A Sweet Potato Vine-Derived Peptide ST2b Alleviates Type 2 Diabetes Via Stabilizing INSIG-1 to Inhibit SREBP-2-driven Lipotoxicity

Sterol Regulatory Element-Binding Protein 2 (SREBP-2) is a core transcription factor that regulates de novo cholesterol synthesis. Targeting the SREBP pathway is regarded as a potential strategy for treating metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). At present, natural specific and effective modulators of this pathway are still very scarce. We identified a novel nonapeptide ST2b from the vine of the medicinal sweet potato Ipomoea batatas L. cv. Simon 1, and its amino acid sequence is GSFKMEGKR. In vitro experiments have shown that ST2b can significantly promote glucose uptake in insulin-resistant HepG2 cells and improve disorders of glycolipid metabolism. In a mouse model of T2DM induced by streptozotocin and a high-fat, high-sugar diet, intragastric ST2b reduced fasting blood glucose and serum insulin levels, improved glucose tolerance and insulin sensitivity, normalized lipid metabolism, and protected metabolic organs. ST2b binds to INSIG-1, stabilizing it by inhibiting degradation, enhancing INSIG-1 interaction with SCAP, blocking SREBP-2 activation, reducing cholesterol synthesis gene transcription. ST2b from sweet potatoes shows promise as a T2DM treatment by inhibiting the SREBP-2 pathway, suggesting its potential as a therapeutic agent or functional food for T2DM.