Abstract
Purpose: To investigate the antidiabetic effect of methanol extract of Aruncus dioicus, and the underlying mechanism(s).
 Methods: Twenty-four adult female albino mice were randomly assigned to four groups of six mice each: normal control group, diabetic control group and two treatment groups. With the exception of normal control group, the diabetic control and treatment groups consisted of leptin receptor-deficient (db/db) type 2 diabetic mice. The diabetic control group was not treated, while the treatment groups received 200 or 400 mg/kg extract/day orally for 4 weeks. The effect of the extract on fasting blood glucose (FBG), proprotein convertase subtilisin/kexin type 9 (PCSK9), glycogen and lipid profiles were determined. The expressions of PCSK9, low-density lipoprotein receptor (LDL-R) and glucokinase (GCK) were determined in liver tissues using western blotting and real-time quantitative polymerase chain reaction (qRT-PCR).
 Results: Fasting blood glucose (FBG) was significantly and dose-dependently reduced in the treatment groups, relative to diabetic control group at different time-points (p < 0.05). Total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were significantly higher in the diabetic control group than in normal control group (p < 0.05). However, treatment with methanol extract of A. dioicus significantly and dose-dependently reversed the changes in the levels of these parameters (p < 0.05). The expressions of LDLR and GCK were significantly down-regulated in diabetic control group, when compared with normal control group, but their expressions were significantly dose-dependently upregulated in the treatment groups (p < 0.05). Treatment with the extract significantly and dose-dependently down-regulated PCSK9 expression (p < 0.05). Liver injury characterized by large distended lipid droplets and fat accumulation was seen in diabetic mice, but treatment with methanol extract of A. dioicus significantly reversed the histopathological changes induced by DM.
 Conclusion: These results indicate that the antidiabetic effect of methanol extract of A. dioicus is exerted via a mechanism involving PCSK9/LDLR pathway.
Highlights
Diabetes mellitus (DM) is a group of heterogeneous disorders characterized by high blood glucose, and it can be type 1 or type 2
Leptin and leptin receptor-deficient rodent model is a well-established model of type 2 DM (T2DM) characterized by insulin resistance, dyslipidemia, hyperglycemia and obesity [13]
The present study investigated the antidiabetic effect of methanol extract of A. dioicus, and the underlying mechanism(s)
Summary
Diabetes mellitus (DM) is a group of heterogeneous disorders characterized by high blood glucose, and it can be type 1 or type 2. Disorders in the metabolism of glucose and lipids are the hallmarks of DM, and these result in micro- and macrovascular complications [1, 2]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been implicated as a drug target in the treatment of DM [3]. Studies have shown that LDLR regulates cholesterol level by controlling its uptake, and its degradation depends on PCSK9 [4]. Clinical and preclinical studies have shown that there is a link between glucose metabolism and PCSK9 [5]. Insulin resistance in DM is reduced by controlling plasma lipid levels via the upregulation of PCSK9 expression [6]
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