Unraveling the molecular heterogeneity in type 2 diabetes: A potential subtype discovery followed by metabolic modeling

Abstract

BackgroundType 2 diabetes mellitus (T2DM) is a complex multifactorial disease with a high prevalence worldwide. Insulin resistance and impaired insulin secretion are the two major abnormalities in the pathogenesis of T2DM. Skeletal muscle is responsible for over 75% of the glucose uptake and plays a critical role in T2DM. Here, we sought to provide a better understanding of the abnormalities in this tissue. MethodsThe muscle gene expression patterns were explored in healthy and newly diagnosed T2DM individuals using supervised and unsupervised classification approaches. Moreover, the potential of subtyping T2DM patients was evaluated based on the gene expression patterns.ResultsA machine-learning technique was applied to identify a set of genes whose expression patterns could discriminate diabetic subjects from healthy ones. A gene set comprising of 26 genes was found that was able to distinguish healthy from diabetic individuals with 94% accuracy. In addition, three distinct clusters of diabetic patients with different dysregulated genes and metabolic pathways were identified. Conclusions This study indicates that T2DM is triggered by different cellular/molecular mechanisms, and it can be categorized into different subtypes. Subtyping of T2DM patients in combination with their real clinical profiles will provide a better understanding of the abnormalities in each group and more effective therapeutic approaches in the future.

Precision subclassification of type 2 diabetes: a systematic review

“…Human genetic risk information is rapidly penetrating clinical medicine. Two sets of papers utilised genomic data to identify diabetes subtypes, either in the form of inherited common genetic variation 10 , 37 or gene expression data from muscle biopsies 38 (Table 2 ). The first approach clustered genetic variants with clinical traits associated with type 2 diabetes to identify subsets of variants predicted to act in shared mechanistic processes.…”

Systematic review of precision subclassification of type 2 diabetes

“…Two sets of papers utilised genomic data to identify diabetes subtypes, either in the form of inherited common genetic variation 8,36 or gene expression data from muscle biopsies 37 (Table 2). The former approach started with genetic variants associated with type 2 diabetes, and clustered their genotype-phenotype associations to identify subsets of variants predicted to act in shared mechanistic processes.…”