Genetic variants in epoxyeicosatrienoic acid processing and degradation pathways are associated with gestational diabetes mellitus.

AIM: To explore the genetic effects of CYP2C8, CYP2C9, CYP2J2, and EPHX2, the key genes involved in epoxyeicosatrienoic acid processing and degradation pathways in gestational diabetes mellitus (GDM) and metabolic traits in Chinese pregnant women. METHODS: A total of 2548 unrelated pregnant women were included, of which 938 had GDM and 1610 were considered as controls. Common variants were genotyped using the Infinium Asian Screening Array. Association studies of single nucleotide polymorphisms (SNPs) with GDM and related traits were performed using logistic regression and multivariable linear regression analyses. A genetic risk score (GRS) model based on 12 independent target SNPs associated with GDM was constructed. Logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders including age, pre-pregnancy body mass index, history of polycystic ovarian syndrome, history of GDM, and family history of diabetes, with GRS entered both as a continuous variable and categorized groups. The relationship between GRS and quantitative traits was also evaluated. RESULTS: The 12 SNPs in CYP2C8, CYP2C9, CYP2J2, and EPHX2 were significantly associated with GDM after adjusting for covariates (all P < 0.05). The GRS generated from these SNPs significantly correlated with GDM. Furthermore, a significant interaction between CYP2J2 and CYP2C8 in GDM (PInteraction = 0.014, ORInteraction= 0.61, 95%CI 0.41-0.90) was observed. CONCLUSION: We found significant associations between GDM susceptibility and 12 SNPs of the four genes involved in epoxyeicosatrienoic acid processing and degradation pathways in a Chinese population. Subjects with a higher GRS showed higher GDM susceptibility with higher fasting plasma glucose and area under the curve of glucose and poorer ß-cell function.

Common single-nucleotide polymorphisms combined with a genetic risk score provide new insights regarding the etiology of gestational diabetes mellitus.

AIMS: Few studies have constructed a genetic risk score (GRS) to predict the risk of gestaional diabetes mellitus (GDM). We tested the hypothesis that single-nucleotide polymorphisms (SNPs) confirmed for diabetes and obesity and the GRS are associated with GDM. METHODS: We conducted a case-control study comprising 971 GDM cases and 1682 controls from the University of Hong Kong Shenzhen Hospital. A total of 1448 SNPs reported with type 2 diabetes (T2D), type 1 diabetes (T1D), and obesity were selected and the GRS based on SNPs associated with GDM was created. RESULTS: We confirmed that rs10830963 (OR = 1.41,95% CI = 1.25, 1.59) in MTNR1B and rs2206734 (OR = 1.38, 95% CI = 1.22, 1.55) in CDKAL1 were strongly associated with the risk of GDM. Compared with participants with GRS based on T2D SNPs in the low tertile, the ORs of GDM across increasing GRS tertiles were 1.63 (95% CI 1.29, 2.06) and 2.72 (95% CI 2.18, 3.38) in the middle and high tertile, respectively. The positive associations between the GRS and the risk of GDM were also observed in GRS based on obesity/waist-to-hip ratio (WHR)/body mass index (BMI) SNPs. The resulting GRS for each allele increase was significantly associated with higher glycemic indices and lower HOMA-B values for GRS based on T2D SNPs, but not for GRS based on T1D SNPs and GRS based on obesity/WHR/BMI SNPs. CONCLUSION: These findings indicate that GDM may share a common genetic background with T2D and obesity and that SNPs associated with insulin secretion defects have a vital role in the development of GDM.

GPSM1 in POMC neurons impairs brown adipose tissue thermogenesis and provokes diet-induced obesity.

OBJECTIVE: G-protein-signaling modulator 1 (GPSM1) has been proved the potential role in brain tissues, however, whether GPSM1 in hypothalamic nuclei, especially in POMC neurons is essential for the proper regulation of whole-body energy balance remains unknown. The aim of our current study was to explore the role of GPSM1 in POMC neurons in metabolic homeostasis. METHODS: We generated POMC neuron specific GPSM1 deficiency mice and subjected them to a High Fat Diet to monitor metabolic phenotypes in vivo. By using various molecular, biochemical, immunofluorescent, immunohistochemical analyses, and cell culture studies to reveal the pathophysiological role of GPSM1 in POMC neurons and elucidate the underlying mechanisms of GPSM1 regulating POMC neurons activity. RESULTS: We demonstrated that mice lacking GPSM1 in POMC neurons were protected against diet-induced obesity, glucose dysregulation, insulin resistance, and hepatic steatosis. Mechanistically, GPSM1 deficiency in POMC neurons induced enhanced autophagy and improved leptin sensitivity through PI3K/AKT/mTOR signaling, thereby increasing POMC expression and α-MSH production, and concurrently enhancing sympathetic innervation and activity, thus resulting in decreased food intake and increased brown adipose tissue thermogenesis. CONCLUSIONS: Our findings identify a novel function of GPSM1 expressed in POMC neurons in the regulation of whole-body energy balance and metabolic homeostasis by regulating autophagy and leptin sensitivity, which suggests that GPSM1 in the POMC neurons could be a promising therapeutic target to combat obesity and obesity-related metabolic disorders.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

The mediating role of maternal metabolites between lipids and adverse pregnancy outcomes of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy, and the demographics of pregnant women have changed in recent decades. GDM is a metabolic disease with short- and long-term adverse effects on both pregnant women and newborns. The metabolic changes and corresponding risk factors should be of great significance in understanding the pathological mechanism of GDM and reducing the incidence of adverse pregnancy outcomes in patients with GDM. The well-known GDM-associated lipids used in clinical tests, such as triglyceride (TG), are thought to play a major role in metabolic changes during GDM, which have a potential causal relationship with abnormal pregnancy outcomes of GDM. Therefore, this study analyzed the relationship between clinical lipid indicators, metabolic profiles, and abnormal pregnancy outcomes in GDM through mediation analysis. By constructing a metabolic atlas of 399 samples from GDM patients in different trimesters, we efficiently detected the key metabolites of adverse pregnancy outcomes and their mediating roles in bridging abnormal lipids and adverse pregnancy outcomes in patients with GDM. Our study confirmed that TG and total cholesterol were independent risk factors for adverse pregnancy outcomes in patients with GDM. Several key metabolites as mediators (e.g., gamma-linolenic acid, heptadecanoic acid, oleic acid, palmitic acid, and palmitoleic acid) have been identified as potential biomarkers for adverse pregnancy outcomes in patients with GDM. These metabolites mainly participate in the biosynthesis of unsaturated fatty acids, which may shed new light on the pathology of GDM and provide insights for further exploration of the molecular mechanisms underlying adverse pregnancy outcomes.

Discovery of metabolic biomarkers for gestational diabetes mellitus in a Chinese population.

BACKGROUND: Gestational diabetes mellitus (GDM), one of the most common pregnancy complications, can lead to morbidity and mortality in both the mother and the infant. Metabolomics has provided new insights into the pathology of GDM and systemic analysis of GDM with metabolites is required for providing more clues for GDM diagnosis and mechanism research. This study aims to reveal metabolic differences between normal pregnant women and GDM patients in the second- and third-trimester stages and to confirm the clinical relevance of these new findings. METHODS: Metabolites were quantitated with the serum samples of 200 healthy pregnant women and 200 GDM women in the second trimester, 199 normal controls, and 199 GDM patients in the third trimester. Both function and pathway analyses were applied to explore biological roles involved in the two sets of metabolites. Then the trimester stage-specific GDM metabolite biomarkers were identified by combining machine learning approaches, and the logistic regression models were constructed to evaluate predictive efficiency. Finally, the weighted gene co-expression network analysis method was used to further capture the associations between metabolite modules with biomarkers and clinical indices. RESULTS: This study revealed that 57 differentially expressed metabolites (DEMs) were discovered in the second-trimester group, among which the most significant one was 3-methyl-2-oxovaleric acid. Similarly, 72 DEMs were found in the third-trimester group, and the most significant metabolites were ketoleucine and alpha-ketoisovaleric acid. These DEMs were mainly involved in the metabolism pathway of amino acids, fatty acids and bile acids. The logistic regression models for selected metabolite biomarkers achieved the area under the curve values of 0.807 and 0.81 for the second- and third-trimester groups. Furthermore, significant associations were found between DEMs/biomarkers and GDM-related indices. CONCLUSIONS: Metabolic differences between healthy pregnant women and GDM patients were found. Associations between biomarkers and clinical indices were also investigated, which may provide insights into pathology of GDM.

Skeletal muscle-targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance.

Obesity, a major health care issue, is characterized by metabolic abnormalities in multiple tissues, including the skeletal muscle. Although dysregulation of skeletal muscle metabolism can strongly influence the homeostasis of systemic energy, the underlying mechanism remains unclear. We found promoter hypermethylation and decreased gene expression of fibroblast growth factor 6 (FGF6) in the skeletal muscle of individuals with obesity using high-throughput sequencing. Reduced binding of the cyclic AMP responsive element binding protein-1 (CREB1) to the hypermethylated cyclic AMP response element, which is a regulatory element upstream of the transcription initiation site, partially contributed to the downregulation of FGF6 in patients with obesity. Overexpression of Fgf6 in mouse skeletal muscle stimulated protein synthesis, activating the mammalian target of rapamycin pathway, and prevented the increase in weight and the development of insulin resistance in high-fat diet-fed mice. Thus, our findings highlight the role played by Fgf6 in regulating skeletal muscle hypertrophy and whole-body metabolism, indicating its potential in strategies aimed at preventing and treating metabolic diseases.

Intrahepatic Cholestasis of Pregnancy and Associated Adverse Maternal and Fetal Outcomes: A Retrospective Case-Control Study.

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy-related liver disease and is associated with an increased risk of adverse neonatal outcomes. Ursodeoxycholic acid (UDCA) is the most effective treatment. This study was aimed at investigating the adverse outcomes of ICP and evaluating the effects of treatment with UDCA in patients with ICP. METHODS: We included 114 women with ICP and 3725 women without ICP (no-ICP group) who delivered in our hospital between September 2017 and August 2019. The prevalence of ICP in this study was 3.15%. We matched each woman with ICP to five controls. Of all the 114 women with ICP, 73 (64.04%) received UDCA while 41 (35.96%) did not. Logistic multivariate regression analysis was used to compare the adverse outcomes between those with ICP and matched controls as well as between those who received UDCA (UDCA group) and those who did not (non-UDCA group). RESULTS: Compared with controls, women with ICP were more likely to have preeclampsia (adjusted odds ratio, aOR = 16.74, 95% CI 5.29-52.98), cesarean section (aOR = 1.76, 95% CI 1.10-2.81), and preterm birth (aOR = 24.35, 95% CI 2.74-216.67). Administration of UDCA reduced the rate of preterm birth (1.37% vs. 14.63%, aOR = 0.10, 95% CI 0.01-0.90). CONCLUSION: ICP increased the risk of preeclampsia, cesarean section, and preterm birth. UDCA could reduce the rate of preterm birth.

Serum growth differentiation factor 11 is closely related to metabolic syndrome in a Chinese cohort.

AIMS/INTRODUCTION: Despite increasing interest in growth differentiation factor 11 (GDF11) based on its involvement in age-related disorders, clinical implications - especially for metabolic diseases - remain unclear. Therefore, we assessed the association between serum GDF11 levels and metabolic disturbance in the Chinese population. MATERIALS AND METHODS: A total of 381 individuals from the Shanghai Nicheng Cohort Study were included. In addition to anthropometry, laboratory and ultrasonography measurements, serum concentrations of GDF11 were measured by enzyme-linked immunosorbent assay. RESULTS: Circulating GDF11 concentrations were unchanged with age (r = -0.064, P = 0.210), but showed an inverse relationship to body mass index, waist circumference and fat-free mass index (all P < 0.05). Correlation analysis showed decreased GDF11 concentrations accompanied by elevated diastolic blood pressure, fasting and 2-h plasma glucose, triglycerides, and low-density lipoprotein cholesterol after adjusting for sex, age and body mass index, whereas variations in aspartate aminotransferase and free thyroxine were consistent with GDF11 (all P < 0.05). Furthermore, people, especially men, with abnormal glycometabolism, body mass index and/or fat accumulation in the liver had lower serum levels of GDF11 (P < 0.05); an increase in metabolic syndrome morbidity along with the circulatory decline of GDF11 was found when stratified by GDF11-level quartiles (P-trend <0.001). Logistic regression showed that serum GDF11 levels were independently correlated with the presence of metabolic syndrome (odds ratio 0.665, 95% confidence interval 0.510-0.867, P = 0.003). CONCLUSIONS: We confirmed GDF11 as an endocrine factor playing a significant role in multiple metabolic processes and an indicator of metabolic syndrome in the Chinese population, particularly in males.

Nerve growth factor is closely related to glucose metabolism, insulin sensitivity and insulin secretion in the second trimester: a case-control study in Chinese.

OBJECTIVE: Inflammation-related factors have been shown to play a significant role throughout pregnancy. In this study, we aimed to explore the relationships between selected inflammatory cytokines and gestational diabetes (GDM) in Chinese pregnant women. DESIGN AND METHODS: This was a 1:1 matched case-control study that included 200 pairs of subjects in the second trimester and 130 pairs of subjects in the third trimester. Serum levels of nerve growth factor (NGF), Interleukin-6 (IL-6), leptin, Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) and Interleukin-1beta (IL-1ß) were measured by enzyme immunoassay. The associations of these inflammatory factors with metabolic parameters were analysed. RESULTS: In the second trimester, GDM patients had higher NGF levels and lower IL-8 levels than did normal controls (P < 0.001 and P = 0.015, respectively). However, in the third trimester, only lower leptin levels were observed in the GDM group (P = 0.031). Additionally, in the second trimester, NGF levels were not only positively associated with fasting, 1-h and 2-h glucose levels and the area under curve of glucose, but also positively related to insulin sensitivity and secretion, as suggested by fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment index of ß-cell secretion (HOMA-ß) (all P < 0.05). Moreover, IL-6 and leptin levels were positively correlated with HOMA-IR and HOMA-ß, and TNF-α levels were positively related to HOMA-IR (all P < 0.05). Except for the relationships between NGF and HOMA-ß and TNF-α and HOMA-IR, the other correlations still existed even after adjusting for confounding factors (all P < 0.05). CONCLUSION: In addition to the positive associations of IL-6 and leptin with insulin resistance and secretion, NGF was higher in the GDM patients and strongly linked to glucose metabolism, insulin resistance and pancreatic ß cell function in Chinese pregnant women in the second trimester.

Serum growth differentiation factor 15 is associated with glucose metabolism in the third trimester in Chinese pregnant women.

OBJECTIVE: Growth differentiation factor 15 (GDF15) has been demonstrated to increase in diabetes as a protective factor. However, studies assessing relationships between GDF15 levels and gestational diabetes mellitus (GDM) are limited. In this study, we aimed to investigate whether GDF15 levels are related to GDM in Chinese subjects. METHODS: We included 200 GDM patients and 200 matched normal controls in the second trimester as well as 130 GDM patients and 130 matched normal controls in the third trimester. Serum GDF15 levels of all participants were determined using an enzyme-linked immunosorbent assay (ELISA). Then, according to GDF15 levels, we equally divided the participants in the second and third trimesters into four subgroups respectively. The relationships of serum GDF15 levels with glucolipid metabolism indicators were analyzed. RESULTS: In the third trimester, GDF15 levels were significantly higher in the GDM patients than in the normal controls (P < 0.001). Additionally, fasting blood glucose (FBG), 1-h postprandial glucose (1h-PG), 2-h postprandial glucose (2h-PG), hemoglobin A1C (HbA1c) and area under curve of glucose (AUCG) from the 75-g oral glucose tolerance test (OGTT) were positively associated with GDF15 levels (P < 0.05), even after adjusting for age, pregestational BMI, changes of BMI until the third trimester, gestational age, twin and family history of diabetes. Moreover, GDF15 levels were higher in the third trimester than in the second trimester (P < 0.001). No significant relationships were found between GDF15 levels and glucolipid metabolism in the second trimester (P > 0.05). CONCLUSIONS: Serum GDF15 levels were positively correlated with glucose metabolism in the third trimester in Chinese pregnant women.