A 3D biomimetic in vitro model of obesity-associated insulin resistance and type 2 diabetes

The World Health Organisation declared obesity a global epidemic.

Obesity is characterised by unhealthy adipose tissue (AT) accumulation and is a significant risk factor for insulin resistance and type 2 diabetes (T2D).

In obese subjects, AT undergoes chronic inflammation associated with hypoxia, fibrosis, and a proinflammatory secretome that can cause insulin resistance and T2D. Understanding the link between AT dysfunction and metabolic complications is critical to developing therapeutics.

However, current in vitro and in vivo models of obesity-associated T2D poorly recapitulate the inflammatory and insulin-resistant AT environment, hindering our ability to understand and treat obesity-linked T2D.

To overcome these limitations, we will develop a non-animal biomimetic 3D in vitro model of human AT under obese conditions (hypertrophy, fibrosis, inflammation, and insulin resistance).

We will engineer biocompatible dynamic hydrogels to recapitulate the physico-mechanical changes of AT during obesity (fibrosis-induced stiffening).

Human preadipocytes will be cultured in the hydrogels, differentiated into mature adipocytes, and cultured in a pro-insulin resistant environment (lipid-induced lipotoxicity, immune cells co-cultures).

Building on this proof of concept model, we will apply for further funding to enhance the model complexity (other AT cells, multi-organ platforms), accelerate drug screening, and develop tailored pharmacological treatments for individuals living with T2D.