Abstract
The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.
Highlights
The gut microbiome plays important roles in the regulation of glucose and energy homeostasis. It plays a critical role in obesity, glycemic control, and type 2 diabetes mellitus (T2DM) (Harris et al, 2012), which is a chronic and multifactorial disease in which diverse physiopathologic mechanisms lead to a persistent state of hyperglycemia
After a 4-week treatment, the levels of fasting blood glucose (p < 0.01, p < 0.001) and postprandial blood glucose (p < 0.01, p < 0.01) in both SZ-A-treated groups were significantly decreased compared to the diabetic model group (DM) group (Figures 1A,B)
SZ-A 100 and SZ-A 200 significantly enhanced insulin secretion nearly 1.73-fold and 1.88-fold from baseline at 15 min after glucose stimulation, respectively (p < 0.01, p < 0.05), compared to the DM group (1.11-fold). Both doses of SZ-A elevated active glucagon-like peptide 1 (GLP-1) levels nearly 2.7-fold and 2.6-fold at 15 min after glucose stimulation from baseline (p < 0.01, p < 0.05), respectively, compared to the DM group (2.1fold). Both doses of SZ-A resulted in decreased blood triglyceride levels after 6 weeks (p < 0.05, p < 0.05), and induced significant weight loss compared to the DM group at the end of treatment (p < 0.01, p < 0.001)
Summary
The gut microbiome plays important roles in the regulation of glucose and energy homeostasis. It plays a critical role in obesity, glycemic control, and type 2 diabetes mellitus (T2DM) (Harris et al, 2012), which is a chronic and multifactorial disease in which diverse physiopathologic mechanisms lead to a persistent state of hyperglycemia. T2DM may be due to the activation of pro-inflammatory mechanisms that involve several factors. Gut microbiota-mediated low-grade inflammation is involved in the onset and progression of T2DM. Studies in mice and humans have shown that there is dysregulation in the gut microenvironment accompanied by immunological and metabolic dysfunctions in individuals who have T2DM (Ge et al, 2018)
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