Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic-inflammatory-aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.

Background:Differential abundance analysis is fundamental to microbiome research and provides valuable insights into host-microbe interactions. However, microbiome data are compositional, highly sparse (with many zero counts), and influenced by differential experimental biases across taxa. Standard statistical methods often overlook these features. Many approaches analyze relative abundances without accounting for compositionality or rely on pseudocounts, potentially leading to spurious associations and inadequate false discovery rate (FDR) control. Methods:We introduce a novel framework for differential abundance analysis of microbiome data: the Compositional Accelerated Failure Time (CAFT) model. CAFT addresses zero read counts by treating them as censored observations that are below a detection limit. This approach is inherently resistant to multiplicative technical bias, eliminates the need for pseudocounts, and addresses compositional bias through the establishment of appropriate score test procedures. Results:Extensive simulations show that CAFT outperforms competing compositional differential abundance methods, including LOCOM, LinDA, ANCOM-BC2, its robust variant, and LDM-clr by offering more robust type I error and FDR control with or without technical bias. Additionally, we applied CAFT to microbiome data on inflammatory bowel disease (IBD) and the upper respiratory tract (URT) to identify differentially abundant gut microbial taxa between IBD patients and healthy controls, as well as URT taxa distinguishing smokers from non-smokers. Conclusion:We present CAFT, a powerful, robust, and efficient approach for compositional differential abundance analysis. CAFT effectively controls Type I error and maintains FDR control, while demonstrating enhanced power in statistical testing. These capabilities render CAFT a useful tool for compositional microbiome data analysis. Availability and implementation:The R package and Vignette are available at https://github.com/mli171/CAFT.

Increasing evidence suggests that human microbiota plays a crucial role in many diseases. Alpha diversity, a commonly used summary statistic that captures the richness and/or evenness of the microbial community, has been associated with many clinical conditions. However, individual studies that assess the association between alpha diversity and clinical conditions often provide inconsistent results due to insufficient sample size, heterogeneous study populations and technical variability. In practice, meta-analysis tools have been applied to integrate data from multiple studies. However, these methods do not consider the heterogeneity caused by sequencing protocols, and the contribution of each study to the final model depends mainly on its sample size (or variance estimate). To combine studies with distinct sequencing protocols, a robust statistical framework for integrative analysis of microbiome datasets is needed. Here, we propose a mixed-effect kernel machine regression model to assess the association of alpha diversity with a phenotype of interest. Our approach readily incorporates the study-specific characteristics (including sequencing protocols) to allow for flexible modeling of microbiome effect via a kernel similarity matrix. Within the proposed framework, we provide three hypothesis testing approaches to answer different questions that are of interest to researchers. We evaluate the model performance through extensive simulations based on two distinct data generation mechanisms. We also apply our framework to data from HIV reanalysis consortium to investigate gut dysbiosis in HIV infection.

Islet autoantibodies in adults classified as having type 2 diabetes (T2D) have been associated with lower adiposity and early insulin requirement. We examined the association between GADA, the most prevalent islet autoantibody, and baseline clinical features in Look AHEAD (Action for Health in Diabetes), a randomized trial of adults with clinically-diagnosed T2D and overweight/obesity from 16 geographically diverse U.S. study centers. GADA was measured by radioligand binding assay in 87% of the randomized cohort at study baseline and categorized as negative (GADA-), low-level (35-199 U/mL, GADA+) or high-level (≥200 U/mL, GADA++). We compared clinical features across GADA categories using Fisher’s exact or Kruskal-Wallis tests. There were 4,492 participants who had a median age 59 years and diabetes duration 5 years. Participants were 59% female, 67% white, 16% Black and 13% Hispanic. GADA was positive (≥35 U/mL) in 216 participants (4.8%); 131 were GADA+ (2.9%) and 85 GADA++ (1.9%). Insulin was used by 15% of GADA-, 25% of GADA+, and 40% of GADA++ (p<0.001). The median HbA1c was 7.0% in GADA-, 7.1% in GADA+, and 7.4% in GADA++ (p=0.004). There was a history of hypothyroidism in 12% of GADA-, 14% of GADA+, and 29% of GADA++ (p<0.001). There was a history of hyperthyroidism in 2% of GADA-, 2% of GADA+, and 7% of GADA++ (p=0.006). GADA level was not associated with age, sex, race/ethnicity, diabetes duration, BMI, waist circumference, or history of microvascular or macrovascular complications. In conclusion, a substantial minority of this population of adults with overweight/obesity who were clinically diagnosed as T2D have GADA positivity, and high levels were strongly associated with phenotypic differences including insulin use and thyroid disease. In contrast to prior studies, GADA was not associated with lower adiposity. These findings highlight the heterogeneity of this population and the need to further study the clinical implications of GADA positivity. Disclosure S.J.Pilla: None. A.Ramelius: None. R.Bennet: None. Å.Lernmark: Advisory Panel; Diamyd Medical. N.N.Mathioudakis: None. J.Clark: None. N.M.Maruthur: Other Relationship; Johns Hopkins HealthCare Solutions. W.C.Knowler: None. A.Balasubramanyam: None. C.S.Hampe: Employee; Immusoft corp. S.Pietropaolo: None. A.M.Anderson: None. M.Li: None. N.Zhao: None. S.L.Zeger: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126825, K23DK128572)

A minority of adults diagnosed with type 2 diabetes (T2D) have islet autoantibodies that may predict diabetes progression. We investigated the association between GADA, the most prevalent islet autoantibody, and longitudinal HbA1c in Look AHEAD (Action for Health in Diabetes), a trial that randomized adults with clinically-diagnosed T2D and overweight/obesity to intensive lifestyle intervention vs. control for 9.6 years, and then followed them observationally. GADA was measured by radioligand binding assay in 87% of the cohort at baseline and categorized as negative, low-level (35-199 U/mL) or high-level (≥200 U/mL). We analyzed the association between GADA category and HbA1c (yearly through year 4, then on alternating years) using linear mixed effects regression adjusted for age, sex, race/ethnicity, calendar time and study arm. Among 4,492 participants, the median age was 59 years and diabetes duration 5 years. GADA was low-level and high-level positive in 131 (2.9%) and 85 (1.9%), respectively. Over a median follow-up of 15.9 years, the modeled mean HbA1c was 7.24% in GADA-, 7.49% in low-level GADA, and 7.67% in high-level GADA (p<0.001). GADA+ participants had consistently higher HbA1c over follow-up in both study arms (Figure). In conclusion, a substantial minority of adults with clinically-diagnosed T2D had GADA positivity that predicted worse glycemic control for more than a decade. Disclosure S.J.Pilla: None. A.Ramelius: None. R.Bennet: None. Å.Lernmark: Advisory Panel; Diamyd Medical. N.N.Mathioudakis: None. J.Clark: None. N.M.Maruthur: Other Relationship; Johns Hopkins HealthCare Solutions. W.C.Knowler: None. A.Balasubramanyam: None. C.S.Hampe: Employee; Immusoft corp. S.Pietropaolo: None. A.M.Anderson: None. M.Li: None. N.Zhao: None. S.L.Zeger: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126825, K23DK128572)

Objective: Expression of circular RNAs (circRNAs) in the peripheral blood of individuals with latent autoimmune diabetes in adults (LADA) and type 2 diabetes mellitus (T2DM) were quantified to identify dysregulated circRNAs compared with control individuals.Methods: circRNAs were obtained from the peripheral blood serum of 12 healthy adults and 12 individuals with LADA and 12 type 2 diabetics. The circRNA expression profiles were analyzed by high-throughput RNA sequencing. The most highly dysregulated circular RNAs were validated by quantitative real-time polymerase chain reaction. A circular RNA-microRNA (miRNA) network diagram predicted the interactions of circular RNAs, miRNAs, and coding genes.Results: A total of 2334 differentially expressed circRNAs were detected among the three groups, with 277 circRNAs in the Group DM versus Group NG; 992 circRNAs in the Group LADA versus Group NG and 1065 circRNAs in the Group DM versus Group LADA. Six circRNAs were identified as the most distinctive differentially expressed targets (p < 0.05). The proposed molecular functions of these differentially expressed circRNAS included the tumor necrosis factor signaling pathway, the FoxO signaling pathway, cellular senescence, and long-term potentiation (all false discovery rate p < 0.05) which may contribute to T2DM and LADA.Conclusion: circRNAs are aberrantly expressed in the peripheral blood of patients with T2DM and LADA and may interact with miRNA and circRNA-derived peptides in the development of diabetes. Further investigations may illustrate the partial pathogenesis of diabetes mellitus.Clinical Trial Registration number: ChiCTR1900020644.

目的 探讨长链非编码RNA(LncRNA)在LADA和T2DM中的表达,并预测LncRNA作用的靶向基因,为LADA和T2DM的诊断及鉴别诊断提供基因表达谱.方法 选取2017年7月至2018年6月于吉林大学第二医院内分泌科就诊的DM患者或正常糖耐量(NGT)人群,分为T2DM组、LADA组及NGT组,每组各4例.采用高通量测序检测,挑选表达差异有统计学意义的LncRNA构建基因表达谱.结果 与NGT组比较,T2DM组LncRNA 68763个表达上调,28523个表达下调;LADA组LncRNA 68748个表达上调,28538个表达下调.各组LncRNA表达差异显著.在有统计学意义的数据中选取2个差异倍数最高的LncRNA(LncRNA ENST00000602845-NCBP2、LncRNA ENST00000364558-HECTD4)进一步分析,并通过GO、KEGG通路分析预测LncRNA的靶基因功能.结论 LADA、T2DM患者LncRNA表达谱与NGT人群存在明显差异,可能通过多种机制参与发病.

Lili Ning Jilin Univeristy Second Hospital Yan Yan Jilin University Second Hospital Xiying Fu Jilin University Second Hospital Yan Cheng Jilin University Second Hospital Mo Li Jilin University Second Hospital Xiujuan Zhang Jilin University Second Hospital Hong Shen Jilin University Second Hospital Maoguang Yang Jilin University Second Hospital Lijuan Wang Jilin University Second Hospital Hanqing Cai (  caihanqing16@163.com ) Jilin University Second Hospital https://orcid.org/0000-0002-9386-5286

BACKGROUND:Long noncoding RNAs (lncRNAs) were previously found to be closely related to the pathogenesis of diabetes. OBJECTIVES:To reveal the differentially expressed lncRNAs and messenger RNAs (mRNAs) involved in type 2 diabetes mellitus (T2DM) and latent autoimmune diabetes in adults (LADA) and predict the lncRNA target genes to derive their expression profiles for the diagnosis of T2DM and LADA and their differential diagnosis. METHODS:Twelve venous blood samples were collected from T2DM patients, LADA patients, and nondiseased subjects to obtain total RNAs. After removing rRNA from total RNAs to establish the desired library for sequencing, quality control and quantification analyses were carried out. The fragments per kilobase of exon model per million reads mapped (FPKM) of lncRNAs were calculated to construct the gene expression profiles of lncRNAs and mRNAs. Fold changes (fold change: 2.0) and p values (p values (. RESULTS:Compared to nondiseased controls, 68,763 versus 28,523 lncRNAs and 133 versus 1035 mRNAs were significantly upregulated and significantly downregulated, respectively, in T2DM patients. For LADA patients, 68,748 versus 28,538 lncRNAs and 219 versus 805 mRNAs were significantly upregulated and significantly downregulated, respectively, relative to nondiseased controls. Compared to T2DM patients, 74,207 versus 23,079 lncRNAs and 349 versus 137 mRNAs were significantly upregulated and significantly downregulated, respectively, in LADA patients. Based on the correlation analysis, seven lncRNA-mRNA pairs (BTG2, A2M, HECTD4, MBTPS1, DBH, FLVCR1, and NCBP2) were significantly coexpressed, and two lncRNAs (ENST00000608916 and ENST00000436373) were newly discovered. CONCLUSION:Significant differences in lncRNA expression were discovered among the three groups. Furthermore, after predicting lncRNA expression profiles, GO/KEGG pathway analysis could deduce the target gene function.

目的 调查吉林省地区病程≤1年的成人糖尿病患者中LADA患者的比例及临床特点,并验证T1DM诊断模型(CODE).方法 选取2015年3月至2018年3月于吉林大学第二医院门诊及住院治疗的、病程≤1年且年龄18～75岁的糖尿病患者397例,检测GADAb,计算其中LADA患者比例,分析其临床特点,并验证CODE.结果 397例糖尿病患者中,LADA患者(LADA组)44例(11.08％),T2DM患者(T2DM组)353例.LADA组BMI、FC-P及2 hC-P均低于T2DM组[(22.70±3.70)vs(25.21±3.86)kg/m2,(0.73±0.59)vs(1.42±1.02)ng/ml,(1.57±1.49)vs(3.31±2.42)ng/ml,P<0.01],有DKA、甲状腺疾病史的比例高于T2DM组(22.7％vs 8.2％,34.1％vs 7.4％,P<0.01).以CODE-C0>10.80为切点时,诊断LADA特异度和灵敏度分别为98.3％ 和11.4％;以CODE-C120>10.91为切点时,诊断LADA特异度和灵敏度分别为96.9％ 和20.5％.结论 LADA在病程≤1年的成人糖尿病患者中占11.08％;与T2DM患者比较,LADA患者BMI、FC-P及2 hC-P水平降低,DKA及甲状腺疾病发生率升高.应用CODE验证LADA的特异度和灵敏度差异较大.

Background: To investigate the characteristic expression of circular RNAs (circRNA) in the peripheral blood of individuals with latent autoimmune diabetes in adults (LADA) and healthy individuals(NG) to identify dysregulated circRNAs that could be used to differentiate between LADA and healthy individuals. Results: A total of 992 differentially expressed circRNAs were detected in the Group LA vs Group NG:209 circRNAs were significantly upregulated and 783 circRNAs downregulated.These circRNAs distributed on all chromosomes, including the sex chromosomes, and most of the differentially expressed circRNAs were derived from exons. Two circRNAs were identified as the most distinctive differentially expressed targets, hsa_circ_0097425 and newly-discovered circRNA-hsa_circ_62540520. We used qRT-PCR to verify the differentially expressed circRNAs, both circRNAs were statistically significant (p <0.05). Further studies have found that the two circRNAs may be associated with metabolic syndrome , inflammation and cell cycle. Conclusion: We determined that differentially expressed circRNAs could be used as new biomarkers for distinguishing LADA from healthy individuals. Further investigations may illustrate the partial pathogenesis of diabetes mellitus. Trial registration: ChiCTR, ChiCTR1900020644. Registered 11 January 2019, http://www.chictr.org.cn/showproj.aspx?proj=30591

目的 探讨LADA患者外周血环状RNA(circRNA)的差异性表达及LADA的发病机制.方法 选取2019年2～4月于吉林大学第二医院内分泌科治疗的12例LADA患者(LADA组),另选取同期我院健康体检者12名为正常对照(NC)组.通过高通量测序筛选出差异性表达的环状RNA表达谱,应用qRT-PCR验证circRNAs的显著失调.通过基因本体论和基因组途径富集分析,预测失调circRNAs的潜在功能.结果 高通量测序共发现992个差异表达的circRNAs,其中209个表达上调,783个表达下调,严格筛选出2个最显著表达的circRNAs(hsa_circ_100670302、hsa_circ_0035809),其中hsa_circ_100670302上调倍数为2.64,hsa_circ_0035809下调倍数为2.68.应用qRT-PCR对差异性表达的circRNA进行验证,均差异有统计学意义(P<0.05),与测序结果一致,可能与IR、免疫防御相关.结论 hsa_circ_100670302、hsa_circ_0035809可能阐明糖尿病的部分发病机制,成为临床诊治LADA新的分子靶点.

研究发现人类基因组可以被广泛转录成大量与疾病发生发展密切相关的非编码RNA（ncRNA）,其中环状RNA是一种内源性非编码RNA,参与人体病理生理过程调控,目前已有多项研究证明环状RNA（circRNA）在糖尿病的发生和发展过程中起着重要的调控作用。1环状RNA真核生物信息的传递过程主要为DNA转录成RNA并翻译成蛋白质。研究表明,人类基因组中至少有90%的DNA序列是被转录成RNA的,但仅有1.5%的DNA序列用于编码蛋白质,大部分的DNA序列则被转录成了非编码RNA。环状RNA是一种内源性非编码RNA,circRNA没有

Osteoporosis is a very common disease among elderly people but still no effective therapy to cure. Drug therapy as the prevent treatment in osteoporosis has been proved valuable in releasing the clinical symptom and prevent the progress of fracture. With the increasing variety of osteoporosis drugs, the comprehension of the effect and side effect of drugs are growing. The laboratory and clinical studies of osteoporosis were reviewed, and the efficacy and safety of drug were summarized in this article, hopefully it can provide theoretical basis for clinical treatment of osteoporosis. Key words: Osteoporosis; Drug therapy; Bisophosphonates; Parathyroid hormone

骨质疏松是2型糖尿病常见的慢性并发症之一,是由众多因素共同导致,与体内多种物质代谢和多项因素的功能障碍有着密切的关系[1,2]。临床工作者在对2型糖尿病患者治疗过程中应增加对骨质疏松的防治意识。1资料与方法1.1一般资料选择2017.09-2018.07于吉林大学第二医院内分泌科住院的2型糖尿病患者58例,其中已确诊2型糖尿病合并骨质疏松患者29例作为观察组（OP组）;2型糖尿病骨量正常患者29例作为对照组

正>糖尿病是由多种原因引起的一类以慢性高血糖为特征的代谢性疾病,近年来,糖尿病的患病率在迅速上升,根据国际糖尿病联合会的糖尿病图谱,世界上大约有4亿人患有2型糖尿病,每年有1000万人被诊断患有糖尿病[1]。按现行的分类标准,糖尿病主要分为1型糖尿病(T1DM)、2型糖尿病(T2DM)、妊娠期糖尿病等特殊类型糖尿病。有些T1DM患者发生在成年期,即成人迟发性自身免疫性糖尿病(laten-

Diabetic nephropathy (DN) is a common clinically relevant complication of diabetes that is associated with damage to the capillaries, yet the etiology of this condition remains unclear. Nuclear factor-kappa B (NF-κB) activation is known to be associated with DN-related inflammation and disease progression. Recent work indicated that microRNAs are diagnostic biomarkers of DN progression associated with inflammation in the progression of DN. miR-218 is known to play key regulatory roles in certain cancers in humans, while its influence on DN pathology remains uncertain. The present study, therefore, sought to assess how miR-218 influences the progression of disease in both a rat streptozotocin-induced model of DN and as well as an in vitro model system in which mouse podocytes were stimulated with high glucose levels. We found miR-218 to be markedly downregulated in both model systems relative to appropriate controls, and this downregulation was associated with IKK-β upregulation. In DN rat model, overexpressing miR-218 was sufficient to reduce renal injury. We further determined that podocyte proliferation was markedly impaired by glucose treatment, leading to the apoptotic death of these cells, and miR-218 mimics were able to reduce these phenotypes. Overexpressing miR-218 also significantly dampened inflammatory responses in this model system, as evidenced by reduced tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β, and MCP-1 levels. We then confirmed that miR-218 targeting the messenger RNA encoding IKK-β using a dual-luciferase reporter assay. Together, our results provide clear evidence that miR-218 regulate NF-κB-mediated inflammation, which is central to DN progression.

妊娠期暴发性1型糖尿病（fulminant type 1diabetes mellitus,F1DM）往往起病急骤,多合并糖尿病酮症酸中毒（diabetic ketoacidosis,DKA）、多脏器功能损害,病情危重,常易出现死胎等不良情况,临床诊治存在一定困难,近期我院收治妊娠期暴发性1型糖尿病1例,现将诊治情况报告如