Machine Learning Model Based on Insulin Resistance Metagenes Underpins Genetic Basis of Type 2 Diabetes

Insulin resistance (IR) is considered the precursor and the key pathophysiological mechanism of type 2 diabetes (T2D) and metabolic syndrome (MetS). However, the pathways that IR shares with T2D are not clearly understood. Meta-analysis of multiple DNA microarray datasets could provide a robust set of metagenes identified across multiple studies. These metagenes would likely include a subset of genes (key metagenes) shared by both IR and T2D, and possibly responsible for the transition between them. In this study, we attempted to find these key metagenes using a feature selection method, LASSO, and then used the expression profiles of these genes to train five machine learning models: LASSO, SVM, XGBoost, Random Forest, and ANN. Among them, ANN performed well, with an area under the curve (AUC) > 95%. It also demonstrated fairly good performance in differentiating diabetics from normal glucose tolerant (NGT) persons in the test dataset, with 73% accuracy across 64 human adipose tissue samples. Furthermore, these core metagenes were also enriched in diabetes-associated terms and were found in previous genome-wide association studies of T2D and its associated glycemic traits HOMA-IR and HOMA-B. Therefore, this metagenome deserves further investigation with regard to the cardinal molecular pathological defects/pathways underlying both IR and T2D.

Automated summary

Insulin resistance (IR) is the precursor and key mechanism of type 2 diabetes (T2D) and metabolic syndrome (MetS), but the pathways shared by IR and T2D are not well understood. This study identified a set of key metagenes shared by IR and T2D using a feature selection method and found that artificial neural network (ANN) performed well in differentiating diabetics from normal glucose tolerant (NGT) persons with 73% accuracy. These key metagenes were also validated in diabetes-associated genetic studies, indicating their potential importance in the molecular pathology of both IR and T2D.