The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain–gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3–V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus, were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain–gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes.

Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, P<0.001), hemoglobin A1c (HbA1c, r=-0.632, P<0.001), triglyceride (TG, r=-0.236, P<0.001) and low density lipoprotein-cholesterol (LDL-C, r=-0.382, P<0.001). A negative correlation of blood glucose with spexin was observed during oral glucose tolerance test (OGTT). Spexin is intensely expressed in normal human endocrine and epithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM.

Objective: Recent studies demonstrate circulating serum spexin levels are reduced in obesity or type 2 diabetes mellitus (T2DM) patients and may play a role in glucose metabolism. The mechanism underlying is not known. In this study, we explore whether spexin has a role in insulin resistance and hepatic glucose metabolism.Methods: The correlation between serum spexin levels and the homeostasis model assessment of insulin resistance (HOMA-IR) was studied in newly diagnosed T2DM patients. After intraperitoneal injection of exogenous spexin for 8 weeks, the effect of spexin on exogenous glucose infusion rates (GIR), and hepatic glucose production (HGP) were assessed by extended hyperinsulinemic-euglycemic clamp in high-fat-diet (HFD)-induced rats. Glucose concentration with CRISPR/Cas9-mediated disruption of spexin expression in HepG2 cells culture was observed. Expression of transcription factors (Forkhead box O1, FoxO1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1α) and key enzymes (G-6-Pase and PEPCK) of gluconeogenesis pathway were observed in vitro and in vivo.Results: The serum spexin level was significantly low in newly diagnosed T2DM patients as compared with healthy patients and significantly negatively correlated with the HOMA-IR values. Exogenous spexin treatment resulted in weight loss and decrease of HOMA-IR value in high-fat-diet (HFD)-induced rats. The exogenous glucose infusion rates (GIR) were higher in the HFD + spexin group than that in the HFD group (358 ± 32 vs. 285 ± 24 μmol/kg/min, P < 0.05). Steady-state hepatic glucose production (HGP) was also suppressed by ~50% in the HFD + spexin group as compared with that in the HFD group. Furthermore, spexin inhibited gluconeogenesis in dose-dependent and time-dependent manner in the insulin-resistant cell model. CRISPR/Cas9-mediated knockdown of spexin in HepG2 cells activated gluconeogenesis. Moreover, spexin was shown regulating gluconeogenesis by inhibiting FoxO1/PGC-1α pathway, and key gluconeogenic enzymes, (PEPCK and G-6-Pase) in both HFD-induced rats and insulin-resistant cells.Conclusions: Spexin plays an important role in insulin resistance in HFD-induced rats and insulin-resistant cells. Regulation of the effects of spexin on insulin resistance may hold therapeutic value for metabolic diseases.

The study is aimed to investigate the pathogenesis underlying the increased prevalence of thyroid nodule (TN) in different levels of metabolic syndrome (MetS) components and analyze the relationships between TN and MetS components. A total of 6,798 subjects, including 2201 patients with TN, were enrolled in this study. Anthropometric, biochemical, thyroid ultrasonographic, and other metabolic parameters were all measured. There was obviously sexual difference in the prevalence of TN (males 26.0%, females 38.5%, resp.). The prevalence of TN in hyperuricemia (45.7% versus 37.4%, P = 0.001), NAFLD (41.2% versus 36.4%, P < 0.05), and MetS (41.4% versus 35.4%, P < 0.001) groups was significantly increased only in females. Insulin resistance [OR = 1.31 (1.15, 1.49)], MetS [OR = 1.18 (1.03, 1.35)], and diabetes [OR = 1.25 (1.06, 1.48)] were all independent risk factors for TN in total subjects, whereas, after stratified analysis of gender, MetS [OR = 1.29, (1.09, 1.53)] and diabetes [OR = 1.47, (1.17, 1.84)] are still strongly and independently associated with the higher risks of TN in female subjects, but not in males. Our results suggest that the components of MetS might associate with the higher risks of TN in women than in men, but further cohort study of this gender disparity in the association between TN and MetS is required.

BackgroundProstate cancer represents the leading cause of male death across the world. A recent genome-wide association study (GWAS) identified five novel susceptibility loci for prostate cancer in the Japanese population. This study is to replicate and fine map the potential association of these five loci with prostate cancer in the Chinese Han population.MethodsIn Phase I of the study, we tested the five single nucleotide polymorphisms (SNPs) which showed the strongest association evidence in the original GWAS in Japanese. The study sample consists of 1,169 Chinese Hans, comprising 483 patients and 686 healthy controls. Then in phase II, flanking SNPs of the successfully replicated SNPs in Phase I were genotyped and tested for association with prostate cancer to fine map those significant association signals.ResultsWe successfully replicated the association of rs13385191 (located in the C2orf43 gene, P = 8.60×10−5), rs12653946 (P = 1.33×10−6), rs1983891 (FOXP4, P = 6.22×10−5), and rs339331 (GPRC6A/RFX6, P = 1.42×10−5) with prostate cancer. The most significant odds ratio (OR) was recorded as 1.41 (95% confidence interval 1.18–1.68) for rs12653946. Rs9600079 did not show significant association (P = 8.07×10−2) with prostate cancer in this study. The Phase II study refined these association signals, and identified several SNPs showing more significant association with prostate cancer than the very SNPs tested in Phase I.ConclusionsOur results provide further support for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in Eastern Asian populations. This study also characterized the novel loci reported in the original GWAS with more details. Further work is still required to determine the functional variations and finally clarify the underlying biological mechanisms.

Placental amino acid transporters and peroxisome proliferator-activated receptors (PPARs) have been implicated to placental development and therefore regulation of fetal growth. We analyzed the correlation between the expression of amino acid transporters and PPARs and investigated whether PPARs control the expression of amino acid transporters in placentas. It was found that protein expression of PPARγ and L-type amino acid transporter 1(LAT1) and 2 (LAT2) was decreased in small-for-gestational-age (SGA) placentas. LAT1, LAT2 and taurine transporter (TAUT) expression correlated to PPARγ level and birth weight. In cultured placental cells, PPARγ agonist stimulated LAT1 and LAT2 and TAUT, which was reversed by PPARγ siRNA. PPARγ up-regulation of LAT1 and TAUT was through specificity protein 1 (Sp-1) while stimulation of LAT2 expression was via induction of gene transcription. Our data suggest that PPARγ, SP-1, LAT1 and LAT2 in placentas are involved in control of fetal growth. PPARγ signaling pathway may be the therapeutic target for intrauterine growth restriction.

The objectives of the study were to investigate serum ANGPTL8 concentrations in different glucose metabolic statuses and to explore the correlations between serum ANGPTL8 levels and various metabolic parameters. Serum ANGPTL8 levels were determined using ELISA in 22 subjects with NGT (normal glucose tolerance), 74 subjects with IGR (impaired glucose regulation), and 33 subjects with T2DM (type 2 diabetes mellitus). Subjects with IFG, IGT, CGI, and T2DM had higher levels of serum ANGPTL8 than subjects with NGT. Serum ANGPTL8 was positively correlated with FPG, fasting C-peptide, and postprandial C-peptide and negatively correlated with BETA/IR when adjusted for age and BMI. Multivariate analysis suggested FPG and fasting C-peptide as independent factors associated with serum ANGPTL8 levels. Serum ANGPTL8 concentrations were significantly increased in IGR and T2DM. Serum ANGPTL8 might play a role in the pathological mechanism of glucose intolerance.