effects of free fatty acids on hepatic glucose metabolism, insulin action and insulin clearance.
Published: 2004
Language: eng
Number of pages: 183
Description: Free fatty acids (FFA), which are often elevated in obesity, are implicated in the causative link between obesity and type 2 diabetes. Impaired hepatic glucose production (HGP), hepatic insulin action and insulin clearance (i.e., leading to hyperinsulinemia) are the key features of obesity associated type 2 diabetes. In this thesis, the hypothesis is postulated that elevation of plasma FFA leads to decrease hepatic insulin action and binding via  similar mechanisms. In an in vivo rat model (Study 1, 2 and 3), the effects of the elevation of FFA on HGP, hepatic insulin action and insulin clearance were investigated. It is reported in Study 1 that FFA increase HGP in parallel with increased hepatic FFA oxidation, and decrease hepatic insulin action and plasma insulin clearance in parallel with hepatic Protein Kinase C (PKC)-delta translocation. These findings suggest that FFA oxidation plays a role in FFA-induced increase in basal HGP, and PKC-delta plays a role in FFA-induced hepatic insulin resistance and decrease in insulin clearance. In study 2, I found that FFA increase basal HGP by increasing in vivo hepatic glucose-6-phosphatase (G6Pase) activity, and induce hepatic insulin resistance by decreasing the ability of insulin to increase in vivo hepatic glucokinase (GK) activity. These data suggest that the rate-limiting enzymes for FFA-induced increase in HGP and hepatic insulin resistance are G6Pase and GK, respectively. Findings of study 3 were that polyunsaturated fatty acids induce less hepatic insulin resistance than saturated or monounsaturated fatty acids, and this effect is paralleled by hepatic PKC-delta translocation but not triglyceride content in the liver. These findings further suggest that PKC-8 mediates FFA-induced hepatic insulin resistance. Also, it appears that liver triglyceride content is not a positive marker for FFA-induced hepatic insulin resistance in our model. In study 4, I found that FFA decrease insulin binding (which is the major determinant of insulin clearance) in an in vitro model (freshly isolated hepatocytes). More importantly, this FFA effect is mediated by PKC-delta but is independent of FFA oxidation. This is similar to the FFA effect on hepatic insulin action as reported in study 1. In conclusion , this thesis provides evidence, for the first time, that elevation of FFA decrease hepatic insulin action and binding possibly via a hepatic PKC-delta mediated mechanism. Thus, by the same molecular mechanism, FFA not only induce hepatic insulin resistance but also generate hyperinsulinemia to potentially overcome, in part, the insulin resistance.
Notes: Adviser: Adria Giacca.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2208.