#9 Altered Islet Function May Promote A Lean Phenotype In Tafazzin Deficient Mice
Laura K Cole, University of Manitoba; Christine Doucette, University of Manitoba; Marilyne Vandel, University of Manitoba; Mario Fonseca, University of Manitoba; Bo Xiang, University of Manitoba; Vern Dolinsky, University of Manitoba; Grant M Hatch, University of Manitoba
Tafazzin is a transacylase that maintains mitochondrial membrane integrity and the function of the mitochondrial respiratory chain. Specifically, tafazzin maintains the content and molecular structure of the unique tetra-acyl phospholipid cardiolipin (CL) located in the inner mitochondrial membrane. Despite abundant evidence that mitochondrial dysfunction is associated with insulin resistance, little is known about the potential role of CL and tafazzin in the trajectory of this disease.
To investigate the in vivo effects of tafazzin deficiency, we have utilized a mouse model with a doxycycline- inducible tafazzin shRNA knock-down.
We have previously established that tafazzin knock-down mice are protected against the development of obesity, and insulin resistance compared to control litter mates. Tafazzin deficiency promotes a lean phenotype due to a coordinated elevation in adipose lipolysis and hepatic fatty acid oxidation. We have now determined that glucagon and insulin levels in the blood and whole islets are significantly reduced with tafazzin deficiency. We have also ascertained that the quantity and function of beta-cells were similar between genotypes. However, despite similar levels of alpha-cells, glucagon secretion during high-glucose conditions was elevated from islets isolated from tafazzin knock-down mice. As a result, tafazzin knock-down mice exhibited significantly higher circulating ratios of glucagon to insulin during glucose challenges.
Our experiments indicate that tafazzin may have a role in regulating islet function. These data also suggest that mice deficient in tafazzin may be protected in part against weight gain by promoting glucagon secretion during fed states. Since, the development of type 2 diabetes is closely related to obesity and pancreatic function altering cardiolipin synthesis may be a novel therapeutic option for patients at risk for type 2 diabetes.