related to Postpartum Abnormal Glucose Metabolism in GDM Patients.

Objective: Increasing evidence suggests that osteocalcin (OC), a marker of bone formation, plays an important role in glucose homoeostasis. Few studies have investigated the relationship between OC levels in gestational diabetes mellitus (GDM) patients and their postpartum glucose metabolism. This study evaluated the relationship between OC levels in late pregnancy, their longitudinal changes, and postpartum glucose metabolism among GDM patients. Measures: Serum OC was measured in late pregnancy and the postpartum period for 721 GDM patients. All patients underwent a 75-g oral glucose tolerance test (OGTT) at 6-8 weeks postpartum. According to postpartum OGTT outcomes, patients were categorized into abnormal glucose metabolism (AGM) (n=255) and normal glucose tolerance (NGT) groups (n=466). Glucose metabolism-related indices were measured and calculated. Logistic regression analysis and linear mixed-effects model were used to assess the association between OC and postpartum AGM. Results: In late pregnancy, OC levels were lower in the AGM group than in the NGT group (13.93 ± 6.90 vs 15.33 ± 7.63 ng/ml, P=0.015). After delivery, OC levels increased in both groups. However, OC levels remained lower in the AGM group than in the NGT group (23.48 ± 7.84 vs 25.65 ± 8.37 ng/ml, P=0.001). Higher OC levels in late pregnancy were associated with decreased risk of progressing to postpartum AGM (OR:0.96, 95%CI:0.94-0.99). Linear mixed-effects analysis showed that postpartum AGM patients exhibited consistently lower OC levels than NGT group from late pregnancy to the postpartum period after adjustment for cofactors (ß=-1.70, 95% CI: -2.78- -0.62). Conclusions: In GDM patients, consistently low levels of OC from late pregnancy to postpartum were associated with increased postpartum AGM risk. The increase in serum OC may act as a protective factor to curb the progression of AGM at postpartum for GDM patients.

Fat mass and obesity-associated protein promotes liver steatosis by targeting PPARα.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The fat mass and obesity-associated protein (FTO) has been shown to be involved in obesity; however, its role in NAFLD and the underlying molecular mechanisms remain largely unknown. METHODS: FTO expression was first examined in the livers of patients with NAFLD and animal and cellular models of NAFLD by real-time PCR and Western blotting. Next, its role in lipid accumulation in hepatocytes was assessed both in vitro and in vivo via gene overexpression and knockdown studies. RESULTS: FTO expression was obviously elevated in the livers of mice and humans with hepatic steatosis, probably due to its decreased ubiquitination. FTO overexpression in HepG2 cells induced triglyceride accumulation, whereas FTO knockdown exerted an opposing effect. Consistent with the findings of in vitro studies, adeno-associated viruses 8 (AAV8)-mediated FTO overexpression in the liver promoted hepatic steatosis in C57BL/6J mice. Mechanistically, FTO inhibited the mRNA of peroxisome proliferator-activated receptor α (PPARα) in hepatocytes. Activation of PPARα by its agonist GW7647 reversed lipid accumulation in hepatocytes induced by FTO overexpression. CONCLUSIONS: Overall, FTO expression is increased in NAFLD, and it promotes hepatic steatosis by targeting PPARα.

Factors associated with progression of different prediabetic status to Diabetes: A Community-based cohort study.

AIMS: To examine the predictive factors associated with the progression of different prediabetic status to diabetes. METHODS: A two-year retrospective cohort study was conducted on 5741 participants aged 40 years or older. Finally, 1685 participants with prediabetes defined by IFG (impaired fasting glucose), IGT (impaired glucose tolerance) and CGI (combined IFG and IGT) were included. Logistic regression model was used to evaluate the risk of prediabetes progression to diabetes. RESULTS: Of the 1685 subjects with prediabetes at baseline, 212 (12.6%) subjects progressed to diabetes and 1473 (87.4%) subjects did not. Logistic regression analysis demonstrated that people with CGI were associated with an increased risk of progressing to diabetes compared to those with IFG (OR, 95% CI: 3.127, 2.047-4.776). Moreover, males, obese people, people with increased BMI and WHR (Waist/ Hip ratio), and hypertension were positively associated with the progression to diabetes, while HOMA-ß was negatively associated with the progression to diabetes. CONCLUSIONS: Subjects with CGI are prone to progressed to diabetes compared to those with IFG or IGT in middle-aged and older person in China. More attention should be paid to male and obese prediabetic subjects, and measures should be taken to control the increase in their BMI and WHR.

Effects of dehydroepiandrosterone alone or in combination with a high-fat diet and antibiotic cocktail on the heterogeneous phenotypes of PCOS mouse models by regulating gut microbiota.

Objective: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disease. The gut microbiota is highly correlated with androgen secretion and insulin resistance (IR), which are two potential major pathogenic mechanisms of PCOS. Currently, an antibiotic cocktail (ABX) is often used to construct pseudo germ-free mouse models for studies on the gut microbiota and PCOS. Our work aimed to study the effects of dehydroepiandrosterone (DHEA), a high-fat diet (HFD) and ABX on the heterogeneous phenotypes of PCOS mouse models by regulating the gut microbiota. Methods: PCOS mouse models were established by subcutaneous injection of DHEA alone or in combination with a HFD in wild-type and pseudo germ-free mice. The changes in ovary morphology and sex hormonal and glycolipid metabolic parameters were evaluated. Results: Wild-type mice treated with DHEA or DHEA+HFD showed a PCOS-like phenotype of hyperandrogenism, anovulation and polycystic ovaries. The former was combined with hyperinsulinemia and IR, while the latter was combined with glucolipid metabolic disorders, extremely heterogeneous hyperinsulinemia and IR. The phenotype of PCOS mice, especially the metabolic parameters, was correlated with the gut microbiota. The pseudo germ-free mice treated with DHEA or DHEA+HFD also showed a PCOS-like phenotype. However, DHEA could not induce hyperinsulinemia or IR in pseudo germ-free mice. Pseudo germ-free mice treated with DHEA+HFD exhibited decreased serum AMH level, glucolipid metabolic disorders and IR. Compared with the wild-type mice, the pseudo germ-free mice treated with DHEA showed significantly higher testosterone and lipid levels and lower blood glucose levels, and they did not present with hyperinsulinemia or IR. Conclusion: A better and stabilized mouse model simulating the pathophysiological defects of PCOS was induced by DHEA alone rather than by DHEA+HFD. The ABX intervention improved glucose metabolic disorders and hyperinsulinemia but aggravated the hyperandrogenism and lipid metabolic disorders of the PCOS mice. This study suggests that the gut microbiota plays an important role in the heterogeneous phenotypes of PCOS mouse models.

Serum spexin differed in newly diagnosed type 2 diabetes patients according to body mass index and increased with the improvement of metabolic status.

Objective: The aim of this study was to explore serum spexin levels in newly diagnosed type 2 diabetes mellitus (T2DM) patients with different body mass indexes (BMIs) and to investigate the changes of spexin after improvement of metabolic indicators. Methods: A total of 323 newly diagnosed T2DM patients from national Metabolic Management Center (MMC) in Shanghai General Hospital were recruited. T2DM patients were categorized into three groups: diabetes with obesity group (DM-OB group, BMI≥28 kg/m2, n=89), diabetes with overweight group (DM-OV group, 24≤BMI<28 kg/m2, n=161), and diabetes with normal weight group (DM-NW group, 18≤BMI<24 kg/m2, n=73). In addition, 41 volunteers with normal glucose tolerance (NGT) were used as controls. Spexin and metabolic parameters were compared at baseline, and changes after MMC follow-up in 100 DM patients were investigated. Results: In the DM-OB group, the level of spexin was significantly lower than that in the DM-OV group and the DM-NW group (P < 0.01). Spexin was significantly negatively related to body mass index (BMI, ß=-0.214, P<0.001), waist circumference (ß=-0.249, P<0.001), visceral fat area (VFA, ß=-0.214, P<0.001), and subcutaneous fat area (SFA, ß=-0.265, P<0.001) after adjustment for age and sex. Among all the metabolic indicators, the decline in BMI in the DM-OB group was the most obvious among those in the three groups (-3.7 ± 0.8 kg/m2 vs. -0.9 ± 0.3 kg/m2 vs. 0.7 ± 0.6 kg/m2, P<0.01) after one year of MMC standardized management. The serum spexin level in the DM-OB group increased the most (1.00 ± 0.10 ng/mL vs. 0.49 ± 0.06 ng/mL in DM-OV group and 0.58 ± 0.09 ng/mL in DM-NW group, P < 0.001). Conclusions: Serum spexin differed in newly diagnosed T2DM patients according to BMI and was lowest in the DM-OB group. With the improvement of metabolic indicators, especially the decline in BMI, serum spexin increased significantly after MMC management.

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study.

Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.