Lettuce-avicularin treatment reverses insulin resistance through stimulation of glycolytic kinases and insulin signaling molecules

In order to recommend a more effective approach to manage insulin resistance, we monitored the activities of glycolytic kinases, insulin signaling molecules, and incretin hormones and identified the possible targets related to the insulin-sensitizing effects of combined pharmacological and dietary intervention involving avicularin and lettuce. Insulin resistance was induced in rats with a fructose-rich diet and confirmed from baseline analysis of FBS (>250 mg/dl), insulin (>25 µIU/ml), and HOMA-IR (>10). For 12 weeks, the insulin-resistant rats were treated exclusively with 5000 mg/kg b.w avicularin (DAvi) or by dietary placement on lettuce (DLet) or a combination of both and compared with non-insulin resistant rats. Avicularin reversed alterations in HbA1c and insulin levels. DLet produced no significant effect on the incretins GLP 1 (P=0.909) and GIP (P=0.990), but DAvi slightly stimulated GLP 1 but not GIP. A strong positive correlation was found between improved β-cell responsiveness and the insulin signaling molecules: Akt2 (r=0.7248), IRS 1 (r=0.5173), and PI3K (r=0.7892). Only the combined avicularin and lettuce reversed the Akt2 levels (P=0.728). The lettuce meal slightly stimulated PI3K but normalized IRS 1 while avicularin treatment slightly stimulated IRS 1 but restored the PI3K levels (P=0.815). The positive correlation between β-cell responsiveness and hexokinase (r=0.5959), PFK (r=0.6222), and PK (r=0.6591) activities were statistically significant. Alterations in glycolytic kinases were reversed by DLet and in combination with avicularin. A combined pharmacological and dietary approach with avicularin and lettuce is required to effectively reverse insulin resistance.