Metabolomics analysis of serum and urine in type 1 diabetes patients with different time in range derived from continuous glucose monitoring.

BACKGROUND: Time in range (TIR), as an important glycemic variability (GV) index, is clearly associated with disease complications in type 1 diabetes (T1D). Metabolic dysregulation is also involved in the risks of T1D complications. However, the relationship between metabolites and TIR remains poorly understood. We used metabolomics to investigate metabolic profile changes in T1D patients with different TIR. METHODS: This study included 85 T1D patients and 81 healthy controls. GV indices, including TIR, were collected from continuous glucose monitoring system. The patients were compared within two subgroups: TIR-L (TIR < 50%, n = 21) and TIR-H (TIR > 70%, n = 14). To screen for differentially abundant metabolites and metabolic pathways, serum and urine samples were obtained for untargeted metabolomics by ultra-performance liquid chromatography‒mass spectrometry. Correlation analysis was conducted with GV metrics and screened biomarkers. RESULTS: Metabolites were significantly altered in T1D and subgroups. Compared with healthy controls, T1D patients had higher serum levels of 5-hydroxy-L-tryptophan, 5-methoxyindoleacetate, 4-(2-aminophenyl)-2,4-dioxobutanoate, and 4-pyridoxic acid and higher urine levels of thromboxane B3 but lower urine levels of hypoxanthine. Compared with TIR-H group, The TIR-L subgroup had lower serum levels of 5-hydroxy-L-tryptophan and mevalonolactone and lower urine levels of thromboxane B3 and phenylbutyrylglutamine. Dysregulation of pathways, such as tryptophan, vitamin B6 and purine metabolism, may be involved in the mechanism of diabetic complications related to glycemic homeostasis. Mevalonolactone, hypoxanthine and phenylbutyrylglutamine showed close correlation with TIR. CONCLUSIONS: We identified altered metabolic profiles in T1D individuals with different TIR. These findings provide new insights and merit further exploration of the underlying molecular pathways relating to diabetic complications.

Impact of gut microbiota and associated mechanisms on postprandial glucose levels in patients with diabetes.

Diabetes and its complications are serious medical and global burdens, often manifesting as postprandial hyperglycemia. In recent years, considerable research attention has focused on relationships between the gut microbiota and circulating postprandial glucose (PPG). Different population studies have suggested that PPG is closely related to the gut microbiota which may impact PPG via short-chain fatty acids (SCFAs), bile acids (BAs) and trimethylamine N-oxide (TMAO). Studies now show that gut microbiota models can predict PPG, with individualized nutrition intervention strategies used to regulate gut microbiota and improve glucose metabolism to facilitate the precision treatment of diabetes. However, few studies have been conducted in patients with diabetes. Therefore, little is known about the relationships between the gut microbiota and PPG in this cohort. Thus, more research is required to identify key gut microbiota and associated metabolites and pathways impacting PPG to provide potential therapeutic targets for PPG.

Medications and medical expenditures for diabetic patients with osteoporosis in Beijing, China: A retrospective study.

AIMS: This study aimed to clarify the changes in treatment regimens and medical expenditures in diabetic patients with osteoporosis. METHODS: We recruited 2,853,036 diabetic patients from the Beijing medical insurance database between 2016 and 2018. Among them, 406,221 patients also had osteoporosis. Clinical characteristics, treatment regimens, and medical costs were investigated in diabetic patients with and without osteoporosis. RESULTS: Diabetes and osteoporosis were most prevalent in participants aged 45---84 years. Compared with diabetic patients without osteoporosis, those with osteoporosis were prone to developing comorbidities and diabetic complications. They often required multiple glucose-lowering drugs and had a higher rate of insulin use. Similarly, osteoporosis leads to an increased number of medications for non-hypoglycemia as well as higher healthcare costs. These medications and costs increased with the number of complications and comorbidities. Interestingly, from 2016 to 2018, although diabetic patients with osteoporosis took more drugs, medical costs were lower year by year. CONCLUSIONS: Osteoporosis might contribute to a worse condition in diabetic patients, and this population often requires more medications with higher medical costs.

A self-controlled, cross-over study of intensive insulin treatment with needle-based injection versus needle-free injection in hospitalized patients with type 2 diabetes.

Background and Aims: Needle injection and needle-free injection were proven effective in improving glycated hemoglobin (HbA1c) in type 2 diabetes mellitus (T2DM) patients. However, it is unclear if needle-free and needle injections of insulin during intensive insulin therapy in hospitalized patients provide similar efficacy and safety benefits. Methods: A self-controlled cross-over study was conducted on 62 patients with T2DM who received intensive long-acting and short-acting insulin injections with or without needles. The 7-point blood glucose test was performed on the 6th day after insulin administration and the injection method switched on the 7th day of hospitalization. The difference was compared in 7-point blood glucose levels. Results: The blood glucose levels at fasting (mean difference=-1.09 ± 2.38mmol/L, 95% CI, -1.69 to -0.48, p=0.0007) and post-breakfast (-1.14 ± 3.02mmol/L, 95%CI, -1.91 to -0.37, p=0.004) were better when patients were receiving needle-free injections compared to when receiving a needle injection. Indeed, daily blood glucose fluctuation, which presented as the area under the curve of glycemia, was decreased in needle-free injection periods (-0.3.48 ± 9.64, 95%CI, -5.95 to -1.01, p=0.0065). There was no significant difference in the dose of long-acting insulin between the two injection methods (-0.32 ± 2.69, 95%CI, -0.99 to 0.37, p>0.05). The dose of fast-acting insulin during the needle-free period was lower than that of when patients received needle injections (-1.66 ± 6.45, 95%CI, -3.29 to -0.025, p<0.05). There was no significant difference in satisfaction between the two regimens (-0.59 ± 1.55,95%CI, -0.938 to 0.509, p=0.557), but there was a significant difference in pain experience, favoring needle-free injections (p < 0.001). Conclusion: Glycemia was better controlled by needle-free insulin injections in hospitalized T2DM patients subjected to intensive glycemic control. These patients also experienced less pain than when insulin was injected with a needle.

Maturity-onset diabetes of the young type 10 caused by an Ala2Thr mutation of INS: A case report.

BACKGROUND: Maturity-onset diabetes of the young 10 caused by the c.4G>A (p.Ala2Thr) mutation is extremely rare, with only two reported studies to date. Herein, we report another case that differs from previous cases in phenotype. CASE SUMMARY: The proband developed diabetes at the age of 27 years, despite having a normal body mass index (BMI). She exhibited partial impairment of islet function, tested positive for islet antibodies, and required high doses of insulin. Her sister also carried the c.4G>A (p.Ala2Thr) mutation, and their mother was strongly suspected to carry the mutated gene. Her sister developed diabetes around 40 years of age and required high doses of insulin, while the mother was diagnosed in her 20s and was managed with oral hypoglycemic agents; neither of them were obese. CONCLUSION: p.Ala2Thr mutation carriers often experience relatively later onset and normal BMI. Treatment regimens vary between individuals.

Application of novel subgroups of Chinese inpatients with diabetes based on machine learning paradigm.

BACKGROUND AND AIMS: Six variables were used to determine five diabetes subgroups in European, Chinese and US populations in previous studies. This study aims to make new classification method of diabetes easier to use in clinical settings. METHODS: Clinical data of 1152 hospitalized diabetic patients were collected and built a highly accurate model based on machine learning paradigm. RESULTS: We visualized the confusion matrix of the classification model. The diagnose accuracy of five clusters (MOD, MARD, SIRD, SIDD and SAID) were 95%, 100%, 99%, 96% and 100%. An online tool (uqzhichen.uqcloud.net) was set up according to the cluster data based on machine learning paradigm. Six variables (age when diagnosed, HbA1c, BMI, HOMA2-ß, HOMA2-IR and GADA) were needed to input in this diagnose system and then a highly accurate subgroup result was showed. CONCLUSIONS: This is a stable and accurate online diagnose system to identify five new subgroups of diabetes based on machine learning paradigm.

Case Report: Diabetes in Chinese Bloom Syndrome.

Bloom syndrome (BS) is a rare autosomal recessive disorder that causes several endocrine abnormalities. So far, only one BS pedigree, without diabetes, has been reported in the Chinese population. We presented the first case of BS with diabetes in the Chinese population and explored the clinical spectrum associated with endocrine. Possible molecular mechanisms were also investigated. Our study indicated that BS may be one rare cause of diabetes in the Chinese population. We also found a new pathogenic sequence variant in BLM (BLM RecQ like helicase gene)(NM_000057.4) c.692T>G, which may expand the spectrum of BLM variants.

A Clinical Prediction Model to Distinguish Maturity-Onset Diabetes of the Young From Type 1 and Type 2 Diabetes in the Chinese Population.

OBJECTIVE: Genetic detection for the diagnosis of maturity-onset diabetes of the young (MODY) in China has low sensitivity and specificity. Better gene detection is urgently needed to distinguish testing subjects. We proposed to use numerous and weighted clinical traits as key indicators for reasonable genetic testing to predict the probability of MODY in the Chinese population. METHODS: We created a prediction model based on data from 306 patients, including 140 patients with MODY, 84 patients with type 1 diabetes (T1D), and 82 patients with type 2 diabetes (T2D). This model was evaluated using receiver operating characteristic curves. RESULTS: Compared with patients with T1D, patients with MODY had higher C-peptide levels and negative antibodies, and most patients with MODY had a family history of diabetes. Different from T2D, MODY was characterized by lower body mass index and younger diagnostic age. A clinical prediction model was established to define the comprehensive probability of MODY by a weighted consolidation of the most distinguishing features, and the model showed excellent discrimination (areas under the curve of 0.916 in MODY vs T1D and 0.942 in MODY vs T2D). Further, high-sensitivity C-reactive protein, glycated hemoglobin A1c, 2-h postprandial glucose, and triglyceride were used as indicators for glucokinase-MODY, while triglyceride, high-sensitivity C-reactive protein, and hepatocellular adenoma were used as indicators for hepatocyte nuclear factor 1-α MODY. CONCLUSION: We developed a practical prediction model that could predict the probability of MODY and provide information to identify glucokinase-MODY and hepatocyte nuclear factor 1-α MODY. These results provide an advanced and more reasonable process to identify the most appropriate patients for genetic testing.

The Effects of Dietary Nutrition Intake on Glycemic Variability in Type 1 Diabetes Mellitus Adults.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) is characterized by an absolute deficiency of insulin and dependence on insulin therapy. Therefore, glycemic control and management are important for T1DM patients, particularly glycemic variability, which is associated with the development of diabetic complications. However, insufficient attention has been paid to the glycemic variability in T1DM patients so far. Our objective was to identify the effects of food intake on glycemic variability in T1DM patients. METHODS: This was a single-center study that took place in the outpatient clinics of Peking Union Medical College Hospital. A total of 68 Chinese T1DM patients between June 2018 and June 2019 were enrolled. After the baseline demographic and clinical characteristics were evaluated, each participant underwent 14-day flash glucose monitoring (FGM). They recorded caloric intake of breakfast, lunch, and dinner at least 3 days/week using a "Menthol Health" app. After 2 weeks, we obtained the FGM data and did further data analysis. Baseline characteristics and glycemic variability index generated by FGM were compared among groups. A general linear model was used to compare data among groups after adjusting for potential confounding factors. The quantitative relationship between two continuous variables was explored by constructing a linear regression equation. RESULTS: The results showed that the C-peptide level was independently correlated with the mean of daily differences (MODD) after adjusting for the possible confounders (ß = - 0.239, p = 0.046). The dietary nutrition intake had no effect on glycemic variability. However, the nutritional composition of carbohydrate, fat, and protein was an independent risk factor for time spent in hypoglycemia (TBR) post adjustment (ß = - 0.213, p = 0.054). However, there was no impact of daily total energy intake on glycemic variability index. CONCLUSION: In our study, dietary nutrition intake had no effect on glycemic variability, but residual ß-cell function was identified as an influencing factor for glycemic variability in T1DM adults. However, nutritional macronutrient composition played some roles in the occurrence of hypoglycemia. This might provide new evidence for the clinical glycemic control and management of T1DM in the Chinese population.

Localized increases in CEPT1 and ATGL elevate plasmalogen phosphatidylcholines in HDLs contributing to atheroprotective lipid profiles in hyperglycemic GCK-MODY.

Glucokinase-maturity onset diabetes of the young (GCK-MODY) represents a rare genetic disorder due to mutation in the glucokinase (GCK) gene. The low incidence of vascular complications in GCK-MODY makes it a natural paradigm for interrogating molecular mechanisms promoting vascular health under prolonged hyperglycemia. Clinical rate of misdiagnosis has remained high, and a reliable serum lipid biomarker that precedes genetic screening can facilitate correct diagnosis and treatment. Herein, we comprehensively quantitated 565 serum lipids from 25 classes in 105 subjects (42 nondiabetic controls, 30 GC K-MODY patients, 33 drug-naïve, and newly-onset T2D patients). At false-discovery rate (FDR) < 0.05, several phosphatidylcholines (PCs) and plasmalogen PCs were specifically increased in GCK-MODY, while triacylglycerols (TAGs) and diacylglycerols (DAGs) were reduced. Correlation matrices between lipids uncovered coregulation between plasmalogen PCs (PCps) and glycerolipid precursors was distinctly enhanced in GCK-MODY compared to T2D. Strengthened positive correlations between serum PCps and circulating HDLs was specifically observed in hyperglycemic subjects (i.e. T2D and GCK-MODY) compared to normglycemic controls, suggesting that HDL-PCps may elicit distinct physiological effects under hyperglycemia. Amongst GCK-MODY patients, individuals harboring variants of GCK mutations with elevated PCps also exhibited higher HDLs. Isolated HDLs displayed localized increases (p < 0.05) in very-long-chain PUFA-PCs and PCps in GCK-MODY. Protein analyses revealed elevated levels of HDL-resident ATGL (P = 0.003) and CEPT1 (P < 0.0001), which mediate critical steps of PCps production along the TAG-DAG-PC axis, in GCK-MODY relative to T2D. A panel of four lipids differentiated GCK-MODY from T2D with AUC of 0.950 (95% CI 0.903-9.997). This study provides the first evidence that enhanced recruitment of CEPT1 and ATGL onto HDLs essentially underlie the atheroprotective profiles associated with GCK-MODY. Resultant increases in the production of HDL-PCps and PUFA-PCs provides an active, circulating form of protection towards the vasculature of GCK-MODY, thereby lowering the incidence of vascular complications despite chronic exposure to hyperglycemia since birth.

Early-life nutrition and metabolic disorders in later life: a new perspective on energy metabolism.

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.

Potential contribution of the gut microbiota to hypoglycemia after gastric bypass surgery.

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 ß-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.

Maternal Exercise Improves High-Fat Diet-Induced Metabolic Abnormalities and Gut Microbiota Profiles in Mouse Dams and Offspring.

Early-life overnutrition programs increased risks of metabolic disorders in adulthood. Regular exercise has been widely accepted to be an effective measure to maintain metabolic health. However, the intergenerational effects of maternal exercise and the specific mechanism are largely unclear. Our objective was to investigate whether maternal exercise could alleviate the metabolic disturbances induced by early-life overnutrition in both dams and offspring and to explore the role of gut microbiota in mediating the effects. C57BL/6 female mice were randomly divided into three groups: the control group, which were fed a normal control diet; high-fat group, which received a high-fat diet; and high-fat with exercise intervention group, which was fed a high-fat diet and received a voluntary wheel running training. The diet intervention started from 3 weeks prior to mating and lasted throughout pregnancy and lactation. The exercise intervention was only prior to and during pregnancy. The male offspring got free access to normal chow diet from weaning to 24 weeks of age. Glucose tolerance test and biochemical parameters were detected in dams at weaning and offspring at 8 and 24 weeks of age. Their cecal contents were collected for the 16 s rDNA amplicon sequencing. The results showed that maternal high-fat diet resulted in significant glucose intolerance, insulin resistance, and lipid profiles disorders in both dams and offspring. Maternal exercise markedly improved insulin sensitivity in dams and metabolic disorders in offspring from young into adulthood. The decrease in unfavorable bacteria and the persistent enrichment of short-chain fatty acids-producers from mothers to adult offspring, particularly the genus Odoribacter, were all associated with the improvement of metabolism by maternal exercise. Overall, maternal exercise could significantly mitigate the detrimental effects of a maternal high-fat diet on metabolism in both dams and male offspring. The continuous alterations in gut microbiota might be a critical factor in deciphering the metabolic benefits of maternal exercise, which provides some novel evidence and targets for combating metabolic diseases.

Generation of an isogenic gene-corrected iPSC line (PUMCHi001-A-1) from a familial partial lipodystrophy type 2 (FPLD2) patient with a heterozygous R349W mutation in the LMNA gene.

Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant metabolic disorder caused by heterozygous mutations in the LMNA gene, which encodes for the lamin A/C. Although multiple mutations have been reported in FPLD2 patients, the mechanism remains unclear due to the lack of cellular models for the disease. We previously have generated an iPSC line (PUMCHi001-A) from a FPLD2 patient with a heterozygous R349W mutation in the LMNA gene. Here we genetically corrected the R349W mutation in the LMNA gene using CRISPR/Cas9 technology to generate an isogenic control, which was an ideal control to exclude differences in genetic background between individuals while investigating the pathogenesis of the mutation in the disease.

Generation of an integration-free induced pluripotent stem cell line (PUMCHi001-A) from a patient with familial partial lipodystrophy type 2 (FPLD2) carrying a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene.

Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant metabolic disorder caused by heterozygous mutations in the LMNA gene, which encodes for the lamin A/C. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 30 year-old male patient with FPLD2 who had a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene using non-integrating episomal vector technique. This iPSC line offers a useful resource to investigate pathogenic mechanisms in FPLD2, as well as a cell-based model for drug development to treat FPLD2.

Co-Occurrence of Multiple Endocrine Abnormalities Induced by the DIHS/DRESS.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse reaction caused by specific drugs. However, little information is available about sequelae following DIHS/DRESS resolution from an endocrinologist's perspective. This study aimed to investigate the endocrine sequelae following DIHS/DRESS, from clinical feature to etiology. METHODS: We retrospectively analyzed the patients diagnosed with DIHS/DRESS in Peking Union Medical College Hospital (PUMCH) during the period of 1 January 2012 to 31 December 2017, and those who developed endocrine disorders after DIHS/DRESS were further examined. We also reviewed the literature, from 1 January 2000 to 31 December 2017, on involvement of endocrine glands in DIHS/DRESS patients. RESULTS: Three patients developed both autoimmune thyroid disease (AITD) and type 1 diabetes (T1DM)/fulminant type 1 diabetes (FT1DM) of the 45 patients. Seven cases involving more than two endocrine glands were reported in the literature. Our results indicated that DIHS/DRESS is a potential etiological factor of autoimmune polyendocrine syndrome (APS), especially APS III. CONCLUSIONS: Patients require careful long-term follow-up after DIHS/DRESS. Involvement of endocrine glands, especially FT1DM, should always be monitored in patients with a history of DIHS/DRESS. This study indicated that DIHS/DRESS could lead to APS, especially APS III, providing novel insights into the etiological factors of APS.

"Gut Microbiota-Circadian Clock Axis" in Deciphering the Mechanism Linking Early-Life Nutritional Environment and Abnormal Glucose Metabolism.

The prevalence of diabetes mellitus (DM) has been increasing dramatically worldwide, but the pathogenesis is still unknown. A growing amount of evidence suggests that an abnormal developmental environment in early life increases the risk of developing metabolic diseases in adult life, which is referred to as the "metabolic memory" and the Developmental Origins of Health and Disease (DOHaD) hypothesis. The mechanism of "metabolic memory" has become a hot topic in the field of DM worldwide and could be a key to understanding the pathogenesis of DM. In recent years, several large cohort studies have shown that shift workers have a higher risk of developing type 2 diabetes mellitus (T2DM) and worse control of blood glucose levels. Furthermore, a maternal high-fat diet could lead to metabolic disorders and abnormal expression of clock genes and clock-controlled genes in offspring. Thus, disorders of circadian rhythm might play a pivotal role in glucose metabolic disturbances, especially in terms of early adverse nutritional environments and the development of metabolic diseases in later life. In addition, as a peripheral clock, the gut microbiota has its own circadian rhythm that fluctuates with periodic feeding and has been widely recognized for its significant role in metabolism. In light of the important roles of the gut microbiota and circadian clock in metabolic health and their interconnected regulatory relationship, we propose that the "gut microbiota-circadian clock axis" might be a novel and crucial mechanism to decipher "metabolic memory." The "gut microbiota-circadian clock axis" is expected to facilitate the future development of a novel target for the prevention and intervention of diabetes during the early stage of life.

A Possible Mechanism: Genistein Improves Metabolism and Induces White Fat Browning Through Modulating Hypothalamic Expression of Ucn3, Depp, and Stc1.

Bioactive food components have gained growing attention in recent years. Multiple studies demonstrated that genistein had beneficial effects on metabolism. However, the exact mechanism by which genistein improves metabolism remains unclear, especially the central regulation. This study was designed to evaluate whether addition of genistein to the high-fat diet could counter metabolic disorders and whether these alterations were associated with gene expression in hypothalamus. C57BL/6 mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.25 g/kg diet) (HFG) or a normal control diet (CON) for 8 weeks. Body weight was assessed during the study. After 8-week intervention, content of inguinal subcutaneous adipose tissue (SAT), perirenal visceral adipose tissue (VAT) and brown adipose tissue (BAT) were weighed. Glucose tolerance test, the serum levels of insulin and lipid were assessed. The mRNA of browning marker was detected in the white fat. The hypothalamus was collected for whole transcriptome sequencing and reverse transcription quantitative PCR validation. The results demonstrated that mice fed HFG diet had lower body weight and SAT mass, decrease levels of low-density lipoprotein cholesterol and free fatty acids, higher browning marker of Ucp1 and Cidea in WAT and an improvement in glucose tolerance and insulin sensitivity compared with those in HF group. Transcriptome sequencing showed that there were three differentially expressed genes in hypothalamus among the three groups, including Ucn3, Depp, and Stc1, which were significantly correlated with the browning markers in WAT and insulin sensitivity. Thus, regulating gene expressions in hypothalamus is a potential mechanism for genistein improving metabolism and inducing WAT browning, which may provide a novel target for the precaution and treatment of T2DM.

Maternal Genistein Intake Mitigates the Deleterious Effects of High-Fat Diet on Glucose and Lipid Metabolism and Modulates Gut Microbiota in Adult Life of Male Mice.

Adverse early-life exposures program increased risk of chronic metabolic diseases in adulthood. However, the effects of genistein supplementation in early life on metabolic health in later life are largely unclear. Our objective was to investigate whether maternal genistein intake could mitigate the deleterious influence of a maternal high-fat diet on glucose and lipid metabolism in offspring and to explore the role of gut microbiota in mediating the transgenerational effects. C57BL/6 female mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.6 g/kg diet) (HFG) or normal control diet (C) for 3 weeks before pregnancy and throughout pregnancy and lactation. The male offspring had ad libitum access to normal chow diet from weaning to 24 weeks of age. Then the content of inguinal subcutaneous adipose tissue (SAT) and epididymal visceral adipose tissue (VAT) were weighed. Glucose tolerance test (GTT), the level of serum insulin and lipid profiles were analyzed. The caecal contents were collected for 16S rDNA sequencing. The results showed that maternal genistein intake could significantly reduce blood glucose levels during GTT, fasting insulin levels, VAT mass and serum triglyceride levels as well as increase high-density lipoprotein cholesterol in adult male offspring. Significant decrease of germs from the Tenericutes phylum and enrichment of Rikenella as well as SCFA (short-chain fatty acid)-producing bacteria, including Alloprevotella, Odoribacter, and Clostridium XlVa, in offspring of genistein fed dams might play crucial roles in the improvement of glucose and lipid metabolism. Overall, early-life genistein intake attenuated the harmful effects of maternal HF on metabolism in adult offspring and the protective effects were associated with the alterations in gut microbiota, which provides new evidence and targets for mitigate the poor effects of adverse early-life exposures on metabolic health in later life.

First Case Report of Maturity-Onset Diabetes of the Young Type 4 Pedigree in a Chinese Family.

Maturity-onset diabetes of the young (MODY) is the most common monogenetic diabetes, which is easily misdiagnosed. We describe the first Chinese MODY4 family with a novel mutation, indicating that MODY4 cannot be excluded in early-onset obese diabetes, and pancreatic exocrine dysfunction could be present in MODY4.