The cellular molecular regulation of differing mechanisms of insulin resistance.

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.

Grant Number: 5R01DK126892-04
NIH Institute/Center: NIH
Principal Investigator: Stanley Andrisse