The cellular molecular regulation of differing mechanisms of insulin resistance.

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Project Summary Molecular & Genetic Problem: Lipid-induced hepatic insulin resistance is due to diacylglyceride (DAG)-induced protein kinase C epsilon (PKCε) activation leading to inhibition of insulin receptor tyrosine kinase [4, 5]. However, nonobese hyperandrogenic (HA) female mice displayed androgen-specific hepatic insulin resistance indicating a lipid-independent pathogenic mechanism [3]. Additionally, high fructose diets (HFrD) compared to high fat diets (HFD) display differing mechanisms of insulin resistance, where high fructose impairs glucokinase and glycogen synthase but high fat lowers p-AKT [6]. Ketohexokinase (KHK, also known as liver fructokinase) is required for HFrD-induced metabolic dysfunction [7]. The Overall Aim is to establish that differing causes of insulin resistance display crosstalk between cellular, molecular, and genetic mechanisms. I will develop 3 mouse models of hepatic insulin resistance: high androgen (HA)-induced, HFD-induced, and HFrD-induced. Using various hepatic specific knockout (KO) mice to eliminate the function of certain pathways (androgen receptor (AR-KO), ketohexokinase (KHK-KO), and protein kinase C (PKC-KO)), I will examine the intersecting pathogenic mechanisms unique to each of the three insulin resistant models. Expected Outcome: I hypothesize that each model of insulin resistance (HA, HFD, and HFrD) will contain its own unique mechanistic aspect with varying aspects of crosstalk. Thus, suggesting the movement towards targeted therapeutic interventions based on the type of insulin resistance.