Abstract
Objective This study aimed to investigate the effects of Danzhi Jiangtang Capsule (DJC) on the proliferation and apoptosis functions of NIT-1 pancreatic β-cells exposed to high-glucose load through GLP-1 activated Akt/ FoxO1 signaling pathway. Methods Cellular apoptosis of NIT-1 pancreatic β-cells was induced by culturing in medium with 33.3mmol/L high glucose (HG). Then low-dose DJC (HG +LD), high-dose DJC (HG +HD), high-dose DJC+ GLP-1 inhibition (HG +HD +GI), and high-dose DJC+AKT inhibition (HG +HD+AI) were added, respectively. Cellular proliferation was accessed by cell counting kit (CCK-8) and cellular apoptosis was measured by Annexin V-FITC/PI staining. The protein levels of phosphorylated phosphatidylinositol-3-kinase (p-PI3K), phosphorylated AKT (p-AKT), phosphorylated Forkhead box protein O1 (p-FoxO1), and cleaved caspase-3 were detected by Western blotting. The mRNA expression of pancreatic duodenal homeobox-1 (PDX-1), CyclinD1, Bcl-2, and insulin was tested by Q-PCR. Results Comparing to HG group, (HG+HD) group showed a significantly increased cellular proliferation. The apoptosis of NIT-1 cells also was obviously reduced, with downregulated cleaved caspase-3 protein level and upregulated PDX-1, CyclinD1, and Bcl-2 mRNA levels (P<0.05). Additionally, (HG+HD) group manifested increased insulin mRNA expression; the protein levels of p-PI3K and p-AKT were markedly increased and p-FoxO1 was decreased. All of the above therapeutic effects by DJC intervention had been reversed by GLP-1 inhibition in (HG+HD+GI) group or AKT inhibition in (HG+HD+AI) group. Conclusion DJC was able to attenuate the toxicity of high-glucose load in NIT-1 pancreatic β-cells, ascribed to the improvement of cellular proliferation and apoptosis by GLP-1/Akt signaling pathway. This study could supply a new mechanism of DJC effects on type 2 diabetes mellitus (T2DM) treatment.
Highlights
The crucial characteristics of type 2 diabetes mellitus (T2DM) are pancreatic β-cell dysfunction initially and insulin resistance [1]
Additional low-dose of Danzhi Jiangtang Capsule (DJC) intervention could attenuate the impaired cellular proliferation induced by high glucose, and this beneficial effect had been amplified when the dose of DJC increased
High-glucose load could reduce the mRNA expression level of insulin in NIT-1 cells, and DJC treatment markedly increased the mRNA level of insulin, which had been reversed by either glucagon-like peptide-1 (GLP-1) inhibition or Akt inhibition
Summary
The crucial characteristics of type 2 diabetes mellitus (T2DM) are pancreatic β-cell dysfunction initially and insulin resistance [1]. Long-term exposure to highglucose load can induce glucotoxicity, which leads to deterioration of β-cell function in many experiments via endoplasmic reticulum stress, oxidation stress, and vasoactive cytokine activation [5,6,7]. Many evidences have shown that pancreatic β-cells dysfunction is a central part of the T2DM progression and β-cells play an important role to maintain glucose metabolism balance via activated insulin secretion [8, 9]. Exploring the underlying mechanisms of βcell dysfunction may attribute to new clinical treatment strategies. DJC has been used for T2DM treatment for years and both clinical
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