Type 2 diabetes is a disease marked by insulin resistance in peripheral tissues. One leading hypothesis to explain insulin resistance in the liver is the instigation of ER stress by high fat/western diet. We have recently characterized a mouse mutant that harbors an ENU induced point mutation in the Sec6111 gene that leads to diabetes via ER stress induced 2-cell apoptosis. By rescuing this mutation specifically in [unreadable] cells using a wild- type version of the gene driven by the rat insulin promoter, we uncovered ER stress in the liver that was a primary result of the mutation in Sec61a1. Since these mice have a normal [unreadable]-cell compartment and normal levels of blood glucose, despite reduced circulating insulin levels we propose to use these mice to test three different hypotheses that will further clarify the role of ER stress in the development of hepatic insulin resistance. Our specific aims are: Specific Aim 1. Test the hypothesis that hepatic ER stress leads to insulin resistance and hepatosteatosis using a lean mouse model. Specific Aim 2. In a lean mouse model, test the hypotheses that (1) ER stress reduces hepatic insulin signaling and (2) that ER stress reduces gluconeogenesis. Specific Aim 3. Test the hypothesis that chronic ER stress influences the promoter occupation and transcription of metabolically relevant genes by the ER-stress-responsive transcription factor XBP1. This research can have immediate impact on the treatment of type 2 diabetes as a clearer view of the etiological circumstances that lead to insulin resistance can guide the development of therapeutic interventions and preventative care. PUBLIC HEALTH RELEVANCE: We propose to characterize the effects that ER stress has on hepatic insulin sensitivity in a novel mouse model that harbors a point mutation in the Sec61a1 gene that we have found leads to ER stress. We will first examine the effects on insulin sensitivity at the physiological level using the hyperinsulinemic- euglycemic clamp technique;followed by examination the effects of ER stress at the cellular level by analyzing the integrity of the insulin signaling pathway and gluconeogenesis;and finally examining the effects of hepatic ER stress at the transcriptional level using the ChIP-seq technique. These studies will allow us to more clearly define the role ER stress plays in the liver and how it interacts with environmental stresses during the development of insulin resistance, and guide the development of therapeutics for treatment and prevention of type 2 diabetes.