Xinhua Xiao

Berberine Moderates Glucose and Lipid Metabolism through Multipathway Mechanism

Berberine is known to improve glucose and lipid metabolism disorders, but the mechanism is still under investigation. In this paper, we explored the effects of berberine on the weight, glucose levels, lipid metabolism, and serum insulin of KKAy mice and investigated its possible glucose and lipid-regulating mechanism. We randomly divided KKAy mice into two groups: berberine group (treated with 250 mg/kg/d berberine) and control group. Fasting blood glucose (FBG), weight, total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), and fasting serum insulin were measured in both groups. The oral glucose tolerance test (OGTT) was performed. RT2 PCR array gene expression analysis was performed using skeletal muscle of KKAy mice. Our data demonstrated that berberine significantly decreased FBG, area under the curve (AUC), fasting serum insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR) index, TC, and TG, compared with those of control group. RT2 profiler PCR array analysis showed that berberine upregulated the expression of glucose transporter 4 (GLUT4), mitogen-activated protein kinase 14 (MAPK14), MAPK8(c-jun N-terminal kinase, JNK), peroxisome proliferator-activated receptor α (PPARα), uncoupling protein 2 (UCP2), and hepatic nuclear factor 4α(HNF4α), whereas it downregulated the expression of PPARγ, CCAAT/enhancer-binding protein (CEBP), PPARγ coactivator 1α(PGC 1α), and resistin. These results suggest that berberine moderates glucose and lipid metabolism through a multipathway mechanism that includes AMP-activated protein kinase-(AMPK-) p38 MAPK-GLUT4, JNK pathway, and PPARα pathway.

Low Birth Weight is Associated With Components of the Metabolic Syndrome

The purpose of the study was to investigate the association between birth weight and number of metabolic syndrome (MetS) components in an urban Chinese cohort. Individuals (N = 2019) who were born between 1921 and 1954 at the Peking Union Medical College Hospital and who had detailed obstetric records volunteered to take part and were examined by medical personnel in a clinical setting between May 2003 and April 2005. Data of birth outcome and results on clinic examination in adulthood were analyzed using analysis of variance and multivariate ordinal regression to estimate the association between birth weight and MetS. Metabolic syndrome was defined as per the National Cholesterol Education Program Adult Treatment Panel III. The prevalence of MetS was 26.74%, whereas 55.43% of the subjects had at least 2 components of MetS. Subjects who presented with all 5 components of MetS exhibited a significantly lower birth weight and higher age, body mass index, and waist circumference at follow-up. Multivariate ordinal regression analysis revealed that, as compared with those with birth weights of 3000 to 3500 g, subjects who had birth weights of less than 2500 g were 66% more likely to develop a greater number of MetS components in adulthood (95% confidence interval, 1.18-2.34; P = .004), whereas those with birth weights between 2500 and 3000 g were 33% more likely to develop a greater number of MetS components as adults (95% confidence interval, 1.09-1.63; P = .005). The present study demonstrated the relationship between low birth weight and increased presentation of MetS components in Chinese adults.

Imbalance of Fecal Microbiota at Newly Diagnosed Type 1 Diabetes in Chinese Children.

Background:Recent studies have indicated that an imbalance of gut microbiota is associated with the development of type 1 diabetes mellitus (T1DM) and there is no literature regarding it in Chinese children yet. The aim of this study was to evaluate the alteration of gut microbiota between children with newly diagnosed T1DM and healthy controls and to determine if gut microbiota could partly explain the etiology of this disease. Methods:A case-control study was carried out with 15 children with T1DM and 15 healthy children. The fecal bacteria composition was investigated by high-throughput sequencing of the V3–V4 region of the 16S rDNA gene and analyzed by the estimators of community richness (Chao) indexes. Results:There was a notable lower richness of fecal bacteria in T1DM group than controls (156.53 ± 36.96 vs. 130.0 ± 32.85, P = 0.047). At the genus level, the composition of Blautia was increased in T1DM group than control group whereas the composition of Haemophilus, Lachnospira, Dialister, and Acidaminococcus was decreased. In addition, we found that the percentage of Blautia was correlated positively with HbA1c (&rgr; = 0.40, P = 0.031), the numbers of T1DM autoantibodies (&rgr; = 0.42, P = 0.023), and the titers of tyrosine phosphatase autoantibodies (IA-2) (&rgr; = 0.82, P = 0.000) in the study. Conclusions:This study showed that gut microbiota was associated with the development of T1DM by affecting the autoimmunity, and the results suggested a potential therapy for T1DM via modulating the gut microbiota.

Novel insights into DNA methylation and its critical implications in diabetic vascular complications

Recent epidemiological and clinical studies have shown that type 2 diabetic patients can develop diabetic vascular complications even after intensive glycaemic control. It has been suggested that this phenomenon could be explained by the hypothesis of ‘metabolic memory’. The underlying mechanisms between these enduring effects and the prior hyperglycaemic state are still not well understood. Preliminary studies demonstrate that hyperglycaemia can regulate gene expression by epigenetic modifications, such as DNA methylation, which can persistently exist even after glucose normalization. Increasing evidence shows that epigenetic mechanisms may play a substantial role in the pathophysiology of diabetes and its associated vascular complications, including atherosclerosis, diabetic cardiomyopathy (DCM), nephropathy and retinopathy. In this review, we will examine the growing role of DNA methylation in diabetes and its vascular complications, thus it can provide critical implications for the early prevention of diabetes and its vascular complications.

The programming effects of nutrition-induced catch-up growth on gut microbiota and metabolic diseases in adult mice.

Substantial evidence indicated that catch‐up growth could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes mellitus in adulthood. However, investigations into the “programming” effects of catch‐up growth on gut microbiota in the offspring are limited. C57/BL6 mice were fed on either low protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the offspring were randomly weaned to either NC or high fat (HF) diet until 32 weeks of age, generating four experimental groups: NC‐NC, NC‐HF, LP‐NC, and LP‐HF. Metabolic parameters and gut microbiota were examined in the offspring. It showed that the NC‐HF and LP‐HF offspring displayed higher body weight (P < 0.05), impaired glucose tolerance (P < 0.001), and elevated serum lipids (P < 0.05) at 32 weeks of age. Both the operational taxonomic units (OTUs) and the Shannon indexes (P < 0.05) showed significantly lower microbial diversity in NC‐HF and LP‐HF offspring. There were significant variations in the compositions of gut microbiota in the NC‐HF and LP‐HF offspring, compared with NC‐NC offspring (P < 0.05). Furthermore, it indicated Lactobacillus percentage was negatively associated with blood glucose concentrations of intraperitoneal glucose tolerance test (r = −0.886, P = 0.019). In conclusion, catch‐up growth predisposes the offspring to gut microbiota perturbation, obesity, impaired glucose tolerance, insulin resistance, and dyslipidemia. Our study is novel in showing the “programming” effects of nutrition‐induced catch‐up growth on gut microbiota and metabolic diseases in later life.

The Placental Microbiota Is Altered among Subjects with Gestational Diabetes Mellitus: A Pilot Study

Gestational diabetes mellitus (GDM) has significant implications for the future health of the mother and child. However, the associations between human placental microbiota and GDM are poorly understood. We aimed to profile the placental microbiota of GDM and further define whether or not certain placental microbiota taxon correlates with specific clinical characteristics. Placenta were collected from GDM women and women with normal pregnancies (n = 10, in each group) consecutively recruited at Peking Union Medical College Hospital. The anthropometric parameters of mother and infant, and cord blood hormones, including insulin, leptin and insulin-like growth factor-1 (IGF-1) were measured. Bacterial genomic DNA was isolated using magnetic beads and the human placental microbiota was analyzed using the Illumina MiSeq Sequencing System based on the V3-V4 hypervariable regions of the 16S rRNA gene. It showed there was no statistical difference in the clinical characteristics of mothers and infants, such as BMI at the beginning of pregnancy and gestational weight gain (GWG), birth weight, and cord blood hormones, including insulin, leptin and IGF-1. We found that the placental microbiota is composed of four dominant phyla from Proteobacteria (the most abundant), Bacteroidetes, Actinobacteria and Firmicutes, with the proportion of Proteobacteria increased, and Bacteroidetes and Firmicutes were decreased of women with GDM. Further analyses suggested that bacterial taxonomic composition of placentas from the phylum level down to the bacteria level, differed significantly between women with GDM and non-GDM women with normal pregnancies. Regression analysis showed a cluster of key operational taxonomic units (OTUs), phyla and genera were significantly correlated with GWG during pregnancy of mothers, and cord blood insulin, IGF-1 and leptin concentrations. In conclusion, our novel study showed that a distinct placental microbiota profile is present in GDM, and is associated with clinical characteristics of mothers and infants. This study contributes to the theoretical foundation on the potential relationship between placental microbiota and GDM.

Dietary Chromium Restriction of Pregnant Mice Changes the Methylation Status of Hepatic Genes Involved with Insulin Signaling in Adult Male Offspring

Maternal undernutrition is linked with an elevated risk of diabetes mellitus in offspring regardless of the postnatal dietary status. This is also found in maternal micro-nutrition deficiency, especial chromium which is a key glucose regulator. We investigated whether maternal chromium restriction contributes to the development of diabetes in offspring by affecting DNA methylation status in liver tissue. After being mated with control males, female weanling 8-week-old C57BL mice were fed a control diet (CON, 1.19 mg chromium/kg diet) or a low chromium diet (LC, 0.14 mg chromium/kg diet) during pregnancy and lactation. After weaning, some offspring were shifted to the other diet (CON-LC, or LC-CON), while others remained on the same diet (CON-CON, or LC-LC) for 29 weeks. Fasting blood glucose, serum insulin, and oral glucose tolerance test was performed to evaluate the glucose metabolism condition. Methylation differences in liver from the LC-CON group and CON-CON groups were studied by using a DNA methylation array. Bisulfite sequencing was carried out to validate the results of the methylation array. Maternal chromium limitation diet increased the body weight, blood glucose, and serum insulin levels. Even when switched to the control diet after weaning, the offspring also showed impaired glucose tolerance and insulin resistance. DNA methylation profiling of the offspring livers revealed 935 differentially methylated genes in livers of the maternal chromium restriction diet group. Pathway analysis identified the insulin signaling pathway was the main process affected by hypermethylated genes. Bisulfite sequencing confirmed that some genes in insulin signaling pathway were hypermethylated in livers of the LC-CON and LC-LC group. Accordingly, the expression of genes in insulin signaling pathway was downregulated. There findings suggest that maternal chromium restriction diet results in glucose intolerance in male offspring through alterations in DNA methylation which is associated with the insulin signaling pathway in the mice livers.

Two unrelated Chinese patients with hyperinsulinism /hyperammonemia (HI/HA) syndrome due to mutations in glutamate dehydrogenase gene.

BACKGROUND Hyperinsulinism/ hyperammonemia (HI/HA) syndrome is caused by excessive activity of glutamate dehydrogenase (GDH) encoded by GLUD1 gene, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. So GDH is important in normal glucose homeostasis. Mutations of GDH result in HI/ HA syndrome. METHODS We have performed protein (leucine) and fat loading test on one patient. We detected the level of serum glucose, insulin and blood ammonia. Genomic DNA of the two patients and their parents is isolated from blood and the exons of GLUD1 gene are amplified by polymerase chain reaction (PCR) for direct sequencing. RESULTS The leucine diet can evocate hypoglycemia obviously. Two heterozygous mutations c.978G>A (R269H) and c.1506C>T (S445L) are identified, respectively. These are both de novo. For one patient, a better blood glucose level can be gained from leucine-restriction diet, and without diazoxide while, for the other patient, diazoxide is necessary. CONCLUSIONS The heterozygous mutations in GLUD1 gene can cause HI/HA syndrome, it is sensitive to the leucine. The diazoxide and leucine-restriction diet do well in controlling the blood glucose level.

Relationship between birth head circumference and adulthood quality of life in Chinese people

Aim:  To determine the relationship between birth size and later QOL for Chinese people.

The association of the PAX4 gene with type 1 diabetes in Han Chinese

AIMS In present study, we aimed to evaluate whether the paired box gene 4 (PAX4) may play a role in the pathogenesis of type 1 diabetes (T1D) in Chinese Han population. METHODS One hundred and thirty-four cases with T1D and 324 non-diabetic control subjects were selected randomly from Han Chinese. Three tag single nucleotide polymorphisms (SNPs, rs712701, rs2233580, rs2233575) according to HapMap data were selected to analyze. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype. RESULTS No difference was found in genotype or allele frequencies between patients and non-diabetic controls in all three SNPs. No difference was found in common haplotypes constructed by these three SNPs, either. For the SNP rs2233575, in non-diabetic controls, the carriers with AA and GA genotypes had lower plasma insulin level than the subjects with GG genotype (P=0.048). CONCLUSIONS The present study identified that the PAX4 gene was not associated with the risk of T1D in a Han Chinese sample, suggesting that it is unlikely to have a major effect on the susceptibility to T1D in this population. This is the first study on the PAX4 gene in a Chinese population.