Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

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.

Morus alba L. (Sangzhi) Alkaloids Promote Insulin Secretion, Restore Diabetic β-Cell Function by Preventing Dedifferentiation and Apoptosis

“…As reported in a phase IIIa clinical study, SZ-A can ameliorate hyperglycemia and reduce HbA1c in type 2 diabetic patients ( Qu et al, 2021 ). In addition, in our previous study, we showed that SZ-A maintains the intestinal flora balance and promotes GLP-1 secretion ( Liu et al, 2021 ). Given that β-cell failure is related to the transition from prediabetes to diabetes, improved β-cell function has a major role in preventing type 2 diabetes.…”

“…The type 2 diabetic KKA y mice have a similar metabolic syndrome phenotype as humans and exhibit hyperglycemia, hyperinsulinemia, hyperlipidemia and obesity. We have reported that SZ-A ameliorates glucose and lipid metabolism in KKA y mice ( Liu et al, 2021 ). In this study, we again identified that non-fasting and fasting blood glucose was reduced significantly with SZ-A treatment ( Figures 1C,D ), which may be ascribed to the increased insulin secretion and sensitivity.…”

“…Given that β-cell failure is related to the transition from prediabetes to diabetes, improved β-cell function has a major role in preventing type 2 diabetes. Our previous research pointed out that SZ-A may ameliorate β-cell dysfunction ( Liu et al, 2021 ). However, the substantial effects and underlying mechanism of SZ-A on islet β-cell function need to be identified further.…”

“…Qu et al ( Qu et al, 2021 ) demonstrated that SZ-A tablets possess effective hypoglycemic effects with few adverse events, suggesting good safety in clinical trials. SZ-A contains three major effective fractions, namely, 1-deoxynojirimycin (DNJ), 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and fagomine (FAG) ( Yang et al, 2015 ; Yang et al, 2017 ), which are extracts from the Chinese herb Morus alba L. (mulberry twig), the dried young branch of Morus alba L. SZ-A not only inhibits the activity of α-glucosidases, especially sucrase and maltase, in vitro ( Liu et al, 2019 ) but also ameliorates intestinal flora imbalance and hyperglycemia in diabetic KKA y mice ( Liu et al, 2015 ; Liu et al, 2021 ; Yuling). However, the protective effect and mechanism of SZ-A on β-cell function in the progression of diabetes remain to be further identified.…”

Screening prolyl hydroxylase domain 2 inhibitory activity of traditional Chinese medicine by CZE‐UV

“…Traditional Chinese medicine (TCM) has exhibited satisfactory efficacy and safety over thousands of years of application and is one of the main sources of modern drug discovery [29]. Moreover, TCM extracts exhibit multicomponent and multitarget properties and can have significant efficacy in complex diseases [30].…”