Abstract

Chronic inflammation, specifically in adipose tissue (fat), drives insulin resistance and type 2 diabetes. Thiazolidinediones (TZDs) are highly effective anti-diabetic drugs that improve how responsive cells are to insulin (insulin sensitivity) and lower blood glucose levels. However, their clinical use is limited by side effects. For decades, scientists have been trying to uncover how these “insulin sensitizers” work, and while several promising mechanisms have been proposed, a definitive answer has not yet emerged. With diabetes constantly rising globally, therapeutic options to treat the underlying insulin resistance independent of weight loss are severely limited. Determining how TZDs induce insulin sensitivity might discover new insulin-sensitizing agents without the unwanted TZD side effects.

Innate immune cells, specifically in the fat, so-called adipose tissue macrophages, play a significant role in obesity-associated inflammation, and their secreted products can regulate glucose homeostasis. The insulin-sensitizing effects of TZDs are linked to changes in these macrophages. They secrete small nanoparticles, termed exosomes, to communicate between different cells and tissues. My study explores how nanoparticles secreted from adipose tissue macrophages in response to TZD treatment improve insulin resistance and metabolic dysfunction. Characterizing the cargo of these nanoparticles could lead to novel anti-diabetic agents.

We hypothesize that TZDs stimulate the release of “metabolically beneficial” exosomes from adipose tissue macrophages that enhance insulin sensitivity and ameliorate glucose intolerance. Uncovering the specific molecule(s) that these macrophages transmit to insulin-target tissues to lower glucose levels could emerge as a novel therapeutic approach to treat diabetes and other metabolic and inflammatory diseases.