Background

Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes.

Methods

For this cohort analysis, 927 participants aged 18–69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by ¹ H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort.

Findings

There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (p_dim1<0·0001, p_dim2=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, p_dim1<0·0001, p_dim2=0·037), pro-inflammatory biomarkers (IL-6: n=348, p_dim1<0·0001, p_dim2=0·013; IL-18: n=350, p_dim1<0·0001, p_dim2=0·38), and elevated cardiovascular risk (n_events=143, p_dim1=0·14, p_dim2<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (n_events=85, p_dim1=0·032, p_dim2=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (n_events=184, p_dim1=0·012, p_dim2=0·044) and cardiac autonomic neuropathy (n_events=118, p_dim1=0·0094, p_dim2=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (n_events=488, p_dim1=0·12, p_dim2=0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction.

Interpretation

These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis.

Funding

German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung.

中文翻译：

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用树状表示分析 2 型糖尿病异质性：来自前瞻性德国糖尿病研究和 LURIC 队列的见解

背景

2 型糖尿病的异质性可以通过使用反向图嵌入降维方法用树状图结构来表示。我们的目的是研究这种方法是否可用于在对新发 2 型糖尿病患者进行纵向随访期间对关键病理生理学成分和糖尿病相关并发症进行分层。

方法

在这项队列分析中，来自德国糖尿病研究 (GDS) 的 927 名 18-69 岁的新近发病 2 型糖尿病参与者被映射到先前开发的二维树上，该树基于九个简单的临床和实验室变量，对年龄和年龄进行了残差处理。性别。通过高胰岛素-正常血糖钳夹评估胰岛素敏感性，通过静脉葡萄糖耐量试验^{评估胰岛素分泌，通过1} H 磁共振波谱评估肝脂质含量，通过 ELISA 评估血清白细胞介素（IL）-6 和 IL-18 ，以及通过功能和临床测量来评估周围和自主神经病变。参与者被随访长达 16 年。我们还调查了路德维希港风险与心血管健康 (LURIC) 队列中 794 名接受侵入性冠状动脉诊断的 2 型糖尿病患者的心力衰竭和全因死亡率。

发现

树上存在钳夹测量的胰岛素敏感性（两个维度：p<0·0001）和胰岛素分泌（p _dim1 <0·0001，p _{dim2 =0·00097）的梯度。}胰岛素敏感性最低的地区个体的肝脂质含量最高（n=205，p _dim1 <0·0001，p _dim2 =0·037），促炎生物标志物（IL-6：n=348，p _dim1 ）最高<0·0001，p _dim2 =0·013；IL-18：n=350，p _dim1 <0·0001，p _dim2 =0·38），心血管风险升高（n_事件=143，p _dim1 =0·38） 14，p _dim2 <0·00081），而位于胰岛素分泌最低分支的个体更倾向于需要胰岛素治疗（n_事件=85，p _dim1 =0·032，p _dim2 =0·12）并且糖尿病感觉运动性多发性神经病（n_事件=184，p _dim1 =0·012，p _dim2 =0·044）和心脏自主神经病（n_事件=118，p _dim1 =0·0094，p _dim2 =0·06）的风险最高）。在 LURIC 队列中，显示胰岛素抵抗的树枝中的全因死亡率最高（n_事件= 488，p _dim1 = 0·12，p _dim2 = 0·0032）。显着梯度将射血分数保留的心力衰竭患者与射血分数降低的心力衰竭患者区分开来。

解释

这些数据定义了树形结构的病理生理学基础，有可能根据常规可用变量对糖尿病相关并发症进行分层，从而扩展糖尿病精准诊断的工具箱。

资金

德国糖尿病中心、德国联邦卫生部、北莱茵-威斯特法伦州文化和科学部、德国联邦教育和研究部、德国糖尿病协会、德国糖尿病研究中心、欧洲共同体、德国研究基金会和施穆茨勒基金会。