Integrin Signaling is a Novel Regulator of Hepatic Insulin Action
Williams, Ashley Silberman
The prevalence of type 2 diabetes has increased dramatically in parallel with excess caloric intake and sedentary lifestyles. Insulin resistance precedes the development of type 2 diabetes. The liver is a major insulin-responsive organ, thus defects in liver insulin action contribute greatly to the insulin resistant state. Hepatic insulin resistance is associated with increased deposition of extracellular matrix proteins such as collagen. Integrin α1β1 is a collagen binding integrin found on hepatocytes. Results from the Dissertation show that integrin α1 is upregulated in hepatocytes during times of nutritional overload and this exerts a protective effect against the development of hepatic insulin resistance in high fat fed mice. Moreover, a downstream integrin signaling molecule, integrin-linked kinase, is also involved in the regulation of hepatic insulin action. The hepatocyte-specific deletion of integrin-linked kinase protects against hepatic insulin resistance in high fat fed mice. The effects of integrin α1β1 and integrin-linked kinase on hepatic insulin sensitivity were independent of their effects on hepatic lipid accumulation. This was evident as results show that integrins promote hepatic lipid accumulation in high fat fed mice regardless of insulin sensitivity. Collectively, these are the first studies to demonstrate a mechanistic link between integrins and hepatic insulin action in vivo. The data within the Dissertation open new avenues for investigation in a novel area of metabolic research and identify innovative therapeutic targets to treat the underlying insulin resistance associated with type 2 diabetes.