Jagannathan Ram, Kondal Dimple, Tiwari Pradeep, Deepa Mohan, Gujral Unjali, Patel Shivani, Mohan Sailesh, Anjana Ranjit, Staimez Lisa, Gupta Ruby, Beyh Yara, Oguntade Ayodipupo, Chang Howard, Ali Mohammed, Quyyumi Arshed, Sun Yan, Prabhakaran Dorairaj, Tandon Nikhil, Mohan Viswanathan, Narayan Km Venkat
Emory Global Diabetes Research Center, Woodruff Health Sciences Center and Emory University.
Centers for Chronic Disease Control, India.
Res Sq. 2025 Jun 23:rs.3.rs-6819284. doi: 10.21203/rs.3.rs-6819284/v1.
Current definitions of type 2 diabetes (T2D) and prediabetes do not capture their pathophysiological heterogeneity. We investigated data-driven subtypes of T2D and prediabetes and evaluated their associations with mortality.
We analyzed data from 14,306 South Asian participants from the CArdiometabolic Risk Reduction cohort using unsupervised k-means clustering based on five variables: age, BMI, HbA1c, insulin resistance, and beta-cell dysfunction. For each subtype of T2D or prediabetes, we estimated Cox hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality and excess years of life lost compared to normal glucose tolerance.
Among 2,639 participants with T2D, three subtypes emerged: Severe Insulin-Deficient Diabetes (SIDD;23.0%), Mild Insulin-Deficient Diabetes (MIDD;54.5%), and Severe Insulin-Resistant Diabetes (SIRD;22.5%). Among 4,992 participants with prediabetes, two subtypes were identified: Insulin-Deficient Prediabetes (IDPD;66.0%) and Insulin-Resistant Prediabetes (IRPD;34.0%). Over a median follow-up of 10.6 years, 1,076 deaths occurred (405 due to CVD). Compared with normal glucose tolerance, SIDD had the highest all-cause mortality HR (3.34 [95%CI, 2.39 to 4.68]), followed by MIDD (1.39[95%CI, 1.05 to 1.84]) and SIRD (1.67[95%CI, 1.15 to 2.41]). Among prediabetes subtypes, IDPD was associated with increased all-cause (HR: 1.32 [95%CI, 1.03 to 1.68]) and CVD mortality (HR:1.53 [95%CI, 1.00 to 2.34]), whereas IRPD was not. Excess years of life lost were greatest for SIDD (17.7 years), followed by MIDD (12.8 years) and SIRD (12.0 years).
Insulin-deficient subtypes made up a high proportion of T2D and prediabetes cases, harboring increased mortality hazards and excess years of life lost relative to normal glucose tolerance.
2型糖尿病（T2D）和糖尿病前期的当前定义未能体现其病理生理异质性。我们研究了数据驱动的T2D和糖尿病前期亚型，并评估了它们与死亡率的关联。
我们分析了来自“降低心血管代谢风险”队列中14306名南亚参与者的数据，使用基于年龄、体重指数（BMI）、糖化血红蛋白（HbA1c）、胰岛素抵抗和β细胞功能障碍这五个变量的无监督k均值聚类法。对于T2D或糖尿病前期的每种亚型，我们估计了全因死亡率和心血管疾病（CVD）死亡率的Cox风险比（HRs），以及与正常糖耐量相比的生命损失年数。
在2639名T2D参与者中，出现了三种亚型：严重胰岛素缺乏型糖尿病（SIDD；23.0%）、轻度胰岛素缺乏型糖尿病（MIDD；54.5%）和严重胰岛素抵抗型糖尿病（SIRD；22.5%）。在4992名糖尿病前期参与者中，识别出两种亚型：胰岛素缺乏型糖尿病前期（IDPD；66.0%）和胰岛素抵抗型糖尿病前期（IRPD；34.0%）。在中位随访10.6年期间，发生了1076例死亡（405例死于CVD）。与正常糖耐量相比，SIDD的全因死亡率HR最高（3.34[95%置信区间，2.39至4.68]），其次是MIDD（1.39[95%置信区间，1.05至1.84]）和SIRD（1.67[95%置信区间，1.15至2.41]）。在糖尿病前期亚型中，IDPD与全因死亡率增加（HR：1.32[95%置信区间，1.03至1.68]）和CVD死亡率增加（HR：1.53[95%置信区间，1.00至2.34]）相关，而IRPD则不然。生命损失年数在SIDD中最多（17.7年），其次是MIDD（12.8年）和SIRD（
