Catestatin, its mimetic, and a natural variant improve insulin sensitivity in diet-induced obese mice: potential therapeutical implications

Abstract ID 99340 Poster Board 088 Objective: In 2019, 11.3% Americans had type 2 diabetes (T2D), which contributed to $412.9 billion in healthcare costs. Insulin resistance (IR) is the hallmark of obesity and T2D. While hepatic IR increases the risk of impaired fasting glucose, insulin-stimulated glucose disposal in skeletal muscle is markedly impaired in both obesity and T2D. We have previously reported that Chromogranin A (CgA)-derived peptide Catestatin (CST: hCgA₃₅₂₋₃₇₂) improves insulin sensitivity in diet-induced obese (DIO) mice by decreasing hepatic glucose production. In addition, we found that retro (carboxyl → amino)-inverso (all D-amino acids) CST (RI-CST) was entirely resistant to proteolytic digestion, displayed enhanced potency towards nicotine-evoked catecholamine secretion, and prolonged the blood pressure lowering action. Here, we investigated the effects of RI-CST and G364S-CST (a natural variant of CST) on insulin sensitivity in DIO mice and compared their effects with WT-CST. Methods and Results: DIO mice were intraperitoneally injected with WT-CST, RI-CST, or G364S-CST (2 μg/g body weight/day; 6 days a week) for 6 weeks. WT-CST caused significant decrease in blood glucose level in DIO mice compared to saline-treated groups after 2 weeks (delta-AUC: 153), 4 weeks (delta-AUC: 275), and 6 weeks (delta-AUC: 271) of treatment. A significant decrease in blood glucose level was seen after 2 weeks (delta-AUC: 113), 4 weeks (delta-AUC: 341), and 6 weeks (delta-AUC: 278) of treatment with RI-CST compared to saline-treated group. G364S-CST also caused significant decrease in blood glucose level in DIO mice compared to saline-treated group after 2 weeks (delta-AUC: 91), 4 weeks (delta-AUC: 434), and 6 weeks (delta-AUC: 321) of treatment. The glucose lowering efficacies were as follows: G364S > RI-CST > WT-CST. While food intake decreased in saline-treated group, there were no changes in food intake after treatments with WT-CST, RI-CST, or G364S-CST. There were no changes in body weight after treatments with saline, WT-CST, RI-CST, or G364S-CST. In contrast, grip-strength was significantly increased after treatments with CST (126%), RI-CST (130%), and G364S-CST (135%). Conclusions: Based on the previous and present findings, we conclude that proteolytically-resistant RI-CST is a better anti-diabetic peptide than naturally occurring WT-CST and G364S-CST. Funding information: This work was supported by the National Institutes of Health (1 R21 AG080246-01, 1 R21 AG078635-01A1, and 1 I21 RX004398-01A1 to S.K.M.).