Catestatin reduces hyperglycemia in insulin-resistant mice by redirecting glucose-6-phosphate from the gluconeogenic to the glycogenic pathway

Abstract

AimDefects in hepatic glycogen synthesis contribute to postprandial hyperglycemia in type 2 diabetic (T2D) patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352-372) has been shown to improve glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST also reduces hyperglycemia by increasing hepatic glycogen synthesis. MethodsWe determined liver glycogen, glucose-6-phosphate (G6P), uridine diphosphate glucose (UDPG), and glycogen synthase (GYS2) activities; plasma insulin, glucagon, norepinephrine (NE), and epinephrine (EPI) levels in fed and fasted liver of lean and obese mice as well as in CST knockout (CST-KO) mice after treatments with saline, CST, or insulin. We also determined glycogen synthesis and glycogenolysis in primary hepatocytes. In addition, we analyzed phosphorylation signals of Insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol dependent kinase-1 (PDK-1), GYS2, glycogen synthase kinase-3{beta} (GSK-3{beta}), AKT (an enzyme in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mTOR (mammalian/mechanistic target of rapamycin) by immunoblotting. ResultsCST stimulated glycogen accumulation in fed and fasted liver and in primary 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 UDPG and increased GYS2 activity, thus redirecting G6P to the glycogenic pathway. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST can improve insulin signals downstream of insulin receptor IR and IRS-1 by enhancing phospho-AKT signals through stimulation of PDK-1 and mTORC2 (mTOR complex 2) activities. ConclusionsWe conclude that CST directly promotes the glycogenic pathway and reduces plasma glucose levels in insulin-resistant mice by (i) reducing glucose production, (ii) increasing glycogen synthesis from UDPG, and (iii) reducing glycogenolysis. This is achieved by enhancing downstream insulin signaling.