SUN-595 - Effects of A 1-Month High-Fructose Diet on Insulin Signaling in Skeletal Muscle of Protein Kinase C Epsilon Heterozygous (Pkcε-Het) Male Mice

Background:
Protein kinase C epsilon (PKCε) plays a central role in insulin signaling and glucose metabolism in liver and skeletal muscle. High-fructose diets (HFrD) are known to induce insulin resistance, a hallmark of type 2 diabetes, by impairing the Akt pathway. The impact of PKCε heterozygosity on insulin signaling under HFrD conditions remains unclear.

Objective:
To investigate the effects of a 1-month high-fructose diet on insulin signaling in skeletal muscle of liver-specific PKCε heterozygous (Liv-PKCε-Het) male mice, with a focus on Akt and Foxo1 phosphorylation as markers of insulin sensitivity.

Methods:
Liv-PKCε-Het mice were assigned to either a high-fructose diet (HFrD) or control diet (CD) for 1 month. Western blot analysis of skeletal muscle tissue assessed phosphorylation of Akt (S473) and Foxo1 (S256), along with total protein levels and insulin receptor expression, under basal and insulin-stimulated conditions.

Results:
HFrD impaired insulin signaling as evidenced by reduced p-Akt/Akt ratios in both basal (HFrD: 0.74 vs CD: 1.00) and insulin-stimulated conditions (HFrD: 1.30 vs CD: 1.20). Paradoxically, downstream p-Foxo1/actin and p-Foxo1/Foxo1 levels were elevated in HFrD-fed mice after insulin stimulation (3.66 and 2.21, respectively), suggesting compensatory mechanisms. Total AKT and Foxo1 protein levels were modestly increased (AKT/actin: 3.86; Foxo1/actin: 1.28), and insulin receptor expression was upregulated (HFrD+Ins: 1.83 vs CD-Basal: 1.00).

Conclusion:
A 1-month high-fructose diet disrupts normal insulin signaling in skeletal muscle of Liv-PKCε-Het mice, characterized by impaired AKT activation despite preserved or enhanced downstream Foxo1 phosphorylation. These results suggest altered feedback or cross-talk within insulin-responsive pathways, highlighting the complex role of PKCε in diet-induced insulin resistance.

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