Leveraging discordancy between obesity and type 2 diabetes to target insulin resistance

Background

Obesity is often associated with type 2 diabetes, but it does not always lead to metabolic disorders. This interesting phenomenon is called discordant diabesity, and its causes are unclear. Investigating those causes could reveal the mechanisms that protect against type 2 diabetes despite obesity.

Hypothesis

We hypothesize that common genetic variation, modulating the expression of specific genes, contributes to discordant diabesity. We also hypothesize that the function of these genes is closely related to metabolic traits.

Methods

In our recent study, we have found that the expression of a gene named DNAH10 in adipose tissue associates with the genetic variation linked to discordant diabesity. To identify the genetic variants that cause the altered gene expression we will use CRISPR-mediated allele editing. To elucidate the role of DNAH10 in adipocytes we will investigate the allele-edited or DNAH10-knockout cells for adipogenic differentiation potential, transcriptome and metabolome profile, insulin resistance, and the function of primary cilia, to which we have localized the DNAH10 gene product.

Results

Our project aims to find the causal genetic variant that alters the expression of DNAH10 and to demonstrate the mechanism through which DNAH10 confers, at least to a certain extent, protection against metabolic disorders. We hope this can lead to novel drug target candidates against insulin resistance.

Conclusions

Our project combines the epidemiological findings with experimental science to find novel approaches for investigating metabolic disorders. We aim to define the clinically relevant function of common genetic variation, and eventually leverage that knowledge to find novel druggable molecular targets to treat insulin resistance.