The Roles of Free Fatty Acids and Inflammation in β-Cell Dysfunction

β-cell lipotoxicity refers to the adverse effects of chronically elevated plasma free fatty acids on β-cell function and mass and plays an important role in type 2 diabetes. The objective of my thesis was to investigate the role of inflammation in fat-induced β-cell dysfunction in vivo. I used in vivo models of 48h intravenous fat infusion in mice followed by hyperglycemic clamps or islet secretion studies ex vivo, and in vitro models of 48h exposure to oleate and palmitate in islets. The first study showed the proinflammatory kinase IKKβ is causally involved in fat-induced β-cell dysfunction during hyperglycemic clamps in vivo, ex vivo in isolated islets of fat-infused rodents and in vitro in oleate-exposed islets. This is the first study to show directly that β-cell IKKβ plays a causal role in fat-induced β-cell dysfunction in vivo. Inflammation induces insulin resistance in the classical insulin target tissues muscle, fat and liver and the purpose of the second study was to determine whether β-cell insulin resistance plays a causal role in fat-induced β cell dysfunction. We used models of pharmacologic and genetic upregulation of insulin signaling, which were protected from fat-induced β-cell dysfunction in vivo and ex vivo. These data are the first to show that β-cell insulin resistance plays a causal role in β-cell dysfunction induced selectively by fat. The intracellular NOD1 receptor of innate immunity also affects metabolism, however its role in β-cell function is unknown and was the focus of the third study. Mouse and human islets expressed NOD1 mRNA, the NOD1 activator FK565 decreased β-cell function and NOD1-KO islets were protected from palmitate-induced β-cell dysfunction in vitro. In vivo, FK565 decreased β-cell function and NOD1-KO mice were protected from palmitate-induced β-cell dysfunction. These data demonstrate that NOD1 plays a causal role in saturated-fat induced β-cell dysfunction in vivo.

Department dc:contributor.department

Physiology

Year dc:date.issued

2017

Author dc:creator

• Ivovic, Aleksandar

Advisor dc:contributor.advisor

• Giacca, Adria

Handle dc:identifier.uri

http://hdl.handle.net/1807/98794

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/98794