Journal of Diabetes最新文献

Long noncoding RNAs and metabolic memory associated with continued progression of diabetic retinopathy 与糖尿病视网膜病变持续进展相关的长非编码 RNA 和代谢记忆

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-18 DOI: 10.1111/1753-0407.70009

Jay Kumar, Pooja Malaviya, Renu A. Kowluru

Progression of diabetic retinopathy resists arrest even after institution of intensive glycemic control, suggesting a “metabolic memory” phenomenon, but the mechanism responsible for this phenomenon is still elusive. Gene expression and biological processes can also be regulated by long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading frame for translation, and several LncRNAs are aberrantly expressed in diabetes. Our aim was to identify retinal LncRNAs that fail to reverse after termination of hyperglycemia. Microarray analysis was performed on retinal RNA from streptozotocin-induced diabetic rats in poor glycemic control for 8 months, followed by in good glycemic control (blood glucose >400 mg/dL), or for 4 months, with four additional months of good glycemic control (blood glucose <150 mg/dL). Differentially expressed LncRNAs and mRNAs were identified through Volcano filtering, and their functions were predicted using gene ontology and pathway enrichment analyses. Compared with age-matched normal rats, rats in continuous poor glycemic control had >1479 differentially expressed LncRNAs (710 downregulated, 769 upregulated), and among those, 511 common LncRNAs had similar expression in Diab and Rev groups (139 downregulated, 372 upregulated). Gene Ontology/pathway analysis identified limited LncRNAs in biological processes, but analysis based on biological processes/molecular function revealed >350 genes with similar expression in Diab and Rev groups; these genes were mainly associated with stress response, cell death, mitochondrial damage and cytokine production. Thus, identifying retinal LncRNAs and their gene targets that do not benefit from termination of hyperglycemia have potential to serve as therapeutic targets to slow down the progression of diabetic retinopathy.

糖尿病视网膜病变的进展即使在强化血糖控制后也不会停止，这表明存在一种 "代谢记忆 "现象，但造成这种现象的机制仍然难以捉摸。基因表达和生物过程也可受长非编码 RNA（LncRNA）的调控，LncRNA 是一种长度为 200 个核苷酸、没有开放阅读框的 RNA，可用于翻译。我们的目的是找出在高血糖终止后不能逆转的视网膜 LncRNA。我们对链脲佐菌素诱导的糖尿病大鼠视网膜 RNA 进行了微阵列分析，这些大鼠血糖控制不良 8 个月，随后血糖控制良好（血糖 400 mg/dL），或血糖控制良好 4 个月，血糖控制良好 4 个月（血糖 150 mg/dL）。通过火山过滤确定了差异表达的 LncRNA 和 mRNA，并利用基因本体论和通路富集分析预测了它们的功能。与年龄匹配的正常大鼠相比，持续血糖控制不良的大鼠有>1479个不同表达的LncRNA（710个下调，769个上调），其中511个常见的LncRNA在Diab组和Rev组有相似的表达（139个下调，372个上调）。基因本体/通路分析在生物过程中发现了有限的LncRNA，但基于生物过程/分子功能的分析发现了350个基因在Diab组和Rev组中有相似的表达；这些基因主要与应激反应、细胞死亡、线粒体损伤和细胞因子的产生有关。因此，确定视网膜 LncRNA 及其基因靶点，这些基因靶点不会从终止高血糖中获益，有可能成为延缓糖尿病视网膜病变进展的治疗靶点。

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引用次数: 0

Subcellular mass spectrometric detection unveils hyperglycemic memory in the diabetic heart 亚细胞质谱检测揭示糖尿病心脏的高血糖记忆。

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-13 DOI: 10.1111/1753-0407.70033

Jiabing Zhan, Yufei Zhou, Yifan Chen, Kunying Jin, Zhaoyang Chen, Chen Chen, Huaping Li, Dao Wen Wang

<div> <section> <h3> Background</h3> <p>Intensive glycemic control is insufficient to reduce the risk of heart failure in patients with diabetes mellitus. While the hyperglycemic memory in the diabetic cardiomyopathy has been well documented, its underlying mechanisms are not fully understood. The present study tried to investigate whether the dysregulated proteins/biological pathways, which persistently altered in diabetic hearts during normoglycemia, participate in the hyperglycemic memory.</p> </section> <section> <h3> Methods</h3> <p>Hearts of streptozotocin-induced diabetic mice, with or without intensive glycemic control using slow-release insulin implants, were collected. Proteins from total heart samples and subcellular fractions were assessed by mass spectrometry, Western blotting, and KEGG pathway enrichment analysis. mRNA sequencing was used to determine whether the persistently altered proteins were regulated at the transcriptional or post-transcriptional level.</p> </section> <section> <h3> Results</h3> <p>Western blot validation of several proteins with high pathophysiological importance, including MYH7, HMGCS2, PDK4, and BDH1, indicated that mass spectrometry was able to qualitatively, but not quantitatively, reflect the fold changes of certain proteins in diabetes. Pathway analysis revealed that the peroxisome, PPAR pathway, and fatty acid metabolism could be efficiently rescued by glycemic control. However, dysregulation of oxidative phosphorylation and reactive oxygen species persisted even after normalization of hyperglycemia. Notably, mRNA sequencing revealed that dysregulated proteins in the oxidative phosphorylation pathway were not accompanied by coordinated changes in mRNA levels, indicating post-transcriptional regulation. Moreover, literature review and bioinformatics analysis suggested that hyperglycemia-induced persistent alterations of miRNAs targeted genes from the persistently dysregulated oxidative phosphorylation pathway, whereas, oxidative phosphorylation dysfunction-induced ROS regulated miRNA expression, which thereby might sustained the dysregulation of miRNAs.</p> </section> <section> <h3> Conclusions</h3> <p>Glycemic control cannot rescue hyperglycemia-induced alterations of subcellular proteins in the diabetic heart, and persistently altered proteins are involved in multiple functional pathways, including oxidative phosphorylation. These findings might provide novel insights into hyperglycemic memory in diabetic cardiomyopathy.</p> <div> <figure>

背景：强化血糖控制不足以降低糖尿病患者发生心力衰竭的风险。虽然糖尿病心肌病的高血糖记忆已被充分记录，但其潜在机制尚未完全明了。方法：收集链脲佐菌素诱导的糖尿病小鼠的心脏，无论是否使用缓释胰岛素植入进行强化血糖控制。通过质谱分析、Western印迹分析和KEGG通路富集分析评估了心脏总样本和亚细胞组分中的蛋白质：对包括MYH7、HMGCS2、PDK4和BDH1在内的几种具有重要病理生理意义的蛋白质进行的Western印迹验证表明，质谱法能够定性而非定量地反映糖尿病患者某些蛋白质的折叠变化。通路分析表明，控制血糖可以有效地挽救过氧化物酶体、PPAR 通路和脂肪酸代谢。然而，即使在高血糖恢复正常后，氧化磷酸化和活性氧的失调仍然存在。值得注意的是，mRNA 测序显示，氧化磷酸化途径中失调的蛋白质并没有伴随着 mRNA 水平的协调变化，这表明存在转录后调控。此外，文献综述和生物信息学分析表明，高血糖诱导的 miRNAs 持续改变针对的是氧化磷酸化途径中持续失调的基因，而氧化磷酸化功能障碍诱导的 ROS 可调控 miRNA 的表达，从而可能维持 miRNAs 的失调：结论：血糖控制不能挽救高血糖诱导的糖尿病心脏亚细胞蛋白的改变，而持续改变的蛋白涉及多种功能通路，包括氧化磷酸化。这些发现可能为糖尿病心肌病的高血糖记忆提供了新的见解。

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引用次数: 0

Structural and functional alterations of the hippocampal subfields in T2DM with mild cognitive impairment and insulin resistance: A prospective study 伴有轻度认知障碍和胰岛素抵抗的 T2DM 患者海马亚区的结构和功能改变：一项前瞻性研究

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-13 DOI: 10.1111/1753-0407.70029

Chen Yang, Huiyan Zhang, Zihan Ma, Yanjun Fan, Yanan Xu, Jian Tan, Jing Tian, Jiancang Cao, Wenwen Zhang, Gang Huang, Lianping Zhao

Background

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and is often accompanied by mild cognitive impairment (MCI). The detrimental effects of T2DM and IR on the hippocampus have been extensively demonstrated. Few studies have examined the effects of IR on structure and function of hippocampal subfields in T2DM-MCI patients.

Method

A total of 104 T2DM patients were recruited in this prospective study and divided into four groups (T2DM-MCI-higherIR, n = 17; T2DM-MCI-lowerIR, n = 32; T2DM-nonMCI-higherIR, n = 19; T2DM-nonMCI-lowerIR, n = 36). Structure and function MRI data were captured. Clinical variables and neuropsychological scores were determined for all participants. Hippocampal subfield volume and functional connectivity were compared among four groups. Partial correlation analysis was performed between imaging indicators, clinical variables, and neuropsychological scores in all patients.

Results

T2DM-MCI-higher IR group had the smallest volumes of bilateral hippocampal tail, right subiculum-body, right GC-ML-DG-body, and right CA4-body. IR in right hippocampal tail, right subiculum-body, and right GC-ML-DG-body exerted main effect. Furthermore, elevated functional connectivity was found between right subiculum-body and bilateral dorsolateral prefrontal cortex and right anterior cingulate–medial prefrontal cortex. Hippocampal subfield volume positively correlates with total cholesterol and triglycerides and negatively correlates with fasting insulin.

Conclusion

The present study found that T2DM-MCI patients have structural and functional alterations in hippocampal subfields, and IR is a negative factor influencing the alteration of hippocampal subfields volume. These findings support the importance of IR in T2DM-MCI patients and might be potential neuroimaging biomarkers of cerebral impairment in T2DM-MCI patients.

背景：2 型糖尿病（T2DM）以胰岛素抵抗（IR）为特征，通常伴有轻度认知障碍（MCI）。T2DM 和 IR 对海马的有害影响已得到广泛证实。很少有研究探讨 IR 对 T2DM-MCI 患者海马亚区结构和功能的影响：方法：这项前瞻性研究共招募了104名T2DM患者，并将其分为四组（T2DM-MCI-高IR组，n = 17；T2DM-MCI-低IR组，n = 32；T2DM-非MCI-高IR组，n = 19；T2DM-非MCI-低IR组，n = 36）。采集了结构和功能磁共振成像数据。确定了所有参与者的临床变量和神经心理学评分。比较了四组患者的海马亚区体积和功能连通性。对所有患者的成像指标、临床变量和神经心理学评分进行了部分相关性分析：结果：T2DM-MCI-高IR组的双侧海马尾部、右侧子丘体、右侧GC-ML-DG体和右侧CA4体的体积最小。右侧海马尾部、右侧子网体和右侧GC-ML-DG体的IR具有主效应。此外，还发现右侧子房体与双侧背外侧前额叶皮层和右侧前扣带回-内侧前额叶皮层之间的功能连接性增强。海马亚区体积与总胆固醇和甘油三酯呈正相关，与空腹胰岛素呈负相关：本研究发现，T2DM-MCI 患者的海马亚区存在结构和功能改变，而 IR 是影响海马亚区体积改变的负性因素。这些发现支持了IR在T2DM-MCI患者中的重要性，并可能成为T2DM-MCI患者脑损伤的潜在神经影像生物标志物。

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引用次数: 0

Associations of maternal serum ferritin levels across gestation with gestational diabetes mellitus: A longitudinal cohort study 妊娠期母体血清铁蛋白水平与妊娠糖尿病的关系：一项纵向队列研究。

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-11 DOI: 10.1111/1753-0407.70027

Huiqin Mo, Jingna Wen, Cuicui Qu, Xiaohua Liu

Background

The longitudinal changes in maternal serum ferritin (SF) levels across gestation, which indirectly reflect iron supplementation, have not been extensively investigated in relation to gestational diabetes mellitus (GDM).

Methods

We conducted a retrospective cohort study at a tertiary maternal hospital in Shanghai. Women with SF concentration measurements at 8.0–13.6 weeks' gestation (GW), 29.0–31.6 GW, and an oral glucose tolerance test (OGTT) at 24–28 GW were included. We utilized logistic regression analysis to assess GDM association with maternal SF levels and longitudinal changes.

Results

The study included 17 560 women, with 2160 (12.3%) participants diagnosed with GDM. Adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for GDM across increasing quartiles of SF concentrations at 8.0–13.6 GW were 1.00 (reference), 1.139 (95% CI: 1.012–1.283), 1.093 (95% CI: 0.969–1.233), and 1.248 (95% CI: 1.111–1.403). Similarly, at 29.0–31.6 GW, increasing quartiles of SF concentrations were associated with higher adjusted ORs for GDM: 1.00 (reference), 1.165 (95% CI: 1.029–1.320), 1.335 (95% CI: 1.184–1.505), and 1.428 (95% CI: 1.268–1.607). Pregnant women with higher SF levels (upper 25th percentile) at 8.0–13.6 GW had a reduced GDM risk if their SF levels decreased to the lower 25th percentile at 29.0–31.6 GW. Conversely, the subgroup with higher SF levels (upper 25th percentile) at both time points had the highest incidence rate of GDM (15.3%, 1.235 [95% CI: 1.087–1.404]).

Conclusions

Maternal SF levels independently and positively associated with GDM risk during early and late gestational stages. Considering the increased GDM risk, routine iron supplementation for iron-replete women is questionable.

背景：母体血清铁蛋白（SF）水平在整个妊娠期的纵向变化可间接反映铁的补充情况，但该变化与妊娠期糖尿病（GDM）的关系尚未得到广泛研究：我们在上海一家三级甲等妇产医院开展了一项回顾性队列研究。研究纳入了在妊娠 8.0-13.6 周（GW）、29.0-31.6 周（GW）和 24-28 周（GW）进行口服葡萄糖耐量试验（OGTT）的 SF 浓度测量结果。我们利用逻辑回归分析评估了 GDM 与母亲 SF 水平的关系及纵向变化：研究共纳入 17 560 名妇女，其中 2160 人（12.3%）被诊断为 GDM。在 8.0-13.6 GW 时，SF 浓度的四分位数越高，GDM 的调整几率比（ORs）（95% 置信区间 [CIs]）分别为 1.00（参考值）、1.139（95% CI：1.012-1.283）、1.093（95% CI：0.969-1.233）和 1.248（95% CI：1.111-1.403）。同样，在 29.0-31.6 GW，SF 浓度的四分位数越高，GDM 的调整 OR 越高：1.00（参考值）、1.165（95% CI：1.029-1.320）、1.335（95% CI：1.184-1.505）和 1.428（95% CI：1.268-1.607）。在 8.0-13.6 GW 时 SF 水平较高（第 25 百分位数偏上值）的孕妇，如果在 29.0-31.6 GW 时 SF 水平降至第 25 百分位数偏下值，则 GDM 风险会降低。相反，在两个时间点都具有较高 SF 水平（第 25 百分位数偏上值）的亚组的 GDM 发生率最高（15.3%，1.235 [95% CI：1.087-1.404]）：母体 SF 水平与妊娠早期和晚期的 GDM 风险呈独立正相关。考虑到 GDM 风险的增加，对铁缺乏的妇女进行常规铁补充是值得商榷的。

{"title":"Associations of maternal serum ferritin levels across gestation with gestational diabetes mellitus: A longitudinal cohort study","authors":"Huiqin Mo, Jingna Wen, Cuicui Qu, Xiaohua Liu","doi":"10.1111/1753-0407.70027","DOIUrl":"10.1111/1753-0407.70027","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The longitudinal changes in maternal serum ferritin (SF) levels across gestation, which indirectly reflect iron supplementation, have not been extensively investigated in relation to gestational diabetes mellitus (GDM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a retrospective cohort study at a tertiary maternal hospital in Shanghai. Women with SF concentration measurements at 8.0–13.6 weeks' gestation (GW), 29.0–31.6 GW, and an oral glucose tolerance test (OGTT) at 24–28 GW were included. We utilized logistic regression analysis to assess GDM association with maternal SF levels and longitudinal changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study included 17 560 women, with 2160 (12.3%) participants diagnosed with GDM. Adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for GDM across increasing quartiles of SF concentrations at 8.0–13.6 GW were 1.00 (reference), 1.139 (95% CI: 1.012–1.283), 1.093 (95% CI: 0.969–1.233), and 1.248 (95% CI: 1.111–1.403). Similarly, at 29.0–31.6 GW, increasing quartiles of SF concentrations were associated with higher adjusted ORs for GDM: 1.00 (reference), 1.165 (95% CI: 1.029–1.320), 1.335 (95% CI: 1.184–1.505), and 1.428 (95% CI: 1.268–1.607). Pregnant women with higher SF levels (upper 25th percentile) at 8.0–13.6 GW had a reduced GDM risk if their SF levels decreased to the lower 25th percentile at 29.0–31.6 GW. Conversely, the subgroup with higher SF levels (upper 25th percentile) at both time points had the highest incidence rate of GDM (15.3%, 1.235 [95% CI: 1.087–1.404]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Maternal SF levels independently and positively associated with GDM risk during early and late gestational stages. Considering the increased GDM risk, routine iron supplementation for iron-replete women is questionable.</p>\u0000 \u0000 <div>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":189,"journal":{"name":"Journal of Diabetes","volume":"16 11","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11551590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex differences of visceral fat with cardiac structure and function in type 2 diabetes: A cross-sectional study 2型糖尿病患者内脏脂肪与心脏结构和功能的性别差异：一项横断面研究

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-07 DOI: 10.1111/1753-0407.70023

Chen Rui-hua, Lin Yi, Xu Huan-bai, Wang Yu-fan, Peng Yong-de

Background

The aim of this study is to analyze the associations among fat distribution, left ventricular (LV) structure, and function in T2DM patients and further assess the sex differences among them.

Methods

Two thousand and one hundred seven T2DM patients were enrolled to this study. Patients' height, weight, BMI, visceral fat area (VFA), baPWV, parameters of cardiac structure and function, and clinical biochemical indicators were measured and collected.

Results

There were significant differences between male and female T2DM patients in age, duration of diabetes, complication ratio of hypertension and dyslipidemia, smoking history, visceral fat, baPWV, and ventricular structure and function (p < 0.05). Compared with the Q1 group, female patients in the highest quartile (Q4) of VFA had a decreased LVEF and significantly increased baPWV (p < 0.05), whereas no such changes were found in males. The correlation analysis showed that LVEF in male patients was negatively correlated with hypertension history, using of CCBs, GLP-1RA, lipid-lowering medications, BMI, WC, WHR, FPG, FC-P, HbA1c, GA, HOMA-IR, Cr, and baPWV, while the LVEF in female patients was negatively correlated with VFA, VSR, VFA/BMI, VFA/H², VFA/weight in females (p < 0.05). LVMI was positively associated with diabetes duration, age, hypertension history, WC, WHR, VFA, SFA, VFA/BMI, VFA/H², VFA/weight, and baPWV in both males and females. Multivariable-adjusted linear regression analysis showed that VFA was independently associated with LVEF (β = − 0.096, p = 0.010), LVMI (β = 0.083, p = 0.038), and baPWV (β = 0.120, p = 0.003) in females.

Conclusions

Values of VFA were independently associated with LVEF, LVMI, and baPWV in women, but not in men, in patients with T2DM.

背景：本研究旨在分析 T2DM 患者的脂肪分布、左心室结构和功能之间的关系，并进一步评估其性别差异：本研究旨在分析 T2DM 患者的脂肪分布、左心室（LV）结构和功能之间的关联，并进一步评估其中的性别差异：本研究共招募了 2 107 名 T2DM 患者。测量并收集患者的身高、体重、体重指数（BMI）、内脏脂肪面积（VFA）、baPWV、心脏结构和功能参数以及临床生化指标：男性和女性 T2DM 患者在年龄、糖尿病病程、高血压和血脂异常并发症比例、吸烟史、内脏脂肪、baPWV、心室结构和功能（p 2，女性的内脏脂肪面积/体重（p 2，男性和女性的内脏脂肪面积/体重、baPWV）方面均存在明显差异。多变量调整线性回归分析显示，VFA 与女性的 LVEF（β = - 0.096，p = 0.010）、LVMI（β = 0.083，p = 0.038）和 baPWV（β = 0.120，p = 0.003）独立相关：结论：在 T2DM 患者中，VFA 值与女性 LVEF、LVMI 和 baPWV 独立相关，但与男性无关。

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引用次数: 0

Clinical characteristics, treatment, and treatment switch after molecular-genetic classification in individuals with maturity-onset diabetes of the young: Insights from the multicenter real-world DPV registry 年轻成熟型糖尿病患者的临床特征、治疗和分子遗传学分类后的治疗转换：来自多中心真实世界 DPV 登记的启示。

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-07 DOI: 10.1111/1753-0407.70028

Stefanie Lanzinger, Katharina Laubner, Katharina Warncke, Julia K. Mader, Sebastian Kummer, Claudia Boettcher, Torben Biester, Angela Galler, Daniela Klose, Reinhard W. Holl

Background

Individuals with maturity-onset diabetes of the young (MODY) are often misdiagnosed as type 1 or type 2 diabetes and receive inappropriate care. We aimed to investigate the characteristics and treatment of all MODY types in a multicenter, real-world setting.

Methods

Individuals with MODY from the diabetes prospective follow-up (DPV) registry were studied. We compared clinical parameters during the first year of diabetes and the most recent treatment year after MODY diagnosis.

Results

A total of 1640 individuals were identified with GCK-MODY (n = 941) and HNF1A-MODY (n = 417) as the most frequent types. Among these, 912 individuals were available with information during the first and the most recent treatment year (median duration of follow-up: 4.2 years [2.6–6.6]). Positive beta cell autoantibodies were present in 20.6% (15.2% IAA). Median age at diagnosis ranged from 9.9 years in GCK-MODY (Q1–Q3: 6.2–13.1 years) and INS-MODY (2.7–13.7 years) to 14.3 years (5.0–17.1) in KCNJ11-MODY. Frequency of oral antidiabetic agents (OAD) use increased and insulin decreased in HNF4A-MODY (OAD: 18% to 39%, insulin: 34% to 23%) and in HNF1A-MODY (OAD: 18% to 31%, insulin: 35% to 25%). ABCC8-MODY was characterized by a decrement in nonpharmacological treatment (26% to 16%) and “insulin only” treatment (53% to 42%), while the proportion of individuals treated with OAD but no insulin increased from 0% to 21%.

Conclusions

Our results indicate that some teams caring for individuals with MODY are hesitant with regard to current recommendations. Registries are an essential source of information and provide a basis for discussing treatment guidelines for MODY.

背景：青年成熟型糖尿病（MODY）患者经常被误诊为 1 型或 2 型糖尿病，并接受不恰当的治疗。我们的目的是在多中心、真实世界环境中调查所有 MODY 类型的特征和治疗情况：方法：我们对糖尿病前瞻性随访（DPV）登记册中的 MODY 患者进行了研究。我们比较了糖尿病第一年的临床参数和确诊 MODY 后最近治疗一年的临床参数：结果：共确定了 1640 人，其中 GCK-MODY（941 人）和 HNF1A-MODY（417 人）是最常见的类型。其中，912 人提供了第一个和最近一个治疗年度的信息（中位随访时间：4.2 年 [2.6-6.6]）。20.6%的患者出现β细胞自身抗体阳性（15.2%为IAA）。诊断时的中位年龄从 GCK-MODY 的 9.9 岁（Q1-Q3：6.2-13.1 岁）和 INS-MODY 的 2.7-13.7 岁到 KCNJ11-MODY 的 14.3 岁（5.0-17.1 岁）不等。在 HNF4A-MODY （OAD：18% 至 39%，胰岛素：34% 至 23%）和 HNF1A-MODY （OAD：18% 至 31%，胰岛素：35% 至 25%）中，口服抗糖尿病药物（OAD）的使用频率增加，而胰岛素的使用频率下降。ABCC8-MODY 的特点是非药物治疗（26% 降至 16%）和 "仅胰岛素 "治疗（53% 降至 42%）的减少，而使用 OAD 但不使用胰岛素治疗的患者比例从 0% 增至 21%：我们的研究结果表明，一些治疗中度糖尿病患者的团队对当前的建议犹豫不决。登记是一个重要的信息来源，为讨论 MODY 的治疗指南提供了基础。

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引用次数: 0

β-Cell gene expression stress signatures in types 1 and 2 diabetes 1 型和 2 型糖尿病的 β 细胞基因表达应激特征。

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-06 DOI: 10.1111/1753-0407.70026

Xiaoyan Yi, Decio L. Eizirik

<p>Diabetes mellitus (DM) is a chronic metabolic disorder that occurs when pancreatic β-cells can no longer produce enough insulin to maintain normal blood glucose levels. DM presently affects 10.5% of the world adult population. While T1D is a disease of “mistaken identity,” where the immune system attacks and destroys pancreatic β-cells in the context of islet inflammation (insulitis),<span><sup>1</sup></span> T2D is associated with sedentary lifestyles and high-fat diets, typically involving ineffective use of insulin and progressive loss of β-cell function.<span><sup>1</sup></span> Both diseases result from multifaceted interactions between genetic and environmental factors, with β-cell failure as the core mechanism of pathogenesis.</p><p>In T1D, the disease arises from a complex interaction between immune cells and β-cells, involving chemokine and cytokine release and signals from stressed or dying β-cells that attract and activate immune cells to the islets and lead to β-cell apoptosis.<span><sup>2</sup></span> Beyond the destruction of β-cells by the immune system, it is now accepted that stress and impaired function of these cells significantly contribute to the onset and progression of the disease.<span><sup>1-3</sup></span> In T2D, the disease is driven by an interplay between insulin resistance and β-cell dysfunction in genetically susceptible individuals, with metabolic stress and perhaps also inflammation impairing insulin secretion and eventually β-cell survival, although to a less degree than in T1D.<span><sup>1, 4, 5</sup></span></p><p>The complexity of diabetes pathogenesis makes it very difficult to identify specific causes of the disease, which hampers the development of adequate therapies to protect β-cells and thus prevent disease. This difficulty was well described by Tolstoy, in his masterpiece “War and Peace,” published 1869 (in this case addressing the Napoleonic war against tsarist Russia): “…the impulse to seek causes is innate in the soul of man. And the human intellect, with no inkling on the immense variety and complexity of circumstances conditioning a phenomena, any one of which may be separately conceived of as the cause of it, snatches the first and most easily understood approximation, and says here is the cause.” In the context of pathophysiology, this had led to the simplistic view of “one gene, one protein, one disease.” However, with the sequencing of the human genome and the subsequent advent of omics technologies that allow interrogating the whole system in a parallel and often also in a sequential way, our understanding of complex diseases changed: we now focus on the dysfunction of gene and transcription factor networks and of post-transcriptional and post-translational mechanisms.</p><p>The advent of single-cell RNA sequencing (scRNA-seq) has provided a new tool for dissecting the molecular intricacies underlying pancreatic islet cells stress and thus addressing mechanisms of disease closer to its real

本分析的一个潜在局限性是从三组中回收的细胞数量不同（27 个非糖尿病对照组回收了 15 281 个细胞，7 个 T1D 回收了 585 个细胞，10 个 T2D 回收了 1455 个细胞），这既是由于供体数量不同，也是由于糖尿病过程中 β 细胞的固有损失（与从糖尿病患者身上分离胰岛的困难有关）。尽管存在这种方法上的局限性，但我们的分析表明，T1D 和 T2D 的所有 β 细胞应激特征均上调，T1D 在所有形式的应激中得分更高（图 1）。值得注意的是，与 T2D 或非糖尿病对照组相比，T1D β 细胞的炎症特征得分增加了 200%。与非糖尿病患者相比，T1D患者的β细胞在衰老、自噬、细胞凋亡和ER应激方面的特征得分也明显增加（20%-43%），而与对照组相比，T2D患者的β细胞在衰老、自噬、细胞凋亡和ER应激方面的特征得分仅轻微增加（6%-27%）。这些结果证实并扩展了Maestas等人6 的观察结果，即T1D和T2D患者的β细胞都经历了多种形式的应激，同时强调T1D患者的β细胞经历了更严重的应激，这与T1D患者的β细胞比T2D患者损失得更快、更多是一致的。5 为了了解 UPR 与糖尿病患者细胞凋亡或细胞衰老之间的关系，我们利用上述特征指数得分进行了相关性分析。在 T1D 和 T2D 中，UPR 与细胞凋亡和细胞衰老之间存在明显的正相关性（图 2），在 T1D 中观察到的相关性最强（图 2A），这与组织学在 T1D 患者的胰岛中检测到的 ER 应激标记物相符12。我们发现，这些应激信号通路共同有效地预测了 T1D（R2 = 0.80）和 T2D（R2 = 0.75）的细胞死亡特征。首先，针对β细胞应激途径--尤其是炎症、ER应激和衰老--可能为T1D提供一种治疗策略，在一定程度上也可为T2D提供一种治疗策略。然而，这些观察结果必须谨慎考虑，因为仅靠基因特征不足以识别衰老，而且衰老分泌表型的许多标记物（转录因子 NF-κB 和 STATs 的下游标记物13 ）也是自身免疫诱导的胰岛炎的一部分，2、5 因此很难区分 T1D 中衰老和炎症诱导的特征。有研究表明，有针对性地消除衰老的 β 细胞可预防非肥胖（NOD）糖尿病小鼠的糖尿病14 ，而且 T1D 患者残留的 β 细胞中存在早期衰老特征，这些都支持衰老成分在 T1D 中的作用15。目前的分析还表明，在 T1D 和 T2D 中，UPR 与细胞凋亡之间以及 UPR 与细胞衰老之间存在正相关，但 T2D 的相关性较小。16 IRE1 是 UPR 的主调控因子之一，可在 "终端 "ER 应激水平诱导 β 细胞凋亡和退化，而在小鼠模型中抑制 IRE1 可保护 β 细胞，并可能为糖尿病提供治疗机会。此外，抑制另一种 UPR 调节因子，即 eIF2α 激酶 PERK，可逆转受压人类胰岛中存在的翻译阻滞，并预防 NOD 小鼠的糖尿病。值得注意的是，不同的 β 细胞应激之间也存在相互影响，因为在 NOD 小鼠胰岛炎发病前，删除 UPR 基因 ATF6 和 IRE1α，会导致 p21 驱动的早期衰老表型，但矛盾的是，这种表型会减少终末 β 细胞衰老和糖尿病的发病率。未来的研究应探索上述应激信号通路及其前沿基因之间的相互作用，以及它们在不同类型糖尿病中对β细胞功能和存活的综合影响。本评论基于 44 例人类胰岛供体的 scRNA-seq 数据，采用指数评分法，突出了 T1D 和 T2D 中的β细胞应激特征。主要研究结果表明，T1D（T2D 的程度较轻）的特征是炎症应激升高和多种应激信号通路紊乱。在 UPR、细胞凋亡和细胞衰老之间观察到了很强的相关性。这些结果为Maestas等人先前的体外研究结果6增添了相关的人类疾病信息，并强调了研究自身免疫性或退行性疾病中受影响人体组织的基因特征对于寻找更好、更有针对性的疗法以解决疾病真正复杂程度的相关性。Decio L. Eizirik负责审阅、编辑和添加内容。两位作者都批准了手稿的最终版本。易小燕和Decio L. Eizirik的贡献巨大，符合国际医学期刊编辑委员会的最新准则。易小燕和Decio L. Eizirik为本著作的担保人。作者的研究得到了突破 T1D（前身为国际 JDRF（3-SRA-2022-1201-S-B [1] 和 3-SRA-2022-1201-S-B [2]））、美国国立卫生研究院--人类胰岛研究网络联合体关于 Beta 细胞死亡&amp；从胰腺 β 细胞基因网络到治疗的生存研究网络联盟（HIRN-CBDS）（U01 DK127786 基金）；以及美国国立卫生研究院 NIDDK 基金 RO1DK126444 和 RO1DK133881-01。作者声明与本评论无利益冲突。

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引用次数: 0

Long noncoding RNAs and metabolic memory associated with continued progression of diabetic retinopathy. 与糖尿病视网膜病变持续进展相关的长非编码 RNA 和代谢记忆。

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-11-01 DOI: 10.1111/1753-0407.70009

Jay Kumar, Pooja Malaviya, Renu A Kowluru

Progression of diabetic retinopathy resists arrest even after institution of intensive glycemic control, suggesting a "metabolic memory" phenomenon, but the mechanism responsible for this phenomenon is still elusive. Gene expression and biological processes can also be regulated by long noncoding RNAs (LncRNAs), the RNAs with >200 nucleotides and no open reading frame for translation, and several LncRNAs are aberrantly expressed in diabetes. Our aim was to identify retinal LncRNAs that fail to reverse after termination of hyperglycemia. Microarray analysis was performed on retinal RNA from streptozotocin-induced diabetic rats in poor glycemic control for 8 months, followed by in good glycemic control (blood glucose >400 mg/dL), or for 4 months, with four additional months of good glycemic control (blood glucose <150 mg/dL). Differentially expressed LncRNAs and mRNAs were identified through Volcano filtering, and their functions were predicted using gene ontology and pathway enrichment analyses. Compared with age-matched normal rats, rats in continuous poor glycemic control had >1479 differentially expressed LncRNAs (710 downregulated, 769 upregulated), and among those, 511 common LncRNAs had similar expression in Diab and Rev groups (139 downregulated, 372 upregulated). Gene Ontology/pathway analysis identified limited LncRNAs in biological processes, but analysis based on biological processes/molecular function revealed >350 genes with similar expression in Diab and Rev groups; these genes were mainly associated with stress response, cell death, mitochondrial damage and cytokine production. Thus, identifying retinal LncRNAs and their gene targets that do not benefit from termination of hyperglycemia have potential to serve as therapeutic targets to slow down the progression of diabetic retinopathy.

糖尿病视网膜病变的进展即使在强化血糖控制后也不会停止，这表明存在一种 "代谢记忆 "现象，但造成这种现象的机制仍然难以捉摸。基因表达和生物过程也可受长非编码 RNA（LncRNA）的调控，LncRNA 是一种核苷酸大于 200 个且没有开放阅读框用于翻译的 RNA，有几种 LncRNA 在糖尿病中异常表达。我们的目的是找出高血糖终止后视网膜LncRNA不能逆转的情况。我们对链脲佐菌素诱导的糖尿病大鼠的视网膜 RNA 进行了微阵列分析，这些大鼠在血糖控制不佳的情况下生活了 8 个月，随后血糖控制良好（血糖 >400 mg/dL），或生活了 4 个月、在 Diab 组和 Rev 组中，511 个常见的 LncRNAs 表达相似（139 个下调，372 个上调）。基因本体/通路分析在生物过程中发现了有限的 LncRNA，但基于生物过程/分子功能的分析发现了超过 350 个基因在 Diab 组和 Rev 组中有相似的表达；这些基因主要与应激反应、细胞死亡、线粒体损伤和细胞因子的产生有关。因此，确定视网膜 LncRNA 及其基因靶点，如果这些基因不能从终止高血糖中获益，则有可能成为减缓糖尿病视网膜病变进展的治疗靶点。

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引用次数: 0

Sarcopenia Sarcopenia.

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-10-29 DOI: 10.1111/1753-0407.70025

Zachary Bloomgarden

<p>The term “sarcopenia” literally means “deficiency of flesh,” and is used to refer to lack of skeletal muscle. Numerous similar concepts in medicine describe the progressive loss, deficiency, atrophy, or wastage of muscle characteristic of many systemic illnesses and of aging itself. Depending on the definition used, sarcopenia affects large subsets of the population, in association with physical inactivity, cigarette smoking, and malnutrition but also paradoxically with obesity. Sarcopenia is seen with diabetes, pulmonary disease, heart disease, malignancy, and with psychiatric and neurologic illnesses including depression/anorexia and Alzheimer's and Parkinson's diseases.<span><sup>1</sup></span> In a study carried out nearly four decades ago, total appendicular skeletal muscle mass was found to decrease in a linear fashion with age both among men and women, regardless of race or ethnic group, showing positive correlation with body weight.<span><sup>2</sup></span> Sarcopenia can be assessed clinically with measures of strength such as the simple self-report of limitation of walking, which increases in prevalence with increasing age, to a greater extent in low- than in high-income countries, and which correlates strongly with all-cause mortality even after adjustment for age, sex, education, marital status, rural residence, and country income level, and additionally for hypertension, diabetes, coronary artery disease, stroke, body mass index (BMI), smoking, physical activity, and depression.<span><sup>3</sup></span> In a study analyzing mortality at >12 year follow-up, those in the highest quintile of the fat-to-muscle mass ratio estimated using bioelectrical impedance among 337 951 UK Biobank participants had increased total and cardiovascular disease (CVD) mortality, both among men and women.<span><sup>4</sup></span></p><p>Clinical conditions associated with sarcopenia overlap with features of frailty such as slowing, falls, fatigue, and weight loss, which may represent disease prodromes,<span><sup>5</sup></span> with a continuum from robustness, with stressors leading to temporary decline in functional capacity, to pre-frailty, with only incomplete recovery from stressors, to actual frailty with failure to recover from stressors eventuating in states of dependence and disability.<span><sup>6</sup></span> The biology of frailty involves a number of factors associated with sarcopenia, including states of dysregulated nutrient sensing, such as abnormalities of mammalian target of rapamycin (mTOR) complex 1, AMP-activated protein kinase (AMPK), and the nutrient scarcity sensors sirtuins 1 and 3, and hormonal changes associated with aging including decreased levels of the anabolic hormones dehydroepiandrosterone sulfate, testosterone, growth hormone, and insulin-like growth factor 1, and increased levels of catabolic hormones, particularly cortisol.<span><sup>7</sup></span> Insulin can best be seen in this context as an anabolic hormone invol

肌肉疏松症 "一词的字面意思是 "缺乏肉体"，指缺乏骨骼肌。医学上有许多类似的概念，描述许多全身性疾病和衰老本身所特有的肌肉逐渐丧失、缺乏、萎缩或流失的现象。根据不同的定义，肌肉疏松症影响着大量人群，与缺乏运动、吸烟和营养不良有关，但也与肥胖有关。肌肉疏松症可见于糖尿病、肺病、心脏病、恶性肿瘤，以及精神和神经疾病，包括抑郁症/厌食症、阿尔茨海默氏症和帕金森氏症。1 近 40 年前进行的一项研究发现，不论种族或族裔，男性和女性的骨骼肌总质量随着年龄的增长呈线性下降，并与体重呈正相关。临床上可以通过测量力量来评估 "肌肉疏松症"，如简单的行走受限自我报告，其患病率随着年龄的增长而增加，在低收入国家比在高收入国家患病率更高，即使在调整了年龄、性别、教育程度、婚姻状况、农村居住地和国家收入水平，以及高血压、糖尿病、冠心病、中风、体重指数（BMI）、吸烟、体力活动和抑郁等因素后，"肌肉疏松症 "仍与全因死亡率密切相关3。在一项对随访 12 年的死亡率进行分析的研究中，在 337 951 名英国生物数据库参与者中，使用生物电阻抗估算的脂肪与肌肉质量比最高的五分之一人群的总死亡率和心血管疾病（CVD）死亡率均有所上升，男性和女性均是如此。与肌肉疏松症相关的临床症状与虚弱的特征重叠，如行动迟缓、跌倒、疲劳和体重减轻，这可能是疾病的前兆，5 其中有一个连续的过程，从因压力导致功能暂时下降的健壮状态，到仅能从压力中完全恢复的虚弱前状态，再到因无法从压力中恢复而最终导致依赖和残疾状态的实际虚弱状态。虚弱的生物学原理涉及与肌肉疏松症相关的一系列因素，包括营养感应失调状态，如哺乳动物雷帕霉素靶标（mTOR）复合体 1、AMP-激活蛋白激酶（AMPK）以及营养稀缺感应器 sirtuins 1 和 3 的异常、与衰老相关的荷尔蒙变化，包括合成代谢荷尔蒙硫酸脱氢表雄酮、睾酮、生长激素和胰岛素样生长因子 1 水平的下降，以及分解代谢荷尔蒙（尤其是皮质醇）水平的上升。78 肌肉疏松症与慢性炎症有关，慢性炎症由细胞衰老和线粒体功能障碍介导，抑制生长因子的表达，造成 DNA 损伤和氧化应激，增加分解代谢。诱导细胞凋亡途径、胰岛素抵抗和内脏肥胖导致循环中促炎脂质衍生分子水平升高，以及包括超氧化物歧化酶、GSH、维生素 E、C 和 A、尿酸和硫氧还蛋白在内的抗氧化防御功能丧失，都会进一步加剧炎症。在对与肌肉疏松症有关的细胞因子进行的孟德尔随机分析中发现，IL-7、单核细胞趋化蛋白 3 和正常 T 细胞表达和分泌的活化调控因子（RANTES）与肌肉疏松症有关，前者能急性上调脂肪分解和脂肪氧化，后者则与肌肉力量下降有关；此外，还发现了几种细胞因子，它们似乎起着保护作用，但在肌肉疏松症状态下却会缺乏，包括肝细胞生长因子（HGF），它通过调节骨髓干细胞的动员和改变来增加骨骼肌的再生；γ 干扰素诱导蛋白（IP）-10，它参与肌肉再生；以及巨噬细胞集落刺激因子（M-CSF），它似乎能增加肌肉的收缩强度。10骨源性细胞因子（osteokines）的作用似乎与骨骼肌源性肌因子类似，间充质前体细胞被称为纤维-脂肪生成祖（FAPs），可生成脂肪细胞、成纤维细胞、成骨细胞和肌细胞。11 FAP 分化异常会导致肌肉再生能力下降，同时免疫反应失调，从而导致持续性低度炎症以及过度脂肪浸润和纤维化。

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引用次数: 0

Association of systolic blood pressure variability with cognitive decline in type 2 diabetes: A post hoc analysis of a randomized clinical trial 收缩压变化与 2 型糖尿病患者认知能力下降的关系：随机临床试验的事后分析。

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2024-10-29 DOI: 10.1111/1753-0407.70020

Junmin Chen, Xuan Zhao, Huidan Liu, Kan Wang, Xiaoli Xu, Siyu Wang, Mian Li, Ruizhi Zheng, Libin Zhou, Yufang Bi, Yu Xu

Background

We aimed to explore the association between visit-to-visit systolic blood pressure variability (BPV) and cognitive function in individuals with type 2 diabetes.

Methods

We performed a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD-MIND) substudy. A total of 2867 diabetes patients with ≥3 BP measurements between the 4- and 20-month visits were included. Visit-to-visit systolic BPV was calculated. Cognitive decline was defined as a Mini-Mental State Exam (MMSE), Digit Symbol Substitution Test (DSST), or Rey Auditory Verbal Learning Test (RAVLT) score greater than 1 standard deviation (SD) below the baseline mean, or a Stroop test score more than 1 SD above the baseline mean. The associations of systolic BPV with risks of cognitive decline were examined using Cox proportional hazards models, and with changes in brain magnetic resonance imaging parameters were evaluated using mixed models.

Results

The risk of cognitive decline defined by the DSST score (but not by other scores) increased significantly with systolic BPV quartiles (p for trend = 0.008), and there was a 55% increased risk for BPV quartile 4 versus quartile 1 (hazard ratio = 1.55, 95% confidence interval 1.10–2.19). Furthermore, a positive correlation was observed between systolic BPV and change in white matter lesion volume (β = 0.07, 95% CI 0.01–0.13).

Conclusions

A greater visit-to-visit systolic BPV was significantly associated with an increased risk of cognitive decline measured by DSST and an increase in white matter lesion volume in patients with type 2 diabetes.

研究背景我们旨在探讨2型糖尿病患者逐次收缩压变异性（BPV）与认知功能之间的关系：我们对控制心血管风险糖尿病记忆行动（ACCORD-MIND）子研究进行了事后分析。共纳入了2867名在4个月和20个月访视期间测量血压≥3次的糖尿病患者。计算各次就诊的收缩压值。认知能力下降的定义是迷你精神状态检查（MMSE）、数字符号替换测试（DSST）或雷伊听觉言语学习测试（RAVLT）得分比基线平均值低 1 个标准差以上，或 Stroop 测试得分比基线平均值高 1 个标准差以上。收缩压与认知能力下降风险的关系采用 Cox 比例危险模型进行检验，与脑磁共振成像参数变化的关系采用混合模型进行评估：根据 DSST 评分（而非其他评分）确定的认知功能下降风险随着收缩压四分位数的增加而显著增加（趋势 p = 0.008），收缩压四分位数比四分位数 1 的风险增加了 55%（危险比 = 1.55，95% 置信区间为 1.10-2.19）。此外，还观察到收缩压与白质病变体积的变化呈正相关（β = 0.07，95% CI 0.01-0.13）：结论：2 型糖尿病患者每次就诊时收缩压升高与 DSST 测定的认知能力下降风险增加和白质病变体积增加显著相关。

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引用次数: 0