Jinkui Shenqi pills improve pancreatic islet function in diabetes by modulating macrophage inflammation through the...

Macrophage infiltration is a key contributor to pancreatic β-cell dysfunction, though the mechanisms of inflammatory activation are unclear. In China, Jinkui Shenqi pills (JSP) are known for its hypoglycemic effects and pancreatic protective properties, but its role in macrophage-mediated inflammation is unstudied.

This study investigated the effects of JSP on macrophage polarization and its underlying molecular mechanisms.

Type 2 diabetes mouse model was induced by high-fat diet combined with streptozotocin. Fasting glucose, insulin, lipid profiles, HOMA-IR, and HOMA-β were measured. Islet structure was evaluated by HE staining and electron microscopy, and qRT-PCR detected dedifferentiation markers. Flow cytometry assessed pancreatic M1 and M2 macrophage percentages. Targeted glucose metabolomics analyzed JSP's effect on succinate levels. In vitro, JSP-containing serum effects on macrophage polarization were analyzed by fluorescence and morphological observations. Succinate was employed to reverse-validate the effects of JSP on the succinate/HIF1α axis. Macrophage-conditioned medium was co-cultured with islet cells to clarify JSP's role in regulating β-cell function. PX478 inhibited HIF1α activity in vivo and in vitro to observe its hypoglycemic, macrophage polarization, and islet-protective effects.

JSP reduced blood glucose and lipid levels, enhanced insulin secretion, and improved insulin resistance. JSP inhibited macrophage infiltration, reduced the M1 macrophages (CD45⁺CD11b⁺F4/80⁺CD86⁺) percentage (p < 0.05), and increased M2 macrophages (CD45⁺CD11b⁺F4/80⁺CD206⁺) percentage (p < 0.01). It improved glycolysis, TCA cycle, and oxidative phosphorylation pathways, inhibited succinate accumulation, and was associated with HIF1α signaling. In vitro, JSP inhibited HIF1α nuclear accumulation, reduced pro-inflammatory cytokines (IL-1, IL-6, TNFα), and increased anti-inflammatory cytokines (IL-4, IL-10), enhanced β-cell insulin secretion; but these effects were reversed by succinate. PX478 was further employed to validate that inhibition of HIF activity attenuated macrophage inflammation, in vivo administration of it led to a significant reduction in blood glucose levels and enhanced islet function.

This study elucidates that JSP mitigates pancreatic β-cell dysfunction by regulating macrophage polarization through the succinate/HIF1α signaling axis. It offers novel insights into the regulatory effects of JSP on energy metabolism.