Potential contribution of the gut microbiota to hypoglycemia after gastric bypass surgery / 中华医学杂志(英文版)

Obesity has become a global health problem. Lifestyle modification and medical treatment only appear to yield short-term weight loss. Roux-en-Y gastric bypass (RYGB) is the most popular bariatric procedure, and it sustains weight reduction and results in the remission of obesity-associated comorbidities for obese individuals. However, patients who undergo this surgery may develop hypoglycemia. To date, the diagnosis is challenging and the prevalence of post-RYGB hypoglycemia (PRH) is unclear. RYGB alters the anatomy of the upper gastrointestinal tract and has a combined effect of caloric intake restriction and nutrient malabsorption. Nevertheless, the physiologic changes after RYGB are complex. Although hyperinsulinemia, incretin effects, dysfunction of β-cells and α-cells, and some other factors have been widely investigated and are reported to be possible mediators of PRH, the pathogenesis is still not completely understood. In light of the important role of the gut microbiome in metabolism, we hypothesized that the gut microbiome might also be a critical link between RYGB and hypoglycemia. In this review, we mainly highlight the current possible factors predisposing individuals to PRH, particularly related to the gut microbiota, which may yield significant insights into the intestinal regulation of glucose metabolic homeostasis and provide novel clues to improve the treatment of type 2 diabetes mellitus.

Early-life nutrition and metabolic disorders in later life: a new perspective on energy metabolism / 中华医学杂志(英文版)

Type 2 diabetes mellitus and metabolic disorders have become an epidemic globally. However, the pathogenesis remains largely unclear and the prevention and treatment are still limited. In addition to environmental factors during adulthood, early life is the critical developmental window with high tissue plasticity, which might be modified by external environmental cues. Substantial evidence has demonstrated the vital role of early-life nutrition in programming the metabolic disorders in later life. In this review, we aim to overview the concepts of fetal programming and investigate the effects of early-life nutrition on energy metabolism in later life and the potential epigenetic mechanism. The related studies published on PubMed database up to March 2020 were included. The results showed that both maternal overnutrition and undernutrition increased the riskes of metabolic disorders in offspring and epigenetic modifications, including DNA methylation, miRNAs, and histone modification, might be the vital mediators. The beneficial effects of early-life lifestyle modifications as well as dietary and nutritional interventions on these deleterious metabolic remolding were initially observed. Overall, characterizing the early-life malnutrition that reshapes metabolic disease trajectories may yield novel targets for early prevention and intervention and provide a new point of view to the energy metabolism.

DNA Methylation and Birth Weight: a Genome-wide Analysis / 生物医学与环境科学（英文）

The study illustrate the inner correlation between global DNA methylation variation and different birth weights. Infant birth weight was used to identify cases and controls. Cord blood and placentas were collected. We performed DNA methylation profiling of bisulphite-converted DNA. We have identified many differentially methylated CpG sites in experimental groups; these sites involved in hundreds of signalings. Among these, more than ten pathways were referred to the glucose and lipid metabolism. Methylation changes in the insulin-signaling pathway (ISP), adipocytokine signaling pathway (ASP) and MAPK signaling pathway are involved in the fetal programming of diabetes..

Imbalance of Fecal Microbiota at Newly Diagnosed Type 1 Diabetes in Chinese Children / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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 (ρ = 0.40, P = 0.031), the numbers of T1DM autoantibodies (ρ = 0.42, P = 0.023), and the titers of tyrosine phosphatase autoantibodies (IA-2) (ρ = 0.82, P = 0.000) in the study.</p><p><b>CONCLUSIONS</b>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.</p>

Positive Association Between Type 2 Diabetes Risk Alleles Near CDKAL1 and Reduced Birthweight in Chinese Han Individuals / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Fetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKAL1, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population.</p><p><b>METHODS</b>Twelve single nucleotide polymorphisms (rs7756992/rs10946398 in CDKAL1, rs1111875 in HHEX, rs391300 in SRR, rs17584499 in PTPRD, rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5) were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed.</p><p><b>RESULTS</b>Birthweight was inversely associated with CDKAL1-rs10946398 (β = -41 g [95% confidence interval [CI]: -80, -3], P = 0.034), common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight (β = -36 g [95% CI: -72, -0.2], P = 0.048). The risk allele in SRR showed a trend toward a reduction of birthweight (P = 0.085).</p><p><b>CONCLUSIONS</b>This study identified the association between type 2 diabetes risk variants in CDKAL1 and birthweight in Chinese Han individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.</p>

Chromium-containing traditional Chinese medicine, Tianmai Xiaoke Tablet improves blood glucose through activating insulin-signaling pathway and inhibiting PTP1B and PCK2 in diabetic rats / 中西医结合学报

<p><b>OBJECTIVE</b>Chromium is an essential mineral that is thought to be necessary for normal glucose homeostasis. Numerous studies give evidence that chromium picolinate can modulate blood glucose and insulin resistance. The main ingredient of Tianmai Xiaoke (TMXK) Tablet is chromium picolinate. In China, TMXK Tablet is used to treat type 2 diabetes. This study investigated the effect of TMXK on glucose metabolism in diabetic rats to explore possible underlying molecular mechanisms for its action.</p><p><b>METHODS</b>Diabetes was induced in rats by feeding a high-fat diet and subcutaneously injection with a single dose of streptozotocin (50 mg/kg, tail vein). One week after streptozotocin-injection, model rats were divided into diabetic group, low dose of TMXK group and high dose of TMXK group. Eight normal rats were used as normal control. After 8 weeks of treatment, skeletal muscle was obtained and was analyzed using Roche NimbleGen mRNA array and quantitative polymerase chain reaction (qPCR). Fasting blood glucose, oral glucose tolerance test and homeostasis model assessment of insulin resistance (HOMA-IR) index were also measured.</p><p><b>RESULTS</b>The authors found that the administration of TMXK Tablet can reduce the fasting blood glucose and fasting insulin level and HOMA-IR index. The authors also found that 2 223 genes from skeletal muscle of the high-dose TMXK group had significant changes in expression (1 752 increased, 471 decreased). Based on Kyoto encyclopedia of genes and genomes pathway analysis, the most three significant pathways were "insulin signaling pathway", "glycolysis/gluconeogenesis" and "citrate cycle (TCA)". qPCR showed that relative levels of forkhead box O3 (FoxO3), phosphoenolpyruvate carboxykinase 2 (Pck2), and protein tyrosine phosphatase 1B (Ptp1b) were significantly decreased in the high-dose TMXK group, while v-akt murine thymoma viral oncogene homolog 1 (Akt1) and insulin receptor substrate 2 (Irs2) were increased.</p><p><b>CONCLUSION</b>Our data show that TMXK Tablet reduces fasting glucose level and improves insulin resistance in diabetic rats. The mechanism may be linked to the inactivation of PTP1B and PCK enzymes, or through intracellular pathways, such as the insulin signaling pathway.</p>

The association between common genetic variation in the FTO gene and metabolic syndrome in Han Chinese / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Genome-wide association studies for type 2 diabetes mellitus (T2DM) identified FTO gene as a locus conferring increased risk for common obesity in many populations with European ancestry. However, the involvement of FTO gene in obesity or T2DM related metabolic traits has not been consistently established in Chinese populations. The objective of this study was to investigate the association of FTO genetic polymorphisms with metabolic syndrome (MetS) in Han Chinese.</p><p><b>METHODS</b>We tested 41 FTO single nucleotide polymorphisms (SNPs) for association between FTO and MetS-related traits. There were a total of 236 unrelated subjects (108 cases and 128 controls), grouped according to the International Diabetes Federation (IDF) criteria.</p><p><b>RESULTS</b>Of the 41 SNPs examined, only SNP rs8047395 exhibited statistical significance (P = 0.026) under a recessive model, after Bonferroni adjustment for multiple testing (OR 1.64, 95%CI 1.11-2.42; P = 0.014). The common distributions of this polymorphism among Chinese--with a minor allele frequency (MAF) of 36% in the control group versus 48% in the MetS group--greatly improved our test power in a relatively small sample size for an association study. Previously identified obesity- (or T2DM-) associated FTO SNPs were less common in Han Chinese and were not associated with MetS in this study. No significant associations were found between our FTO SNPs and any endophenotypes of MetS.</p><p><b>CONCLUSIONS</b>A more common risk-conferring variant of FTO for MetS was identified in Han Chinese. Our study substantiated that genetic variations in FTO locus are involved in the pathogenesis of MetS.</p>

Relationship between perinatal characteristics and later activities of daily living in Chinese elderly people / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>There are no reports on the association between perinatal characteristics and comprehensive physical function in Chinese elderly people. In this study, we traced 875 subjects who were born at the Peking Union Medical College Hospital (PUMCH) of China from 1921 to 1941. The purpose of this study was to determine the effects of perinatal characteristics on activities of daily living (ADL) function in the geriatric period.</p><p><b>METHODS</b>Birth data of 875 subjects were obtained from obstetric birth records of PUMCH. Adulthood data collection was conducted in the outpatient clinics of PUMCH. During the clinic visits, trained research staff administered physical examinations, activities of daily living scale and a demographic questionnaire. ADLs of all subjects were assessed with the activities of daily living scale.</p><p><b>RESULTS</b>There were 101 subjects whose ADL function was limited and the rate of ADL limitation was 11.5%. Binary logistic regression analyses results showed that the main influencing factors of ADL were age, maternal age at birth, occupation, daily exercise and chronic disease. Subjects whose maternal age at their birth exceeded 35 years were at 2.202 times (1.188 - 4.083) greater risk of ADL limitation when we applied multivariate logistic regression models.</p><p><b>CONCLUSIONS</b>This study validated the relationship between perinatal characteristics and ADL in the geriatric period. An older maternal age at birth could predict a higher ADL limitation rate in the geriatric period.</p>

Effects of glucagon on islet beta cell function in patients with diabetes mellitus / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To evaluate islet beta cell response to intravenous glucagon (a non-glucose secretagogue) stimulation in diabetes mellitus.</p><p><b>METHODS</b>Nineteen patients with type 1 diabetes (T1D) and 131 patients with type 2 diabetes (T2D) were recruited in this study. T2D patients were divided into two groups according to therapy: 36 cases treated with insulin and 95 cases treated with diet or oral therapy. The serum C-peptide levels were determined at fasting and six minutes after intravenous injection of 1 mg of glucagon.</p><p><b>RESULTS</b>Both fasting and 6-minute post-glucagon-stimulated C-peptide levels in T1D patients were significantly lower than those of T2D patients (0.76 +/- 0.36 ng/mL vs. 1.81 +/- 0.78 ng/mL, P < 0.05; 0.88 +/- 0.42 ng/mL vs. 3.68 +/- 0.98 ng/mL, P < 0.05). In T1D patients, the C-peptide level after injection of glucagon was similar to the fasting level. In T2D, patients treated with diet or oral drug had a significantly greater fasting and stimulated C-peptide level than those patients received insulin therapy (2.45 +/- 0.93 ng/mL vs. 1.61 +/- 0.68 ng/mL, P < 0.05; 5.26 +/- 1.24 ng/mL vs. 2.15 +/- 0.76 ng/mL, P < 0.05). The serum C-peptide level after glucagon stimulation was positively correlated with C-peptide levels at fasting in all three groups (r = 0.76, P < 0.05).</p><p><b>CONCLUSIONS</b>The 6-minute glucagon test is valuable in assessing the function of islet beta cell in patients with diabetes mellitus. It is helpful for diagnosis and treatment of diabetes mellitus.</p>

Influence of short-term high-fat diet on glucose and lipid metabolism in male Han Chinese with type 2 diabetes mellitus / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the influence of short-term high-fat diet (HFD) on glucose and lipid metabolism in male Han Chinese with type 2 diabetes mellitus (T2DM).</p><p><b>METHODS</b>Middle-aged T2DM men supported with solely diet or diet and metformin were enrolled into the study. The design was an unblinded crossover design. Each of the subjects randomly received one from two types of isocalorie (8786.4 kJ/d) standard diet for three consecutive days on two occasions, with a 6-week wash-out period in between. The component ratios of fat, carbohydrate, and protein were 50%, 35%, and 15% vs. 25%, 60%, and 15% in patients administered with HFD or high carbohydrate diet (HCD). The 24-hour blood samples during the third day were collected. On the morning of the forth day an intravenous glucose tolerance test (IVGTT) was conducted with 25g of glucose.</p><p><b>RESULTS</b>According to the determination results of 24-hour profile samples, HFD resulted in a markedly increased circulating level of non-esterified fatty acid (NEFA) as compared to HCD (P < 0.001). Nearly significant higher (P = 0.056) FPG was observed 72 hours after the administration of HFD. Circulating insulin levels were comparable between the two diets. A significantly higher HDL-C was also observed after HFD administration (P < 0.05). As assessed by the IVGTT, acute insulin response of glucose (AIRg) tended to increase after the HFD administration (P = 0.06). Fasting plasma glucagons (GLG) level and AUC(Glucagon) during breakfast period (8:00-12:00) were significantly higher after HFD administration than that of after HCD administration.</p><p><b>CONCLUSIONS</b>Short-term HFD induced the increase of NEFA with lower glucose exposure to the patietns. Fasting plasma glucose increased at the fourth day without remarkable changes of insulin levels which may be due to the increase of hepatic glucose output after HFD administration. The short-term HFD in our study induced early stage of insulin resistance. GLG seemed to play a role in this procedure. beta-cell dysfunction may need a longer high NEFA exposure.</p>

Association between A1168C polymorphism in PAX4 gene and type 1 diabetes in Han Chinese / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore whether A1168C polymorphisms in paired box gene 4 (PAX4) are associated with type 1 diabetes mellitus (T1DM) in Chinese Han population.</p><p><b>METHODS</b>Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype A1168C polymorphisms in PAX4 gene. Totally 109 patients with T1DM and 251 control subjects were recruited. The frequency distributions of genotypes between two groups were analyzed by SPSS software.</p><p><b>RESULTS</b>The genotype distributions were in Hardy-Weinberg equilibrium both among T1DM cases and control subjects. No difference was observed in the genotype frequencies and allele frequencies between T1DM cases and control subjects (P > 0.05), nor was any disease association detected when patients were stratified according to age at diagnosis or sex (P > 0.05).</p><p><b>CONCLUSION</b>The A1168C single nucleotide polymorphism in PAX4 gene may not play an essential role in genetic T1DM susceptibility in Chinese Han population.</p>

Relationship between hemoglobin A1c and blood glucose throughout the day in well-glycemic-controlled medical nutrition therapy alone type 2 diabetic patients / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the relationship between glycosylated hemoglobin A1c (HbA1c) and blood glucose levels of eight different points throughout the day in well-glycemic-controlled medical nutrition therapy (MNT) alone type 2 diabetic patients.</p><p><b>METHODS</b>Data were collected as' capillary blood glucose value of eight different sample points among sixteen observing days in thirty MNT alone type 2 diabetic patients. The correlation between HbA1c and capillary blood glucose value was evaluated by Pearson's correlation method.</p><p><b>RESULTS</b>The r-values between HbA1c and capillary blood glucose of 3:00, 6:00, and bedtime (22:00-23:00) were 0.81, 0.79, and 0.78, respectively (P < 0.001). The best correlation was found between the mean value of 8-point blood glucose value throughout the day and HbA1c (r = 0.84, P < 0.001).</p><p><b>CONCLUSION</b>Fasting blood glucose and postabsorptive blood glucose have better correlations with HbA1c compared with other points in this group of well-glycemic-controlled MNT alone type 2 diabetic patients.</p>

Effects of vitamin D receptor gene polymorphisms on susceptibility to type 1 diabetes mellitus / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes mellitus (T1DM) in the Chinese Han population.</p><p><b>METHOD</b>One hundred and thirty-six Chinese Han people, including 54 T1DM patients and 82 unrelated healthy subjects as control were genotyped by polymerase chain reaction-restriction fragment length polymorphism for three restriction sites in the VDR gene, which were ApaI, TaqI, and BamI.</p><p><b>RESULTS</b>The frequency of B allele of BsmI site in VDR gene was significantly higher in T1DM patients than in healthy subjects (P = 0.033) while no difference was found between the two groups in the distribution of ApaI and TaqI polymorphisms.</p><p><b>CONCLUSION</b>The BsmI polymorphism of VDR gene may be associated with the susceptibility to T1DM in the Chinese Han population of Beijing.</p>

Association analysis of 30 type 2 diabetes candidate genes in Chinese Han population / 中国医学科学院学报

<p><b>OBJECTIVE</b>To identify the susceptibility genes of type 2 diabetes in Chinese Han population.</p><p><b>METHODS</b>Single nucleotide polymorphism (SNP) discovery, genotyping and haplotype construction were performed in 30 candidate genes. Case-control study were carried out in a population-based sample and confirmed by the transmission disequilibrium test (TDT) analysis in 77 trio pedigrees. The effects of the SNP rs5210 on gene expression were studied by reporter gene technique.</p><p><b>RESULTS</b>The case-control studies showed that several SNPs on KCNJ11 gene was associated with type 2 diabetes in Chinese Han population, in which the allele frequency of SNP rs5219, the genotype frequency of rs5210, rs2285676 and rs5219, and the frequency of haplotype GA combined of the rs5219 and rs5215 showed significant difference between these two groups (P < 0.05). In addition, TDT test also showed statistical significance on this haplotype GA (P < 0. 05). The reporter gene assay showed that the effect on gene expression was significantly different between two alleles of rs5210 (P < 0.05).</p><p><b>CONCLUSION</b>KCNJII gene is one of the susceptibility genes of type 2 diabetes in Chinese Han population.</p>

Construction and identification of recombinant firefly luciferase reporter plasmid pGL2-PEPCK-Luc / 中国医学科学院学报

<p><b>OBJECTIVE</b>To evaluate in vitro regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene promoter on gene transcription, and construct luciferase reporter plasmid pGL2-PEPCK-Luc.</p><p><b>METHODS</b>A 550 bp fragment of PEPCK promoter cut from plasmid pPEPCK-int was inserted into transitional vector PBS-SK to construct a transition plasmid PBS-PEPCK. Then the recombinant luciferase reporter plasmid pGL2-PEPCK-Luc was cloned.</p><p><b>RESULTS</b>Restriction enzymes and nucleotide sequence conformed that the coupling site of recombinant plasmid was correct without base mutation and deletion, and the sequence inserted was the same as data of GeneBank. The luciferase could be expressed in hepatoma cell transfected by pGL2-PEPCK-Luc.</p><p><b>CONCLUSION</b>Established a new means to study transcriptional regulation of PEPCK promoter.</p>

Effect of insulin, cAMP, and dexamethasone on phosphoenolpyruvate carboxykinase gene promoter in vitro / 中国医学科学院学报

<p><b>OBJECTIVE</b>To study the effect of insulin, cyclic adenosine monophosphate (cAMP), and dexamethasone (DEX) on 550 bp (-600 -/+ 69) fragment of phosphoenolpyruvate carboxykinase (PEPCK) gene promoter by reporter gene.</p><p><b>METHODS</b>The recombinant pGL2-PEPCK-Luc and the control plasmid pSV-beta-Galactosidase were co-transfected to rat hepatoma cell line (CBRH7919) by lipofectin. By measuring luciferase activity, we evaluated in vitro regulation of PEPCK gene promoter on reporter gene transcription.</p><p><b>RESULTS</b>cAMP and DEX stimulated PEPCK promoter obviously; meanwhile, they also had accumulative effects. At different physiological concentrations, insulin had a suppressive effect on PEPCK promoter, which was dose-independent.</p><p><b>CONCLUSION</b>There is a perfect feedback mechanism for PEPCK promoter in hepatoma cell. 550 bp (-600 -/+ 69) fragment of PEPCK may be a candidate gene in the gene therapy of diabetes.</p>

Evaluation of enzymatic method for determination of serum beta-hydroxybutyrate and its clinical application / 中国医学科学院学报

<p><b>OBJECTIVE</b>To evaluate an enzymatic method for determining serum beta-hydroxybutyrate (beta-HB) with the National Committee for Clinical Laboratory Standards (NCCLS) projects, and to discuss its clinical values in diabetic ketoacidosis (DKA).</p><p><b>METHODS</b>The precision, accuracy, specificity, linearity and interference of the enzymatic method were analyzed. This method was used to determine serum beta-HB in 60 cases of normals, 50 cases of diabetes, and 34 cases of DKA by autochemistry analyzer.</p><p><b>RESULTS</b>Enzymatic beta-HB assay was precise (within-run CV, day-to-day CV, and total CV < 5%). The linearity studies showed the method was linear up to 4 mmol/L. Recovery rate was 98.5%-104.1%. Hemolysis (Hemoglobin up to 18.2 g/L), icteric samples with total bilirubin up to 224 mumol/L, and lipemia up to triglyceride concentration of 2.28 mmol/L did not interfere with the beta-HB results in this method. Serum beta-HB levels were significantly elevated in DKA patients compared with DM patients and controls (P < 0.01). Positive rate of serum beta-HB in DKA patients was significantly higher than that of urinary ketone (P < 0.05).</p><p><b>CONCLUSIONS</b>Enzymatic method is convenient and reliable, allows full automation, and is rapid enough to be used for both routine and urgent determinations of serum beta-HB. It can be used in diagnosing and monitoring treatment of DKA.</p>