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The prevalence and correlates of advanced fibrosis in patients with and without diabetes mellitus and metabolic dysfunction-associated steatotic liver disease: A cross-sectional study. 伴有和不伴有糖尿病和代谢功能障碍相关的脂肪变性肝病患者的晚期纤维化患病率及其相关因素:一项横断面研究
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-10-01 Epub Date: 2025-08-06 DOI: 10.1016/j.jdiacomp.2025.109147
Emir Muzurović, Goran Topić, Nevena Todorović, Manfredi Rizzo, Ksenija Zečević

Background: The severity of liver fibrosis serves as a crucial prognostic indicator, reflecting liver-related and cardiovascular-related outcomes, as well as mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Type 2 diabetes mellitus (T2DM) is a major risk factor for developing metabolic dysfunction-associated steatohepatitis (MASH), and in patients with both T2DM and MASH, identifying those with advanced fibrosis is critical.

Methods: This cross-sectional study included 162 MASLD patients (47 with T2DM, 38 with prediabetes and 77 individuals without diabetes). The aim of this study was to determine the prevalence of advanced fibrosis in MASLD patients with and without DM and prediabetes, using a 2-step approach with fibrosis-4 index followed by liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), and to evaluate the predictive cardiometabolic risk factors for the development of advanced fibrosis in these patients.

Results: Among patients with prediabetes and T2DM, 12.9 % were identified with F3 stage fibrosis, 6.5 % had F4 stage, totaling 19.4 % with advanced fibrosis or cirrhosis, assessed by VCTE. In contrast, among individuals without diabetes, 1.78 % was found to have F3 stage fibrosis, while 7.14 % had F4. In patients with T2DM or prediabetes, body mass index (BMI) was a significant predictor of advanced fibrosis (p = 0.02), with each unit increase in BMI linked to a 1.3-fold higher risk of advanced fibrosis and cirrhosis, and higher high-density lipoprotein cholesterol (HDL-C) levels were associated with lower odds of having F3 or F4 stage fibrosis (p = 0.04). In MASLD patients without diabetes, triglycerides (TGs) showed a significant positive correlation with liver stiffness (p = 0.04), male sex was significantly associated with a higher susceptibility to increased liver stiffness (p = 0.04), and males had 0.91 times the odds of developing advanced fibrosis and cirrhosis (p = 0.02). No significant correlations were observed between liver stiffness and age, sex, aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose levels, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or TGs in patients with T2DM or prediabetes. In MASLD patients without diabetes, no significant correlations were found between liver stiffness and factors such as age, BMI, AST, ALT, TC, LDL-C, HDL-C, or glucose levels.

Conclusion: In conclusion, the prevalence of advanced fibrosis or cirrhosis in patients with both, MASLD and T2DM, is very high. In MASLD patients with T2DM or prediabetes, higher BMI and lower levels of HDL-C are significant predictors of advanced fibrosis or cirrhosis.

背景:肝纤维化的严重程度是一个重要的预后指标,反映了代谢功能障碍相关脂肪变性肝病(MASLD)患者的肝脏相关和心血管相关结局以及死亡率。2型糖尿病(T2DM)是发生代谢功能障碍相关脂肪性肝炎(MASH)的主要危险因素,在T2DM和MASH患者中,识别晚期纤维化至关重要。方法:本横断面研究纳入162例MASLD患者(47例合并T2DM, 38例合并糖尿病前期,77例无糖尿病)。本研究的目的是确定伴有或不伴有糖尿病和糖尿病前期的MASLD患者的晚期纤维化患病率,采用两步方法,通过振动控制瞬时弹性成像(VCTE)测量纤维化-4指数,然后测量肝脏硬度(LSM),并评估这些患者发生晚期纤维化的预测性心脏代谢危险因素。结果:通过VCTE评估,在糖尿病前期和T2DM患者中,12.9%被鉴定为F3期纤维化,6.5%为F4期,总计19.4%为晚期纤维化或肝硬化。相比之下,在没有糖尿病的个体中,1.78%的人被发现有F3期纤维化,而7.14%的人有F4期。在T2DM或前驱糖尿病患者中,体重指数(BMI)是晚期纤维化的重要预测指标(p = 0.02), BMI每增加一个单位,晚期纤维化和肝硬化的风险增加1.3倍,高密度脂蛋白胆固醇(HDL-C)水平升高与F3或F4期纤维化的风险降低相关(p = 0.04)。在没有糖尿病的MASLD患者中,甘油三酯(tg)与肝脏僵硬度呈显著正相关(p = 0.04),男性与肝脏僵硬度增加的易感性显著相关(p = 0.04),男性发展为晚期纤维化和肝硬化的几率是男性的0.91倍(p = 0.02)。T2DM或前驱糖尿病患者的肝脏硬度与年龄、性别、天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、葡萄糖水平、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)或tg之间无显著相关性。在没有糖尿病的MASLD患者中,肝脏僵硬度与年龄、BMI、AST、ALT、TC、LDL-C、HDL-C或葡萄糖水平等因素之间没有显著相关性。结论:综上所述,MASLD和T2DM患者的晚期纤维化或肝硬化患病率非常高。在伴有2型糖尿病或前驱糖尿病的MASLD患者中,较高的BMI和较低的HDL-C水平是晚期纤维化或肝硬化的重要预测因素。
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引用次数: 0
Can fibrate therapy redefine the management of diabetic retinopathy? A comprehensive systematic review and meta-analysis of efficacy and safety 贝特治疗能否重新定义糖尿病视网膜病变的治疗?疗效和安全性的综合系统评价和荟萃分析。
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-27 DOI: 10.1016/j.jdiacomp.2025.109178
Kai-Yang Chen , Hoi-Chun Chan , Chi-Ming Chan
<div><h3>Background</h3><div>Diabetic retinopathy (DR) is a severe microvascular diabetes complication and a leading cause of preventable blindness. Fibrates, being lipid-lowering agents, have been found to have promise in modifying DR progression.</div></div><div><h3>Objective</h3><div>To determine fibrates' effectiveness and safety profile in reducing the incidence, progression, and severity of diabetic retinopathy.</div></div><div><h3>Methods</h3><div>Randomized controlled trials and observational cohort studies that compared fibrate therapy with no fibrate therapy in patients with diabetes were eligible for this systematic review and meta-analysis. The outcomes of interest included the incidence of DR, long-term progression, progression to Proliferative Diabetic Retinopathy (PDR), and adverse effects. Risk of bias was assessed using the RoB 2 and ROBINS-I tools, and results were synthesized narratively due to heterogeneity in the study populations, follow-up durations, and diagnostic methods.</div></div><div><h3>Results</h3><div>Only 17 articles were eligible for inclusion in this study. Fibrates significantly reduced the incidence of diabetic retinopathy (OR 0.72 (95 % CI: 0.66–0.77), <em>p</em> < 0.001; I<sup>2</sup> = 26.53 %) and slowed long-term progression (OR 0.67 (95 % CI: 0.57–0.79), p < 0.001).; I<sup>2</sup> = 26.39 %) compared to placebo. Combining fibrates with statin reduces DR progression by 17 % compared to fibrate alone HR 0.84 (95 % CI: 0.80–0.89), <em>p</em> < 0.001; I<sup>2</sup> = 31.7 %. While progression to proliferative diabetic retinopathy showed a favorable trend (RR 0.71 (95 % CI: 0.15–3.32), <em>p</em> = 0.67, the result was not statistically significant. Analysis of adverse events, including all-cause mortality (OR 0.86 (95 % CI: 0.62–1.19), <em>p</em> = 0.36; I<sup>2</sup> = 0 %), revealed no significant safety benefits in comparison between fibrates and placebo.</div></div><div><h3>Conclusion</h3><div>Fibrates significantly reduce both the incidence and long-term progression of diabetic retinopathy. Safety analyses revealed no significant difference between placebo and fibrates in reducing serious adverse events or all-cause mortality.</div><div><strong>What is known about this research topic?</strong><ul><li><span>•</span><span><div>Diabetic retinopathy (DR) is a leading cause of preventable blindness, with limited systemic therapies beyond glycemic and blood pressure control.</div></span></li><li><span>•</span><span><div>Fibrates, primarily lipid-lowering agents, have shown potential benefits for microvascular complications, including DR, in trials like FIELD and ACCORD Eye.</div></span></li></ul></div><div><strong>What this study adds and its future implications</strong><ul><li><span>•</span><span><div>This meta-analysis confirms fibrates significantly reduce the incidence and long-term progression of DR, with fenofibrate showing the greatest benefit.</div></span></li><li><span>•</span><span><div>Alt
背景:糖尿病视网膜病变(DR)是一种严重的微血管糖尿病并发症,也是可预防失明的主要原因。贝特类,作为降脂剂,已被发现在改变DR进展方面有希望。目的:确定贝特类药物在降低糖尿病视网膜病变的发生率、进展和严重程度方面的有效性和安全性。方法:比较糖尿病患者贝特治疗与非贝特治疗的随机对照试验和观察性队列研究符合本系统评价和荟萃分析的要求。研究结果包括DR的发生率、长期进展、进展为增殖性糖尿病视网膜病变(PDR)和不良反应。使用rob2和ROBINS-I工具评估偏倚风险,由于研究人群、随访时间和诊断方法的异质性,对结果进行叙述性综合。结果:只有17篇文章符合纳入本研究的条件。与安慰剂相比,贝特酯显著降低了糖尿病视网膜病变的发生率(OR 0.72 (95% CI: 0.66-0.77), p 2 = 26.53%),并减缓了长期进展(OR 0.67 (95% CI: 0.57-0.79), p 2 = 26.39%)。贝特类药物联合他汀类药物与单独贝特类药物相比,DR进展减少17% (HR 0.84) (95% CI: 0.80-0.89), p 2 = 31.7%。进展为增生性糖尿病视网膜病变有良好趋势(RR 0.71 (95% CI: 0.15 ~ 3.32), p = 0.67,但结果无统计学意义。不良事件分析,包括全因死亡率(OR 0.86 (95% CI: 0.62-1.19), p = 0.36;I2 = 0%),显示贝特类药物与安慰剂相比没有显著的安全性益处。结论:贝特类药物可显著降低糖尿病视网膜病变的发病率和长期进展。安全性分析显示,安慰剂和贝特类药物在减少严重不良事件或全因死亡率方面无显著差异。关于这个研究课题我们知道些什么?这项研究补充了什么及其未来的意义。
{"title":"Can fibrate therapy redefine the management of diabetic retinopathy? A comprehensive systematic review and meta-analysis of efficacy and safety","authors":"Kai-Yang Chen ,&nbsp;Hoi-Chun Chan ,&nbsp;Chi-Ming Chan","doi":"10.1016/j.jdiacomp.2025.109178","DOIUrl":"10.1016/j.jdiacomp.2025.109178","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Diabetic retinopathy (DR) is a severe microvascular diabetes complication and a leading cause of preventable blindness. Fibrates, being lipid-lowering agents, have been found to have promise in modifying DR progression.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;To determine fibrates' effectiveness and safety profile in reducing the incidence, progression, and severity of diabetic retinopathy.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Randomized controlled trials and observational cohort studies that compared fibrate therapy with no fibrate therapy in patients with diabetes were eligible for this systematic review and meta-analysis. The outcomes of interest included the incidence of DR, long-term progression, progression to Proliferative Diabetic Retinopathy (PDR), and adverse effects. Risk of bias was assessed using the RoB 2 and ROBINS-I tools, and results were synthesized narratively due to heterogeneity in the study populations, follow-up durations, and diagnostic methods.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Only 17 articles were eligible for inclusion in this study. Fibrates significantly reduced the incidence of diabetic retinopathy (OR 0.72 (95 % CI: 0.66–0.77), &lt;em&gt;p&lt;/em&gt; &lt; 0.001; I&lt;sup&gt;2&lt;/sup&gt; = 26.53 %) and slowed long-term progression (OR 0.67 (95 % CI: 0.57–0.79), p &lt; 0.001).; I&lt;sup&gt;2&lt;/sup&gt; = 26.39 %) compared to placebo. Combining fibrates with statin reduces DR progression by 17 % compared to fibrate alone HR 0.84 (95 % CI: 0.80–0.89), &lt;em&gt;p&lt;/em&gt; &lt; 0.001; I&lt;sup&gt;2&lt;/sup&gt; = 31.7 %. While progression to proliferative diabetic retinopathy showed a favorable trend (RR 0.71 (95 % CI: 0.15–3.32), &lt;em&gt;p&lt;/em&gt; = 0.67, the result was not statistically significant. Analysis of adverse events, including all-cause mortality (OR 0.86 (95 % CI: 0.62–1.19), &lt;em&gt;p&lt;/em&gt; = 0.36; I&lt;sup&gt;2&lt;/sup&gt; = 0 %), revealed no significant safety benefits in comparison between fibrates and placebo.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;Fibrates significantly reduce both the incidence and long-term progression of diabetic retinopathy. Safety analyses revealed no significant difference between placebo and fibrates in reducing serious adverse events or all-cause mortality.&lt;/div&gt;&lt;div&gt;&lt;strong&gt;What is known about this research topic?&lt;/strong&gt;&lt;ul&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;div&gt;Diabetic retinopathy (DR) is a leading cause of preventable blindness, with limited systemic therapies beyond glycemic and blood pressure control.&lt;/div&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;div&gt;Fibrates, primarily lipid-lowering agents, have shown potential benefits for microvascular complications, including DR, in trials like FIELD and ACCORD Eye.&lt;/div&gt;&lt;/span&gt;&lt;/li&gt;&lt;/ul&gt;&lt;/div&gt;&lt;div&gt;&lt;strong&gt;What this study adds and its future implications&lt;/strong&gt;&lt;ul&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;div&gt;This meta-analysis confirms fibrates significantly reduce the incidence and long-term progression of DR, with fenofibrate showing the greatest benefit.&lt;/div&gt;&lt;/span&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;•&lt;/span&gt;&lt;span&gt;&lt;div&gt;Alt","PeriodicalId":15659,"journal":{"name":"Journal of diabetes and its complications","volume":"39 11","pages":"Article 109178"},"PeriodicalIF":3.1,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neuroinflammation and osteomyelitis in adults with Type 2 diabetes mellitus and peripheral neuropathy without and with foot lesions. What comes first? 神经炎症和骨髓炎的成人2型糖尿病和周围神经病变,没有或有足部病变。什么是第一位的?
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-24 DOI: 10.1016/j.jdiacomp.2025.109176
Maria Sambataro , Luisa Sambado , Mayra Colardo , Anna Furlan , Piero Maria Stefani , Elisabetta Durante , Antonio Antico , Stefania Conte , Silvia Della Bella , Laura Nollino , Zavan Barbara , Nicola Menegotto , Elisa Vian , Marco Segatto , Matteo Fassan
<div><h3>Aims</h3><div>Diabetic foot is the leading cause of both major and minor non-traumatic amputations yet a truly understanding of the phenomenon is still lacking. The updated definition for diabetes-related foot disease from the International Working Group on the Diabetic Foot (IWGDF 2023 update) is “disease of the foot of a person with current or previously diagnosed diabetes mellitus that includes one or more of the following: peripheral neuropathy, peripheral artery disease, infection, ulcer(s), neuro‐osteoarthropathy, gangrene, or amputation”, but what comes first? Our hypothesis is that distal sensory and autonomic neuropathy activate neuroischemic signaling and dysregulation of bone cell apoptosis portending to infections.</div></div><div><h3>Methods</h3><div>We studied 374 adults with Type 2 diabetes mellitus (T2DM) and diabetic neuropathy (DN) divided into the following subgroups: 106 partecipants without foot lesions (DNp); 119 nonmacrovascular partecipants with ulcers/lesions/osteomyelitis (DNpU); 149 revascularized partecipants with ulcers/lesions/osteomyelitis (DNpUV) and a group of 53 healthy adults as healthy control (NC). During routine foot care visits participants underwent neuro electrophysiology tests and vascular assessment. Biopsy specimens from exposed bone (grade III University of Texas wound classification, TUC) were cultured according to microbiological standards and histological analysis was performed. Pro/anti-inflammatory cytokines and blood cells subsets (lymphocytes subpopulations, classical, non-classical and SLAN<sup>+</sup> monocytes, classical DCs, innate lymphoid cells) were analyzed. Nerve Growth Factor (NGF) species, fractalkine/CX3CL1 migration marker, autophagy markers (Ulk1, Beclin1, LC3, and p62), pro/anti-apoptotic proteins (Bax, Bcl2, cleaved Caspase-3), signal transduction of proteins involved in inflammation and cell survival (p65-NF-kB, Akt and ERK1/2) were measured.</div></div><div><h3>Results</h3><div>Sural nerve (sS) conduction velocity (CV) and sensory Action Potential (sAP) thresholds defined DN. II and III TUC associates with progressive worsening of neuronal function while vibration perception threshold (VPT) and systolic/diastolic orthostatic hypotension inversely correlated with TcPO<sub>2</sub> and critical ischemia. In III TUC versus I TUC diabetic foot ulcer (DFU) and DNp samples the amount of circulating mature NGF (mNGF) was significantly reduced (<em>p</em> < 0.01) while immature NGF (proNGF) was significantly increased (<em>p</em> < 0.05). In all groups we found higher number of SLAN+ monocytes co-expressing CX3CR1 directly correlating with proNGF levels, worse autonomic and sensory testing and inversely correlating with mNGF levels, sensory nerves CV and AP, innate lymphoid cells and subsets of lymphocytes. Surprisingly, we found 59 bone's biopsies with an altered histological pattern but negative microbiological cultures. In all biopsied patients CX3CR1-SLAN+ cells were
目的:糖尿病足是主要和次要非创伤性截肢的主要原因,但对这一现象的真正理解仍然缺乏。糖尿病足国际工作组(IWGDF 2023更新)对糖尿病相关足病的最新定义是“当前或以前诊断为糖尿病的人的足病,包括以下一种或多种:周围神经病变、外周动脉疾病、感染、溃疡、神经骨关节病变、坏疽或截肢”,但哪一种先出现?我们的假设是远端感觉和自主神经病变激活神经缺血信号和骨细胞凋亡失调,预示着感染。方法:我们研究了374名患有2型糖尿病(T2DM)和糖尿病性神经病变(DN)的成年人,将其分为以下亚组:106名无足部病变(DNp)的参与者;119名患有溃疡/病变/骨髓炎(DNpU)的非大血管参与者;149例溃疡/病变/骨髓炎患者(DNpUV)和53名健康成人作为健康对照组(NC)。在常规足部护理访问期间,参与者进行了神经电生理测试和血管评估。暴露骨活检标本(三级德克萨斯大学伤口分类,TUC)按照微生物标准培养并进行组织学分析。分析促/抗炎细胞因子和血细胞亚群(淋巴细胞亚群、经典、非经典和SLAN+单核细胞、经典dc、先天淋巴样细胞)。检测神经生长因子(NGF)种类、fractalkine/CX3CL1迁移标志物、自噬标志物(Ulk1、Beclin1、LC3和p62)、促/抗凋亡蛋白(Bax、Bcl2、cleaved Caspase-3)、参与炎症和细胞存活的信号转导蛋白(p65-NF-kB、Akt和ERK1/2)。结果:腓肠神经(sS)传导速度(CV)和感觉动作电位(sAP)阈值定义DN。II和III型TUC与神经元功能进行性恶化有关,而振动感知阈值(VPT)和收缩期/舒张期直立性低血压与TcPO2和严重缺血呈负相关。在III型TUC与I型TUC糖尿病足溃疡(DFU)和DNp样本中,循环成熟NGF (mNGF)的数量显著减少(p +SLAN+CD16+炎症单核细胞),与骨ERK1/2激活磷酸化呈负相关。结论:DN可能是糖尿病足发生的重要因素。本体感觉减少和交感直立性低血压破坏足部结构,改变骨内神经营养因子导致血管信号,在感染骨髓炎之前和独立于感染骨髓炎之前早期激活骨凋亡和CX3CR1+单核细胞。这些数据提示了对糖尿病足生理病理的主要参与者的新解释,并可能标志着新的靶向治疗方法的发展。
{"title":"Neuroinflammation and osteomyelitis in adults with Type 2 diabetes mellitus and peripheral neuropathy without and with foot lesions. What comes first?","authors":"Maria Sambataro ,&nbsp;Luisa Sambado ,&nbsp;Mayra Colardo ,&nbsp;Anna Furlan ,&nbsp;Piero Maria Stefani ,&nbsp;Elisabetta Durante ,&nbsp;Antonio Antico ,&nbsp;Stefania Conte ,&nbsp;Silvia Della Bella ,&nbsp;Laura Nollino ,&nbsp;Zavan Barbara ,&nbsp;Nicola Menegotto ,&nbsp;Elisa Vian ,&nbsp;Marco Segatto ,&nbsp;Matteo Fassan","doi":"10.1016/j.jdiacomp.2025.109176","DOIUrl":"10.1016/j.jdiacomp.2025.109176","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Aims&lt;/h3&gt;&lt;div&gt;Diabetic foot is the leading cause of both major and minor non-traumatic amputations yet a truly understanding of the phenomenon is still lacking. The updated definition for diabetes-related foot disease from the International Working Group on the Diabetic Foot (IWGDF 2023 update) is “disease of the foot of a person with current or previously diagnosed diabetes mellitus that includes one or more of the following: peripheral neuropathy, peripheral artery disease, infection, ulcer(s), neuro‐osteoarthropathy, gangrene, or amputation”, but what comes first? Our hypothesis is that distal sensory and autonomic neuropathy activate neuroischemic signaling and dysregulation of bone cell apoptosis portending to infections.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We studied 374 adults with Type 2 diabetes mellitus (T2DM) and diabetic neuropathy (DN) divided into the following subgroups: 106 partecipants without foot lesions (DNp); 119 nonmacrovascular partecipants with ulcers/lesions/osteomyelitis (DNpU); 149 revascularized partecipants with ulcers/lesions/osteomyelitis (DNpUV) and a group of 53 healthy adults as healthy control (NC). During routine foot care visits participants underwent neuro electrophysiology tests and vascular assessment. Biopsy specimens from exposed bone (grade III University of Texas wound classification, TUC) were cultured according to microbiological standards and histological analysis was performed. Pro/anti-inflammatory cytokines and blood cells subsets (lymphocytes subpopulations, classical, non-classical and SLAN&lt;sup&gt;+&lt;/sup&gt; monocytes, classical DCs, innate lymphoid cells) were analyzed. Nerve Growth Factor (NGF) species, fractalkine/CX3CL1 migration marker, autophagy markers (Ulk1, Beclin1, LC3, and p62), pro/anti-apoptotic proteins (Bax, Bcl2, cleaved Caspase-3), signal transduction of proteins involved in inflammation and cell survival (p65-NF-kB, Akt and ERK1/2) were measured.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Sural nerve (sS) conduction velocity (CV) and sensory Action Potential (sAP) thresholds defined DN. II and III TUC associates with progressive worsening of neuronal function while vibration perception threshold (VPT) and systolic/diastolic orthostatic hypotension inversely correlated with TcPO&lt;sub&gt;2&lt;/sub&gt; and critical ischemia. In III TUC versus I TUC diabetic foot ulcer (DFU) and DNp samples the amount of circulating mature NGF (mNGF) was significantly reduced (&lt;em&gt;p&lt;/em&gt; &lt; 0.01) while immature NGF (proNGF) was significantly increased (&lt;em&gt;p&lt;/em&gt; &lt; 0.05). In all groups we found higher number of SLAN+ monocytes co-expressing CX3CR1 directly correlating with proNGF levels, worse autonomic and sensory testing and inversely correlating with mNGF levels, sensory nerves CV and AP, innate lymphoid cells and subsets of lymphocytes. Surprisingly, we found 59 bone's biopsies with an altered histological pattern but negative microbiological cultures. In all biopsied patients CX3CR1-SLAN+ cells were ","PeriodicalId":15659,"journal":{"name":"Journal of diabetes and its complications","volume":"39 11","pages":"Article 109176"},"PeriodicalIF":3.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The cardiovascular–kidney–metabolic staging in type 2 diabetes: the clock starts ticking early 2型糖尿病的心血管-肾脏-代谢分期:时钟开始提前
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-22 DOI: 10.1016/j.jdiacomp.2025.109177
Karolina Hoffmann , Anna Paczkowska , Viviana Maggio , Manfredi Rizzo
Nishizawa et al. demonstrate that cardiovascular–kidney–metabolic (CKM) staging is a strong predictor of all-cause mortality in type 2 diabetes, even before contemporary ardiorenal therapies were widely available. In their cohort, mortality rose sharply from stage 3 onward, underscoring that pathological risk begins well before overt cardiorenal failure. Because CKM staging relies on routine clinical data, it offers a pragmatic framework for early risk stratification, yet it is often applied too late. Integrating CKM assessment into electronic health systems and initiating cardiorenalprotective interventions in stages 1–2 could substantially improve outcomes. Future studies should validate CKM staging in modern therapy settings and evaluate stageguided interventions.
Nishizawa等人证明,即使在当代心肾治疗广泛应用之前,心血管肾代谢(CKM)分期也是2型糖尿病全因死亡率的一个强有力的预测指标。在他们的队列中,死亡率从3期开始急剧上升,强调病理性风险早在明显的心衰之前就开始了。由于CKM分期依赖于常规临床数据,它为早期风险分层提供了一个实用的框架,但它通常应用得太晚。将CKM评估纳入电子卫生系统,并在1-2阶段启动心血管保护干预措施,可显著改善预后。未来的研究应该在现代治疗环境中验证CKM分期,并评估分期指导的干预措施。
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引用次数: 0
A comparative analysis of cost-utility: Chiglitazar vs. sitagliptin in patients with type 2 diabetes in China 成本-效用比较分析:中国2型糖尿病患者的奇列他和西格列汀
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-10 DOI: 10.1016/j.jdiacomp.2025.109174
Zeyu Xie , Zhuoru Liang , Guimei Zheng , Weiling Cao

Background

As a structurally unique peroxisome proliferator-activated receptor pan-agonist, chiglitazar has showed dual therapeutic benefits for glycemic control and lipid management in type 2 diabetes mellitus (T2DM). Despite these clinical advantages, comprehensive pharmacoeconomic evaluations comparing chiglitazar with conventional therapies like sitagliptin remain unavailable for China's healthcare system.

Objective

This study aimed to conduct a comparative cost-utility analysis of chiglitazar versus sitagliptin for T2DM treatment in China, evaluating long-term clinical and economic outcomes from a healthcare system perspective.

Methods

Data on patient demographics and post-treatment effects were collected from a double-blind, phase 3, randomized controlled trial conducted in China. The United Kingdom Prospective Diabetes Study Outcomes Model 2.1 was employed to evaluate the long-term effectiveness and associated costs. Uncertainties were addressed using one-way and probabilistic sensitivity analyses. Additionally, the binary search method was utilized to estimate an optimal annual cost for sitagliptin in scenario analyses.

Results

After a 40-year simulation, the life expectancy results were comparable among treatments: 14.93 years for chiglitazar 32 mg, 14.94 years for chiglitazar 48 mg, and 14.93 years for sitagliptin 100 mg. The corresponding quality-adjusted life years (QALYs) reached 12.82, 12.83, and 12.81, respectively. Total accumulated costs over the simulation period were $44,241.09 (chiglitazar 32 mg), $45,044.25 (chiglitazar 48 mg), and $44,821.45 (sitagliptin 100 mg). Long-term economic evaluation revealed that chiglitazar 32 mg provided the optimal cost-effectiveness, whereas sitagliptin 100 mg was the least economically advantageous option. Both one-way and probabilistic sensitivity analyses confirmed the robustness of these findings. Scenario analysis showed that sitagliptin 100 mg only becomes cost-effective when its annual cost is reduced by at least 42.33 % compared to chiglitazar 32 mg.

Conclusion

Based on cost-utility analysis within the Chinese healthcare context, chiglitazar demonstrates significantly better long-term health outcomes and cost-effectiveness relative to sitagliptin for T2DM management.
作为一种结构独特的过氧化物酶体增殖物激活受体泛激动剂,chiglitazar在2型糖尿病(T2DM)的血糖控制和脂质管理方面显示出双重治疗效果。尽管有这些临床优势,但在中国的医疗保健系统中,比较齐格列他与西格列汀等传统疗法的综合药物经济学评估仍然缺乏。目的:本研究旨在对中国治疗2型糖尿病的奇列他与西格列汀进行成本-效用比较分析,从医疗保健系统的角度评估长期临床和经济结果。方法收集在中国进行的一项双盲、3期随机对照试验的患者人口统计学和治疗后效果数据。采用英国前瞻性糖尿病研究结果模型2.1来评估长期有效性和相关成本。使用单向和概率敏感性分析来解决不确定性。此外,在情景分析中,利用二分搜索法估计西格列汀的最佳年成本。经过40年的模拟,不同治疗组的预期寿命结果是相似的:吉列他32 mg组14.93年,吉列他48 mg组14.94年,西格列汀100 mg组14.93年。相应的质量调整寿命年(QALYs)分别达到12.82、12.83和12.81。模拟期间的总累积成本为44,241.09美元(吉列扎32毫克),45,044.25美元(吉列扎48毫克)和44,821.45美元(西格列汀100毫克)。长期经济评估显示,32 mg的奇列他具有最佳的成本效益,而100 mg的西格列汀是最不经济的选择。单向和概率敏感性分析都证实了这些发现的稳健性。情景分析显示,100 mg西格列汀与32 mg齐格列他相比,只有年成本降低至少42.33%时才具有成本效益。结论:基于中国医疗环境下的成本-效用分析,相对于西格列汀,奇格列扎在T2DM治疗中表现出更好的长期健康结果和成本-效益。
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引用次数: 0
Efficacy of levocetirizine in reducing albuminuria and inflammatory biomarkers in patients with diabetic kidney disease: A randomized controlled trial 左西替利嗪降低糖尿病肾病患者蛋白尿和炎症生物标志物的疗效:一项随机对照试验
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-10 DOI: 10.1016/j.jdiacomp.2025.109175
Maryam A. Rizk , Sahar M. El-Haggar , Osama M. Ibrahim , Hossam Arafa Ghazi
Globally, the prevalence of diabetes mellitus is rising. One of the main causes of end-stage renal disease (ESRD) and a risk factor for higher morbidity and death in diabetic patients is diabetic nephropathy (DN), sometimes referred to as diabetic kidney disease (DKD). DN, a microvascular consequence of diabetes, affects 20–40 % of diabetics globally. The study's objective was to assess if levocetirizine may have albuminuria lowering effect and anti-inflammatory effect in patients treated with angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors therapy by reducing albuminuria and improving DKD indicators.

Patients and methods

A controlled, parallel, trial was carried out on sixty DKD patients. Sixty patients were divided into two groups at random. Group 1 (control group) received an empagliflozin 10 mg once day in addition to 80 mg valsartan. Group 2 (levocetirizine group) received the same medications as the control group plus a 5 mg of levocetirizine once daily in the evening, titrated dose based on each patient's creatinine clearance (CrCl) for three months. Serum creatinine, serum urea, serum cystatin-C, HbA₁c, tumor necrosis factor alpha (TNF-α), estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio (UACR) were measured at baseline and compared to these data three months after drug administration.

Results

Levocetirizine decreased significantly UACR at the end of the three-months (p = 0.037) compared to the control group. There was no variation in eGFR between the two groups, eGFR was significantly lower than baseline (p < 0.001) in both groups. Comparing the levocetirizine group to the control group, there is a substantial drop in TNF-α (p = 0.004), cystatin-C (p = 0.034), and HbA₁c (p = 0.007).

Conclusion

Levocetirizine reduces albuminuria, inflammatory, and renal indicators, which makes it a potentially has albuminuria lowering effect and anti-inflammatory drug which decreases disease progression.

Trial registration identifier

NCT05638880
在全球范围内,糖尿病的患病率正在上升。糖尿病肾病(DN)是终末期肾病(ESRD)的主要原因之一,也是糖尿病患者发病率和死亡率较高的危险因素之一,有时也被称为糖尿病肾病(DKD)。DN是糖尿病的一种微血管后果,影响着全球20 - 40%的糖尿病患者。该研究的目的是评估左西替利嗪是否通过减少蛋白尿和改善DKD指标,在接受血管紧张素受体阻滞剂(ARBs)和钠-葡萄糖共转运蛋白2 (SGLT2)抑制剂治疗的患者中具有降低蛋白尿和抗炎作用。患者与方法对60例DKD患者进行对照、平行试验。60例患者随机分为两组。1组(对照组)在缬沙坦80 mg的基础上给予恩格列净10 mg, 1次/ d。第2组(左西替利嗪组)给予与对照组相同的药物治疗,另加5 mg左西替利嗪,每日1次,晚间1次,根据每位患者的肌酐清除率(CrCl)滴定剂量,持续3个月。在基线时测量血清肌酐、血清尿素、血清胱抑素c、HbA₁c、肿瘤坏死因子α (TNF-α)、肾小球滤过率(eGFR)和尿白蛋白/肌酐比(UACR),并与给药后三个月的数据进行比较。结果与对照组相比,左西替利嗪在3个月末显著降低UACR (p = 0.037)。两组间eGFR无差异,两组eGFR均显著低于基线(p < 0.001)。与对照组相比,左西替利嗪组TNF-α (p = 0.004)、胱抑素- c (p = 0.034)和HbA₁c (p = 0.007)均有显著下降。结论左西替利嗪可降低蛋白尿、炎症和肾脏指标,具有降低蛋白尿和抑制疾病进展的潜在抗炎药物作用。试验注册标识nct05638880
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引用次数: 0
Contents/Barcode 内容/条形码
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-06 DOI: 10.1016/S1056-8727(25)00220-X
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引用次数: 0
Relationship between flow-mediated dilation and urinary albumin-creatinine ratio in patients with type 2 diabetes mellitus 2型糖尿病患者血流介导扩张与尿白蛋白-肌酐比值的关系
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-09-01 DOI: 10.1016/j.jdiacomp.2025.109162
YuDie Fang , Lijuan Jing , YunXia Zhu , Hongping Wang , Juan Xia , Tao Lei , Jun Lu , Jie Gao

Aims

To investigate the association between Flow-Mediated Dilation (FMD) and the urinary albumin-to-creatinine ratio (UACR) in individuals with type 2 diabetes mellitus (T2DM).

Methods

This cross-sectional study involved 194 individuals diagnosed with T2DM. Participants were categorized into two groups based on their UACR levels: the diabetic kidney disease group (DKD) (UACR≥30 mg/g) and the non-diabetic kidney disease group (non-DKD) (UACR <30 mg/g). The relationship between FMD and UACR was evaluated through Spearman correlation analysis and multivariable logistic regression analysis. Additionally, the predictive capacity of FMD for DKD was determined using receiver operating characteristic curve analysis.

Results

Median FMD was lower in DKD group than in non-DKD group (3.9 vs 4.9, p = 0.011). Furthermore, a notable negative correlation was observed between FMD and UACR (r = −0.253, p < 0.05). Through logistic regression analysis, an increase in FMD by one standard deviation (SD) corresponded to a 35.6 % decrease in the likelihood of elevated UACR (OR: 0.644 [0.459–0.904]) (Model 1). Consistent findings were noted even after accounting for variables such as sex, age, BMI, hypertension, smoking habits, and alcohol intake (Model 2), as well as HbA1c levels, disease duration, and triglycerides (Model 3). The area under the ROC curve (AUC) for FMD was 0.686 (95 % CI 0.596–0.777).

Conclusions

FMD is independently correlated with UACR, which provides a clinical basis for the prevention and control of vascular complications in early DKD.
目的探讨2型糖尿病(T2DM)患者血流介导的舒张(FMD)与尿白蛋白与肌酐比值(UACR)之间的关系。方法本横断面研究纳入194例诊断为T2DM的患者。参与者根据UACR水平分为两组:糖尿病肾病组(DKD) (UACR≥30 mg/g)和非糖尿病肾病组(非DKD) (UACR≤30 mg/g)。通过Spearman相关分析和多变量logistic回归分析评价口蹄疫与UACR的关系。此外,利用受试者工作特征曲线分析确定FMD对DKD的预测能力。结果DKD组FMD中位数低于非DKD组(3.9 vs 4.9, p = 0.011)。此外,FMD与UACR呈显著负相关(r = - 0.253, p < 0.05)。通过logistic回归分析,FMD每增加一个标准差(SD), UACR升高的可能性降低35.6% (OR: 0.644[0.459-0.904])(模型1)。即使在考虑了性别、年龄、BMI、高血压、吸烟习惯和酒精摄入量(模型2)以及HbA1c水平、疾病持续时间和甘油三酯(模型3)等变量后,也注意到一致的结果。口蹄疫的ROC曲线下面积(AUC)为0.686 (95% CI 0.596 ~ 0.777)。结论sfmd与UACR独立相关,为预防和控制早期DKD血管并发症提供了临床依据。
{"title":"Relationship between flow-mediated dilation and urinary albumin-creatinine ratio in patients with type 2 diabetes mellitus","authors":"YuDie Fang ,&nbsp;Lijuan Jing ,&nbsp;YunXia Zhu ,&nbsp;Hongping Wang ,&nbsp;Juan Xia ,&nbsp;Tao Lei ,&nbsp;Jun Lu ,&nbsp;Jie Gao","doi":"10.1016/j.jdiacomp.2025.109162","DOIUrl":"10.1016/j.jdiacomp.2025.109162","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the association between Flow-Mediated Dilation (FMD) and the urinary albumin-to-creatinine ratio (UACR) in individuals with type 2 diabetes mellitus (T2DM).</div></div><div><h3>Methods</h3><div>This cross-sectional study involved 194 individuals diagnosed with T2DM. Participants were categorized into two groups based on their UACR levels: the diabetic kidney disease group (DKD) (UACR≥30 mg/g) and the non-diabetic kidney disease group (non-DKD) (UACR &lt;30 mg/g). The relationship between FMD and UACR was evaluated through Spearman correlation analysis and multivariable logistic regression analysis. Additionally, the predictive capacity of FMD for DKD was determined using receiver operating characteristic curve analysis.</div></div><div><h3>Results</h3><div>Median FMD was lower in DKD group than in non-DKD group (3.9 vs 4.9, <em>p</em> = 0.011). Furthermore, a notable negative correlation was observed between FMD and UACR (<em>r</em> = −0.253, <em>p</em> &lt; 0.05). Through logistic regression analysis, an increase in FMD by one standard deviation (SD) corresponded to a 35.6 % decrease in the likelihood of elevated UACR (OR: 0.644 [0.459–0.904]) (Model 1). Consistent findings were noted even after accounting for variables such as sex, age, BMI, hypertension, smoking habits, and alcohol intake (Model 2), as well as HbA1c levels, disease duration, and triglycerides (Model 3). The area under the ROC curve (AUC) for FMD was 0.686 (95 % CI 0.596–0.777).</div></div><div><h3>Conclusions</h3><div>FMD is independently correlated with UACR, which provides a clinical basis for the prevention and control of vascular complications in early DKD.</div></div>","PeriodicalId":15659,"journal":{"name":"Journal of diabetes and its complications","volume":"39 10","pages":"Article 109162"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Trends in mean serum insulin and hyperinsulinemia among US adults without diabetes 1999–2018 1999-2018年美国无糖尿病成年人平均血清胰岛素和高胰岛素血症趋势
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-28 DOI: 10.1016/j.jdiacomp.2025.109159
Tammie M. Johnson , James R. Churilla

Purpose

The purpose of this study is to examine trends for mean serum insulin concentration (pmol/L) and prevalence of hyperinsulinemia (≥4.358 pmol/L fasting insulin) in US adults without diabetes.

Methods

We used data from the 1999–2018 National Health and Nutrition Examination Survey (NHANES). Participants (n = 14,150) were ≥20 years of age, not pregnant, had no history of diabetes, had a fasting blood glucose measure of less than 126 mg/dL, and had valid responses to all study variables. Consecutive cycles of NHANES data from 1999 to 2018 (20 years) were aggregated into five four-year intervals.

Results

The Annual Percent Change (APC) for mean fasting insulin ranged from 5.64 (adjusted for body mass index) to 7.65 % when unadjusted (all p-values for trend <0.0001). The APC for hyperinsulinemia prevalence ranged from 19.4 % (adjusted for waist circumference) to 22.3 % when unadjusted (all p-values for trend <0.0001). The subanalyses by gender consistently revealed significant positive trends for both outcomes.

Conclusions

This study illustrates a significant positive trend for mean fasting insulin concentrations and hyperinsulinemia among US adults over 20 years. Monitoring serum insulin and hyperinsulinemia trends provides insights into the continuing rise in type 2 diabetes (T2D) and opportunities for T2D prevention.
目的本研究的目的是检查美国无糖尿病成人平均血清胰岛素浓度(pmol/L)和高胰岛素血症(≥4.358 pmol/L空腹胰岛素)的流行趋势。方法使用1999-2018年国家健康与营养检查调查(NHANES)的数据。参与者(n = 14,150)年龄≥20岁,未怀孕,无糖尿病史,空腹血糖测量值低于126 mg/dL,对所有研究变量均有有效反应。1999年至2018年(20年)的连续周期NHANES数据汇总为5个4年周期。结果平均空腹胰岛素的年百分比变化(APC)范围为5.64(经体重指数调整)至7.65%(趋势p值均为0.0001)。高胰岛素血症患病率的APC范围从19.4%(根据腰围调整)到未调整时的22.3%(趋势p值均为0.0001)。按性别划分的亚组分析一致显示两种结果都有显著的积极趋势。结论:本研究表明,在20岁以上的美国成年人中,平均空腹胰岛素浓度和高胰岛素血症呈显著上升趋势。监测血清胰岛素和高胰岛素血症的趋势可以了解2型糖尿病(T2D)持续上升的趋势,并为预防T2D提供机会。
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引用次数: 0
Atypical complications and co-morbidities of type 1 diabetes in young adults 年轻人1型糖尿病的非典型并发症和合并症
IF 3.1 3区 医学 Q3 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-08-27 DOI: 10.1016/j.jdiacomp.2025.109158
Steven James , Rebecca Barber , Jess Forster , Lindsay Sawatsky , Samantha Berry , Olive James , Kerrie Abel , Claire Trigg , Kim C. Donaghue , Maria E. Craig , Mahira Saiyed , Sheryl S. Salis , Jamie Wood , Willem Staels

Aims

Our review aimed to determine the prevalence of – and factors associated with – hearing loss, oral and olfactory disease, frozen shoulder, trigger finger, and hair loss in young adults with type 1 diabetes. These conditions were selected based on research team interests, existing literature, and group discussion.

Methods

We conducted a quantitative narrative review using a systematic process to identify cohort and cross-sectional studies involving young adults with type 1 diabetes (mean age 18–30 years). PubMed, CINAHL, and Cochrane were searched (January 2000–February 2024). Grey literature was not restricted, and quality appraisal was undertaken. Extracted data were synthesised and summarised narratively.

Results

The initial search found 3924 records and after title, abstract and full-text review, 19 records met inclusion criteria. Hearing loss prevalence ranged from 22.6 to 48.0 %, with age, diabetes duration, and systolic blood pressure identified as prominent associated features. For oral disease, peridontitis prevalence was 4.7 %, while alveolar bone loss ranged from 24.6 to 43.9 %; age was the primary associated factor. No eligible data were identified regarding frozen shoulder, trigger finger, or hair loss.

Conclusions

Further research is needed to characterize the prevalence and risk factors of atypical complications in type 1 diabetes. Clinical care should be guided by a robust understanding of these under-recognised comorbidities.
目的:本综述旨在确定年轻1型糖尿病患者听力损失、口腔和嗅觉疾病、肩周炎、扳机指和脱发的患病率及其相关因素。这些条件是根据研究小组的兴趣、现有文献和小组讨论选择的。方法:我们采用系统的方法进行定量叙述性回顾,以确定涉及年轻1型糖尿病患者(平均年龄18-30岁)的队列和横断面研究。检索PubMed, CINAHL和Cochrane(2000年1月- 2024年2月)。不限制灰色文献,进行质量评价。对提取的数据进行综合和叙述总结。结果初步检索到3924篇文献,经标题、摘要和全文审核,符合纳入标准的文献有19篇。听力损失的患病率从22.6%到48.0%不等,年龄、糖尿病病程和收缩压被认为是显著的相关特征。口腔疾病方面,牙周炎患病率为4.7%,而牙槽骨丢失率为24.6%至43.9%;年龄是主要的相关因素。没有关于肩周炎、扳机指或脱发的合格数据。结论1型糖尿病非典型并发症的患病率及危险因素有待进一步研究。临床护理应以对这些未被充分认识的合并症的充分了解为指导。
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引用次数: 0
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Journal of diabetes and its complications
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