Ganzhirong Granule Inhibits Hepatic Gluconeogenesis through the SIRT3-MPC1-PC/PDH Axis in Type 2 Diabetes

Sitong Chen; Dan Yang; Chenxu Jing; Xuenan Chen; Wenqi Jin; Dan Lv; Tiejun Liu; Yangyang Liu

doi:10.3791/69500

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Research Article

Ganzhirong Granule Inhibits Hepatic Gluconeogenesis through the SIRT3-MPC1-PC/PDH Axis in Type 2 Diabetes

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DOI:

10.3791/69500

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December 12th, 2025

Sitong Chen¹^,² , Dan Yang¹^,³ , Chenxu Jing¹^,³ , Xuenan Chen¹^,³ , Wenqi Jin¹^,² , Dan Lv¹^,² , Tiejun Liu¹^,² , Yangyang Liu¹^,⁴

¹College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, ²Department of Gastroenterology, The Affiliated Hospital to Changchun University of Chinese Medicine, ³Research Center of Chinese Traditional Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, ⁴Preventive Treatment Center, The Affiliated Hospital to Changchun University of Chinese Medicine

Summary

This study investigated whether Ganzhirong Granule ameliorates hyperglycemia in type 2 diabetes by inhibiting hepatic gluconeogenesis through the SIRT3-MPC1-PC/PDH axis.

Abstract

Type 2 diabetes mellitus (T2DM) is a global metabolic disorder characterized by hepatic insulin resistance and excessive gluconeogenesis. Ganzhirong Granule (GZRG), a traditional Chinese medicine formula, has shown potential in managing T2DM, but its underlying mechanisms, particularly concerning hepatic gluconeogenesis, remain unclear. This study investigated whether GZRG ameliorates hyperglycemia by modulating the SIRT3-mediated signaling pathway. The anti-diabetic effects of GZRG were evaluated in high-fat diet (HFD)-induced T2DM mice and free fatty acid (FFA)-induced insulin-resistant HepG2 cells. Metabolic parameters, glucose and pyruvate tolerance, insulin sensitivity, and lipid profiles were assessed. Molecular mechanisms were explored through the overexpression and knockdown of SIRT3, examining the expression of key proteins (SIRT3, MPC1, PC, PDH-E2, PCK1, and G6Pase) in the gluconeogenic pathway. GZRG treatment significantly ameliorated hyperglycemia, enhanced insulin sensitivity, and improved lipid metabolism in both T2DM mice and insulin-resistant (IR) HepG2 cells. It attenuated hepatic steatosis and suppressed gluconeogenesis. Mechanistically, GZRG downregulated SIRT3 expression, which led to concomitant reductions in MPC1 and PC levels and an increase in PDH-E2. This shift in protein expression redirected pyruvate metabolism away from gluconeogenesis. SIRT3 overexpression reversed the suppressive effects of GZRG on gluconeogenesis, whereas SIRT3 knockdown synergized with GZRG. GZRG alleviates T2DM by inhibiting hepatic gluconeogenesis through the SIRT3-MPC1-PC/PDH axis. These findings elucidate a novel molecular mechanism of GZRG and highlight SIRT3 as a potential therapeutic target for T2DM management.

Introduction

Type 2 diabetes mellitus (T2DM) has emerged as one of the most prevalent and debilitating chronic metabolic disorders worldwide, posing a substantial public health and economic burden¹^,². Characterized by insulin resistance (IR) and progressive pancreatic β-cell dysfunction, T2DM is primarily driven by impaired glucose and lipid homeostasis³^,⁴. Among the multiple organs involved in glucose regulation, the liver plays a central role by controlling endogenous glucose production through glycogenolysis and gluconeogenesis⁵. Exc....