Page 48 - N. Metabolism and metabolic diseases

[N. Metabolism and metabolic diseases-27]

Truncated SOCS3 (ΔSOCS3) Overcomes Insulin Resistance

Associated with Type 2 Diabetes By Attenuating

Phosphorylation Of Akt

Hyeontae Kang¹, Kuysook Lee¹, Jisook Jeon¹, Sujeong Kim¹, Youngsil Choi¹, Daewoong Jo¹

¹R&D, Cellivery, Seoul 03929, Korea

Leptin signaling is negatively regulated by suppressor of cytokine signaling 3 (SOCS3) that binds to the leptin
receptor and promotes leptin resistance. Prolonged leptin stimulation is further associated with hyperinsulinemia
and insulin resistance, defining feature of Type 2 diabetes mellitus (T2DM). To investigate the interplay between

leptin and insulin signaling, we developed a cell-permeable dominant-interfering SOCS3 (CP-∆SOCS3) protein, fused
with a sequence optimized-advanced macromolecule transduction domain (aMTD) for delivering into cells and

tissues. CP-ΔSOCS3 was treated in diet-induced obese (DIO) mice to evaluate the increment of insulin sensitivity
and glucose control. CP-ΔSOCS3 was delivered into cells and tissues examined including brain, liver, spleen and

lung. Insulin pretreatment attenuates phosphorylation of Akt in HepG2 cells; whereas, insulin sensitivity was restored
by CP-ΔSOCS3. DIO mice treated with CP-ΔSOCS3 showed 12.1% body weight loss in 14 days and Blood glucose

at 2 hrs decreased by 66.7% in the treated group as compared to the diluent group. These results suggest CP-
ΔSOCS3 recombinant protein has therapeutic effect on obesity and blood glucose control so that it may provide a

mechanism-specific therapy for T2DM.