Postpartum life interventions to prevent type 2 diabetes in women with gestational diabetes: A systematic review and meta-analysis.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a major metabolic disease that seriously endangers life and health, but women with gestational diabetes mellitus are at increased risk for developing type 2 diabetes mellitus. This study aimed to evaluate the effectiveness of postpartum lifestyle intervention on the prevention of type 2 diabetes mellitus, and the effect of lifestyle intervention on glycemic outcomes and anthropometric measures. MATERIALS AND METHODS: We searched PubMed and other databases to retrieve articles published before May 21, 2023, on randomized controlled trials of postnatal lifestyle interventions (diet and/or physical activity) in women with gestational diabetes mellitus. We estimated the pooled odds ratios using fixed or random effects models and conducted a subgroup analysis of the different intervention methods to explore differences in the different lifestyle interventions. RESULTS: The review included 17 randomized controlled trials. Overall, lifestyle changes started after a pregnancy complicated by gestational diabetes mellitus an 11% (RR = 0.89; 95% CI: 0.74-1.07) reduction in diabetes risk; significant differences were found for weight (MD = -1.33; 95% CI: [-1.76; -0.89], P < 0.00001) body mass index (MD = -0.53; 95% CI: [-0.74, -0.32], P < 0.00001), and waist circumference change (MD = -1.38; 95% CI: [-2.12; -0.64], P = 0.0002) but not for fasting glucose (MD = -0.06; 95% CI: [-0.19; 0.06], P = 0.32), 2 h glucose (MD = -0.12; 95% CI: [-0.30; 0.06], P = 0.19), and hemoglobin A1c (MD = -0.11; 95% CI: [-0.23; 0.02], P = 0.09). Subgroup analyses showed no significant differences in the effects of different lifestyle interventions on the incidence of type 2 diabetes, blood glucose levels, and anthropometric parameters. CONCLUSION: Our comprehensive meta-analysis of lifestyle interventions can improve modifiable anthropometric measures in women with gestational diabetes. We need further research to provide more intensive lifestyle intervention, more scientific intervention methods, and to reduce the incidence of type 2 diabetes in patients with gestational diabetes.

Decreased expression of programmed death-1 on CD8+ effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes.

AIMS: Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D. METHODS: A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients' peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet's inflammation in NOD mice. RESULTS: Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p < 0.05). The frequencies of PD-1+ CD8+ Tem cells were decreased in patients with T1D who were positive for two or more autoantibodies compared with the patients with one autoantibody (13.46% vs 46.95 ± 12.72%, *p < 0.05). Meanwhile, the frequencies of PD-1+ CD8+ central memory T (Tcm) cells were also significantly decreased in patients with two or more autoantibodies compared with other groups (≥ 2AAb vs HC 33.1 ± 8.92% vs 43.71 ± 11.78%, *p < 0.05; ≥ 2AAb vs AAb-33.1 ± 8.92% vs 41.65 ± 11.2%, *p < 0.05; ≥ 2AAb vs 1AAb 33.1 ± 8.92% vs 48.09 ± 10.58%, ***p < 0.001). The frequencies of PD-1+CD8+ Tem cells were positively correlated with fasting serum C-peptide levels (r = 0.4308, *p < 0.05) and C-peptide levels 2 h after meal in T1D patients (r = 0.5723, **p < 0.01). The frequencies of PD-1+CD8+ Tcm cells were only negatively correlated with the levels of HbA1c (r = - 0.2992, *p < 0.05). Similarly, the frequencies of PD-1+CD8+ Tem were significantly decreased in intervention group (anti-mouse PD-1 mAb) compared with the control group (14.22 ± 6.455% vs 27.69 ± 9.837%, *p < 0.05). Pathologically, CD8, PD-1 and PD-L1 were strongly expressed in the islets of diabetic mice after PD-1 blockade. CONCLUSIONS: It is the first report of the expression of PD-1 on CD8+ Tem cells in T1D in the present study. Our observations suggest that the PD-1/PD-L1 signal pathway on CD8+ Tem cells of T1D subjects might identify a new pathway for delaying the occurrence and development by inhibiting autoimmunity.

The associations between fasting plasma glucose levels and mortality of COVID-19 in patients without diabetes.

AIMS: Coronavirus disease 2019 (COVID-19) which is a novel pneumonia can rapidly progress to acute respiratory distress syndrome, septic shock, and multiple organ dysfunction syndrome. It has appeared in 196 countries around the world. We aimed to clarify the associations between fasting plasma glucose levels and mortality of COVID-19 in patients without diabetes. METHODS: We performed a retrospective, single-center study of 151 patients without diabetes in Tongji Hospital from January 1, 2020 to February 28, 2020. Past medical histories, clinical features and laboratory parameters were collected in these patients. RESULTS: Compared with survivors, non-survivors were more likely to have underlying medical conditions including hypertension and chronic pulmonary diseases. Non-survivors had higher C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-2R, IL-6, IL-8 and, tumor necrosis factor-α (TNF-α) levels, while lower lymphocyte counts as compared with those of survivors (all P<0.05). Besides, patients with higher fasting plasma glucose (FPG) had higher IL-6, IL-8, CRP levels and mortality; while lower lymphocyte counts. After adjusting for age and gender, each tertile increment of FPG levels conferred 3.54-fold higher risks of death (odds ratio, 3.54; 95% confidential interval, 1.25-10.06, P=0.018). CONCLUSIONS: Non-survivors combined with more comorbidities, more severe infection, and worse liver, kidney and cardiac function in patients without diabetes. Additionally, fasting plasma glucose levels were significantly associated with the risk of death in patients even with normal FPG and HbA1c levels.

Mechanism of higher risk for COVID-19 in diabetes: a mask to lift.

PURPOSE: This essay aims to propose suggestions on what we can learn from previous investigations to conduct further studies on the potential mechanisms underlying the effect of diabetes mellitus on COVID-19. METHODS: We reviewed some literature on diabetes and other types of coronavirus infection such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) and made some summaries and comparisons. RESULTS: Diabetes affect the occurrence and progression of COVID-19. CONCLUSIONS: In-depth and comprehensive exploration of the mechanism of diabetes affecting COVID-19 should be carried out.

The expression of Tim-1 and Tim-4 molecules in regulatory T cells in type 1 diabetes.

PURPOSE: The TIM family comprises of eight genes in the mouse, three of which are conserved in humans (TIM-1, TIM-3, and TIM-4). Previous studies have revealed the relationships between Tim3+ Tregs and autoimmune disease. There was little study about the expression of Tim1 and Tim4 surface molecules on Tregs. We evaluated the frequency of the Tim1+Tregs and Tim4+Tregs in type 1 diabetes (T1D) in the present study. METHODS: A total of 28 patients with T1D and 14 gender-, age-, and ethnically matched healthy volunteers were recruited. PBMCs from these individuals were isolated and analyzed by flow cytometry. Splenocytes from mice were also analyzed by flow cytometry. RESULTS: There is no difference in the frequency of Treg cells in peripheral blood isolated from T1D patients. Tim1 on CD4+CD25+ T cells decreased significantly in PBMC of patients with T1D(1.19 ± 0.17% vs 2.78 ± 0.38%, 95% CI:0.87-2.31, P < 0.0001), while expression of Tim4 on CD4+CD25+ T cells in PBMC was less frequent in patients with T1D than healthy people(3.0 ± 0.39% vs 6.25 ± 1.08%, 95% CI:1.08-5.43, P = 0.0044). The frequencies of CD4+CD25+Tim1+ T cells and CD4+CD25+Tim4+ T cells also decreased in spleen of hyperglycemic NOD mice. There were no significant correlations between CD4+CD25+Tim1+T-cells, CD4+CD25+Tim4+T-cells and any clinical features such as age, HbA1c, Fasting C-peptide, diabetic autoantibodies, disease duration, total cholesterol, LDL, HDL, and TG. CONCLUSIONS: It is the first report of the expression of Tim1 and Tim4 molecules on Treg cells in T1D in the present study. We also presented evidence that the frequencies of Tim1+Tregs and Tim4+Tregs decreased significantly in both type 1 diabetic patients and hyperglycemic NOD mice. However, the specific functions of Tim1+Tregs and Tim4+Tregs are still unclear.

A novel mutation in INS gene linked to permanent neonatal diabetes mellitus.

PURPOSE: Neonatal diabetes mellitus (NDM) is caused by mutations in the genes responsible for pancreatic ß cell mass or function. This study aimed to screen the mutations in the KCNJ11, ABCC8, and INS genes in a Chinese patient with clinical features of NDM. METHODS: The entire coding sequence and exon/intron boundaries of KCNJ11, ABCC8, and INS genes were detected by Sanger sequencing. The pathogenicity of the mutation was determined by using online prediction programs SIFT and Mutation Taser. The conformational alterations which contribute to the change of protein function were analyzed at the structural level. RESULTS: A novel mutation L35Q (B11) of the INS gene was discovered in the patient. As L35 residue contributes to its hydrophobic core of the protein, the L35Q substitution is predicated to affect B19-A20 disulfide bond and therefore disrupt the folding of the proinsulin, which ultimately results in beta cell apoptosis by inducing ER stress. CONCLUSIONS: This case could help us understand the role of the INS mutation in the development of diabetes.

Association of PD-1 and PD-L1 Genetic Polymorphyisms with Type 1 Diabetes Susceptibility.

AIMS: The programmed death- (PD-) 1/PD-1 ligand (PD-L) pathway plays an important role in regulating T cell activation and maintaining peripheral tolerance. Accumulated studies showed that PD-1/PD-L1 pathway was involved in the development of type 1 diabetes (T1DM). Since the genetic background of type 1 diabetes differs greatly among the different population, we aim to investigate the association of genetic polymorphisms in PD-1 and PD-L1 with T1DM susceptibility in Chinese population. METHODS: In total, 166 T1DM patients and 100 healthy controls were enrolled into the study. Genomic DNA was extracted from 4 mL peripheral blood samples collected from each subject. Genotyping of 8 selected SNPs of PD-1 and PD-L1 was carried out by the pyrosequencing PSQ 24 System using PyroMark Gold reagents (QIAGEN). RESULTS: SNP rs4143815 in PD-L1 was significantly associated with T1DM. People carrying the C allele of rs4143815 suffering less risk of T1DM and T1DM patients with G/G genotype showed higher levels of autoantibody (AAB) positive incidence compared with C allele carriers. No significant associations were found in other SNPs. CONCLUSIONS: Our results indicate that rs4143815 of PD-L1 is significantly associated with T1DM and may serve as a new biomarker to predict the T1DM susceptibility.

Soluble B7-H3 (sB7-H3) is over-expressed in the serum of type 1 diabetes patients.

Type 1 Diabetes (T1D) is an autoimmune disease resulting from insulin-secreting ß-cells mediated by autoreactive T cells. We demonstrated increased level of sB7-H3 in T1D patients than in healthy control group. This result suggests that B7-H3 may be may be a promising biomarker associated with the pathogenesis of T1D.

Gut microbiota profiling in Han Chinese with type 1 diabetes.

AIMS: To investigate whether microbial dysbiosis is associated with T1D in Chinese population and to explore relationships between the composition of gut microbiome and clinical data. METHODS: In this study, we recruited 10 healthy and 12 T1D Han Chinese subjects between the ages of 12 to 33. Fecal samples were collected for DNA extraction and 16S rRNA sequencing, followed by analyses of the gut microbiota composition. RESULTS: Bacterial communities differed between healthy and T1D subjects. At the phylum level, Bacteroidetes and Firmicutes are the dominant phyla in T1D patients and healthy controls, respectively. The linear discriminant analysis (LDA) effect size (LEfSe) algorithm detected 28 bacterial taxonomic clades showing statistically differences (13 increased and 15 decreased) in T1D patients. Association analyses of clinical data and microbial community abundance demonstrated that abundances of Faecalibacterium were negatively correlated with HbA1c levels (Z = -2.614, P = 0.017). The numbers of detected anti-islet cell autoantibodies were positively correlated with Bacteriodes (Z = 2.531, P = 0.011) and Bilophila (Z = 2.477, P = 0.013) abundances, while negatively correlated with abundances of Streptococcus (Z = -2.041, P = 0.041) and Ruminococcaceae (Z = -2.23, P = 0.026). CONCLUSIONS: These results suggest that Han Chinese T1D patients possess distinctly different gut microbiota, compared to healthy subjects, characterized by increased Bacteroidetes/Firmicutes ratio, negative correlation of Faecalibacterium abundance with HbA1c, and positive correlation of Bacteroides abundance with the presence of autoantibodies.

Angiopoietin-like protein 8 in early pregnancy improves the prediction of gestational diabetes.

AIMS/HYPOTHESIS: Screening high-risk individuals for gestational diabetes mellitus (GDM) in early pregnancy conventionally relies on established maternal risk factors; however, the sensitivity and specificity of these factors are not satisfactory. The present study aimed to determine whether the concentration of angiopoietin-like protein 8 (ANGPTL8), either alone or combined with other risk factors in early pregnancy, could be used to predict subsequent GDM. METHODS: From August 2015 to January 2016, 474 women receiving prenatal care at around 12-16 weeks of gestation were recruited into the study. ANGPTL8 levels were measured at the first prenatal visit. All the participants received a 75 g OGTT during weeks 24-28 of gestation. RESULTS: ANGPTL8 levels in early pregnancy were considerably higher in women who developed GDM than those who maintained normal glucose tolerance (2822 ± 938 vs 2120 ± 1118 pg/ml, respectively; p < 0.0001). Multivariable logistic regression revealed that ANGPTL8 levels were significantly associated with risk of GDM independent of conventional risk factors. In addition, women in the highest quartile of ANGPTL8 concentration had an 8.75-fold higher risk of developing GDM compared with women in the lowest quartile (OR8.75, 95%CI 2.43, 31.58). More importantly, incorporating ANGPTL8 into the conventional prediction model significantly increased the AUC for prediction of GDM (0.772vs 0.725; p = 0.019). CONCLUSIONS: Our study suggests that ANGPTL8 levels in early pregnancy are significantly and independently associated with risk of GDM at 24-28 weeks of gestation. Combining ANGPTL8 levels with conventional risk factors could thus improve the prediction of GDM.

Genome-wide gene expression profiling reveals that CD274 is up-regulated new-onset type 1 diabetes mellitus.

AIMS: Early studies have identified type 1 diabetes mellitus (T1DM) as a disease that is caused by the autoimmune destruction of the insulin-producing pancreatic ß-cells. Genetics, environment and the immune pathogenesis of T1DM are three major pillars of T1DM research. We try to understand the changes in the gene expression profile during the pathogenesis of T1DM. METHODS: We performed a systematic search in the Gene Expression Omnibus (GEO) database for microarray studies of T1DM with samples taken at or before the T1DM onset. RESULTS: The results of an integrated analysis of different GEO datasets and a comparison of the gene expression level in T1DM samples taken at the time of appearance of the islet autoantibodies, 1 year before T1DM onset, and at the time of T1DM onset showed that CD274, which encodes PD-L1, was up-regulated in the newly onset T1DM samples. CD274 had a stable expression level in the control samples but showed a gradual up-regulation from the appearance of autoantibodies to the onset of T1DM. CONCLUSIONS: These results indicate that CD274 up-regulation in T1DM is correlated with disease pathogenesis. PD-L1 might play a protective role in preventing the pancreatic islets from autoimmune destruction, which may help researchers find strategies for preventing the destruction process of pancreas ß-cells in T1DM.

The efficacy and safety of DPP4 inhibitors in patients with type 1 diabetes: A systematic review and meta-analysis.

AIMS: Dipeptidyl peptidase-4 (DPP4) inhibitors are a novel class of antidiabetic medication in the treatment of type 2 diabetes mellitus. Several studies have indicated that DPP4 inhibitors could be used for type 1diabetes (T1DM). Here, we performed a meta-analysis to assess the efficacy and safety of DPP4 inhibitor therapy in patients with T1DM. METHODS: We conducted searches on Medline, Cochrane Library, Web of Science, and EMBASE for relevant studies published before November 21, 2015. Mean difference (MD) with 95% confidence interval (CI) was calculated for the mean glycated hemoglobin (HbA1c) changes and insulin dosage from baseline to endpoint. Risk ratio (RR) with 95% CI was calculated for severe hypoglycemia. Data was extracted by two independent reviewers, and the meta-analysis was performed using Review Manager version 5.3. RESULTS: Six randomized controlled trials with a total of 228 individuals were finally included into the meta-analysis. DPP4 inhibitors reduced daily insulin dosage significantly (MD -2.41U/day, 95% CI [-3.87, -0.94], P=0.001) but did not reduce HbA1c level (MD 0.0% (0mmol/mol), 95% CI [-0.16, 0.15], P=0.97). Furthermore, DPP4 inhibitors did not change the incidence of severe hypoglycemia (RR 0.81, 95% CI [0.34, 1.93], P=0.64). CONCLUSION: In patients with T1DM, DPP4 inhibitors combined with insulin do not increase or decrease the risk of hypoglycemia and do not decrease HbA1c levels.

Increased angiopoietin-like protein 8 levels in patients with type 2 diabetes and cardiovascular disease.

In the present study, we recruited 124 patients with type 2 diabetes, among which 22 had a history of cardiovascular disease (CVD). The study demonstrated that compared with type 2 diabetes without CVD, those with CVD had remarkably higher levels of angiopoietin-like protein 8 (ANGPTL8). Moreover, the close relationship between ANGPTL8 and CVD was independent of conventional CVD risk factors.

Betatrophin Levels were Increased in Pregnant Women with or without Gestational Diabetes Mellitus and Associated with Beta Cell Function.

Purpose betatrophin has been reported to boost ß cell expansion in insulin resistant states. Pregnancy is a well-recognized physiological state of insulin resistance. Betatrophin levels in pregnant women and their relationships with metabolic variables remain to be elucidated. Methods A total of 49 pregnant women and 31 age-matched unpregnant women with normal glucose regulation (UP-NGR) were included. Among these subjects, according to results from 75 g oral glucose tolerance test (OGTT), 22 women were diagnosed as having gestational diabetes mellitus (GDM). Results Our study found that pregnant women, regardless of their glucose regulation status, had remarkably higher triglycerides (TG), total cholesterol (TC), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of ß-cell function (HOMA-ß). However, GDM patients had much lower HOMA-ß compared with those of pregnant women with normal glucose regulation (P-NGR). Participants of the P-NGR group had almost 4 times higher levels of betatrophin than those of the UP-NGR group. Although betatrophin levels were lower in the GDM group than those of the P-NGR group, the difference did not reach statistical significance. Spearman correlation analysis showed that betatrophin levels were positively and significantly associated with total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-c), FINS and HOMA-ß. However, adjustments of TC, TG and HDL-c eliminated the association between HOMA-ß and betatrophin. Conclusions Pregnant women have significantly higher betatrophin levels in comparison to unpregnant women. Betatrophin levels are positively and significantly associated with ß cell function and lipid levels. Furthermore, lipids may contribute to the association between betatrophin and ß cell function.

Betatrophin Levels were Increased in Pregnant Women with or without Gestational Diabetes Mellitus and Associated with Beta Cell Function / Níveis de betatrofina aumentados em grávidas com ou sem diabetes mellitus gestacional e associados à função das células beta

Abstract Purpose betatrophin has been reported to boost β cell expansion in insulin resistant states. Pregnancy is a well-recognized physiological state of insulin resistance. Betatrophin levels in pregnant women and their relationships with metabolic variables remain to be elucidated. Methods A total of 49 pregnant women and 31 age-matched unpregnant women with normal glucose regulation (UP-NGR) were included. Among these subjects, according to results from 75 g oral glucose tolerance test (OGTT), 22 women were diagnosed as having gestational diabetes mellitus ( GDM ). Results Our study found that pregnant women, regardless of their glucose regulation status, had remarkably higher triglycerides (TG), total cholesterol (TC), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β). However, GDM patients had much lower HOMA-β compared with those of pregnant women with normal glucose regulation (P-NGR). Participants of the P-NGR group had almost 4 times higher levels of betatrophin than those of the UP-NGR group. Although betatrophin levels were lower in the GDM group than those of the P-NGR group, the difference did not reach statistical significance. Spearman correlation analysis showed that betatrophin levels were positively and significantly associated with total cholesterol, triglycerides, highdensity lipoprotein cholesterol (HDL-c), FINS and HOMA-β. However, adjustments of TC, TG and HDL-c eliminated the association between HOMA-β and betatrophin. Conclusions Pregnant women have significantly higher betatrophin levels in comparison to unpregnant women. Betatrophin levels are positively and significantly associated with β cell function and lipid levels. Furthermore, lipids may contribute to the association between betatrophin and β cell function.

Resumo Introdução Betatrofina tem sido relacionada à expansão de células β em estado de resistência à insulina. A gravidez é um conhecido estado fisiológico de resistência à insulina. Níveis de betatrofina em gestantes e sua relação com variáveis metabólicas ainda precisam ser esclarecidas. Métodos Um total de 49 gestantes e 31 não gestantes de mesma idade com níveis normais de glicose (UP-NGR) foram incluídas. Dentre elas, de acordo com os resultados da curva glicêmica, base em 75 g, 22 mulheres foram diagnosticadas com diabetes mellitus gestational ( DMG ). Resultados Nosso estudo identificou que gestantes, independente de seus níveis de glicose, tiveram notáveis níveis elevados de triglicerídeos (TG), colesterol (TC), insulina em jejum (FINS), HOMA-IR e HOMA-β. Contudo, pacientes com DMG tiveram bem menos HOMA-β se comparadas às gestantes com níveis normais de glicose ( P-NGR ). Participantes do grupo P-NGR tiveram níveis de betatrofina quase quarto vezes maiores ao das participantes do grupo UP-NGR. Embora os níveis de betatrofina sejam menores no grupo DMG do que no P-NGR, a diferença não obteve significância estatística. Análise da correlação de Spearman demonstrou que os níveis de betatrofina foram positiva e significativamente associados ao TC, TG, HDL-c (high-density lipoprotein cholesterol), FINS e HOMA-β. Contudo, ajustes em TC, TG e HDL-c eliminaram a associação entre HOMA-β e betatrofina. Conclusões Gestantes têm níveis de betatrofina significativamente maiores do que não gestantes. Níveis de betatrofina são positive e significativamente associados às células β funcionais e níveis de lipídeos. Além disso, lipídeos podem contribuir na associação entre betatrofina e células β funcionais.

Lipasin, a biomarker of diabetic retinopathy.

The present study recruited 74 participants with type 2 diabetes, among which 23 had retinopathy. Those with retinopathy had a longer duration of diabetes and higher levels of lipasin compared with those without retinopathy. Logistic regression revealed that lipasin was independently and significantly associated with retinopathy even after adjustments for confounders.