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

Abstract

Background:Morus alba L. (Sangzhi) alkaloids (SZ-A), extracted from the Chinese herb Morus alba L. (mulberry twig), have been shown to ameliorate hyperglycemia in type 2 diabetes and have been approved for diabetes treatment in the clinic. However, their versatile pharmacologic effects and regulatory mechanisms are not yet completely understood.Purpose: This study explored the protective effects of SZ-A on islet β cells and the underlying mechanism.Methods: Type 2 diabetic KKAy mice were orally administered SZ-A (100 or 200 mg/kg, once daily) for 11 weeks, and oral glucose tolerance, insulin tolerance, intraperitoneal glucose tolerance and hyperglycemia clamp tests were carried out to evaluate the potency of SZ-A in vivo. The morphology and β-cell dedifferentiation marker of KKAy mouse islets were detected via immunofluorescence. The effect of SZ-A on glucose-stimulated insulin secretion was investigated in both the islet β-cell line MIN6 and mouse primary islets. Potential regulatory signals and pathways in insulin secretion were explored, and cell proliferation assays and apoptosis TUNEL staining were performed on SZ-A-treated MIN6 cells.Results: SZ-A alleviated hyperglycemia and glucose intolerance in type 2 diabetic KKAy mice and improved the function and morphology of diabetic islets. In both MIN6 cells and primary islets, SZ-A promoted insulin secretion. At a normal glucose level, SZ-A decreased AMPKα phosphorylation, and at high glucose, SZ-A augmented the cytosolic calcium concentration. Additionally, SZ-A downregulated the β-cell dedifferentiation marker ALDH1A3 and upregulated β-cell identifying genes, such as Ins1, Ins2, Nkx2.2 and Pax4 in KKAy mice islets. At the same time, SZ-A attenuated glucolipotoxicity-induced apoptosis in MIN6 cells, and inhibited Erk1/2 phosphorylation and caspase 3 activity. The major active fractions of SZ-A, namely DNJ, FAG and DAB, participated in the above regulatory effects.Conclusion: Our findings suggest that SZ-A promotes insulin secretion in islet β cells and ameliorates β-cell dysfunction and mass reduction under diabetic conditions both in vivo and in vitro, providing additional supportive evidence for the clinical application of SZ-A.

Review of the correlation between Chinese medicine and intestinal microbiota on the efficacy of diabetes mellitus

“…Mulberry total biotobasine significantly increased the abundance of microbiota that promote SCFA production such as Erysipelotrichaceae and Bacteroides and reduced the abundance of harmful microbiota such as Desulfovibrio and Rikenellaceae . Therefore, mulberry total biotobasine promotes insulin secretion and ameliorates the β cells of diabetes rats’ dysfunction and mass reduction both in vivo and in vitro ( 48 ).…”

Caffeic Acid Dimethyl Ether Ameliorates Excessive Glucose and Lipid-Induced Insulin Secretion Dysfunction in Pancreatic Beta-Cells through the miR-378b–PI3K–AKT Pathway

“…Terefore, the search for safe and efective novel drugs to prevent and treat insulin secretion disorders has been a major research focus worldwide. In recent years, natural drugs such as mulberry alkaloids, cordycepin, and berberine have received attention for their potential in improving insulin secretion [27][28][29]. Cafeic acid dimethyl ether (CADE), also known as methyl ferulic acid, is a bioactive monomer extracted from traditional Chinese herbs [30].…”

Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity

“…This pharmacological feature is conducive to faster and better control of postprandial blood glucose, while greatly reducing adverse reactions such as flatulence and exhaust in East Asian patients consuming carbohydrates as their staple food (Nojima et al, 1998;Liu et al, 2021). In addition to selectively inhibiting intestinal a-glucosidase, an in-depth study of the mechanism underlying the effects of SZ-A found that exerts multiple in vitro and in vivo pharmacological effects on the regulation of pancreatic islet ß-cell function, insulin resistance, lipid metabolism, intestinal flora, and inflammation (Cao et al, 2021;Liu et al, 2021;Chen et al, 2022;Lei et al, 2022;Sun et al, 2022). In a previous study, the therapeutic effects and mechanism of action of SZ-A on lipid metabolism were explored in high-fat diet (HFD)-induced obesity and non-alcoholic fatty liver disease (NAFLD) mice.…”