@article {Bandyopadhyay2020.10.31.363481, author = {Gautam Bandyopadhyay and Kechun Tang and Nicholas J.G. Webster and Geert van den Bogaart and Sushil K. Mahata}, title = {Catestatin reduces hyperglycemia in insulin-resistant mice by redirecting glucose-6-phosphate from the gluconeogenic to the glycogenic pathway}, elocation-id = {2020.10.31.363481}, year = {2020}, doi = {10.1101/2020.10.31.363481}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Objective Defects in hepatic glycogen synthesis contribute to postprandial hyperglycemia in type 2 diabetic (T2D) patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352-372) inhibits dephosphorylation of glucose 6-phosphate (G6P) and improves glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST also reduces hyperglycemia by increasing hepatic glycogen synthesis.Methods We determined liver glycogen, G6P, and UDP glucose (UDPG); plasma insulin, glucagon, norepinephrine (NE), and epinephrine (EPI); glycogen synthase (GYS) and phosphoglucomutase (PGM) enzyme activities in fed and fasted liver of lean and obese wild-type and genetically obese CST knockout (KO) mice after treatments with saline, CST or insulin. We determined glycogen synthesis and glycogenolysis in cultured hepatocytes. We analyzed phosphorylation signals of GYS2 and GSK-3β by immunoblotting.Results CST stimulated glycogen accumulation in fed and fasted liver and in cultured hepatocytes. CST reduced plasma NE and EPI levels, suggesting that CST promotes glycogenesis by inhibiting catecholamine-induced glycogenolysis. CST also directly stimulated glycogenesis and inhibited NE and EPI-induced glycogenolysis in hepatocytes. CST elevated the levels of G6P and UDPG and increased GYS and PGM activities, redirecting G6P to the glycogenic pathway. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role that CST plays in hepatic glycogenesisConclusions We conclude that CST directly promotes the glycogenic pathway and reduces plasma glucose levels in insulin-resistant mice by (i) reducing glucose production from G6P, (ii) increasing glycogen synthesis from G6P via formation of UDPG, and (iii) reducing glycogenolysis.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2020/11/01/2020.10.31.363481}, eprint = {https://www.biorxiv.org/content/early/2020/11/01/2020.10.31.363481.full.pdf}, journal = {bioRxiv} }