Mango ginger (Curcuma amada Roxb.) may alleviate the effect of high-fat diet/streptozotocin-induced diabetes by activation of the GSK-3β/Fyn/Nrf2 pathway

Abstract

Mango ginger (MG) exhibits antioxidant, anti-inflammatory, and antihyperglycemic effects; however, the exact mechanism of action of MG extract in relation to its antidiabetic properties remains unclear. To investigate the potential antidiabetic effect of MG extract, we used a high-fat diet (HFD)/low-dose streptozotocin (STZ)-induced type 2 diabetic rat model. A total of 28 male Wistar rats were randomly divided into four groups: (i) Control, (ii) MG (50 mg/kg/day of MG extract), (iii) HFD + STZ (40 mg/kg i.p.), and (iv) HFD + STZ + MG. Following a 12-week administration of MG extract, significant reductions were observed in serum glucose, insulin, free fatty acid, cholesterol, and triglyceride levels in diabetic rats (p < .0001 for all). MG extract supplementation led to an increase in the total antioxidant capacity of the serum and a decrease in malondialdehyde (MDA) levels in both the serum and liver (p < .0001). Furthermore, hepatocellular fat accumulation was partially attenuated in the HFD + STZ + MG group. Notably, MG extract inhibited glycogen synthase kinase-3β (GSK-3β) in the liver (p < .01) and downregulated Fyn expression, resulting in elevated nuclear factor erythroid 2-related factor 2 (Nrf2) activity in the HFD + STZ + MG group compared to the HFD + STZ group (p < .05). The increased activity of Nrf2 in the HFD + STZ + MG group likely promoted the upregulation of heme oxygenase 1 (HO-1) in the liver (p < .0001). In conclusion, MG extract may exert antidiabetic effects by augmenting the antioxidant defense system through the regulation of GSK-3β/Fyn/Nrf2 in a rat model of type 2 diabetes.

Keywords: Nrf2; antioxidant capacity; diabetes; insulin resistance; mango ginger.

FIGURE 1

Effects of mango ginger (MG) supplementation on body weight (a), alanine transaminase (ALT, b), aspartate transaminase (AST, c), cholesterol (d), triglyceride (e), free fatty acid (FFA, f), creatinine (g), and blood urea nitrogen (BUN, h) in high‐fat diet (HFD)/streptozotocin (STZ)‐induced type 2 diabetic rats. The error lines on the bars point out the standard deviation of the mean. Different symbols above the bars indicate statistical differences among the groups (ANOVA and Tukey's post‐hoc test; **p < .01 and ****p < .0001 compared to the control group; ^### p < .001 and ^#### p < .0001 compared to the MG group; ^$$ p < .01 and p < .0001 compared to the HFD + STZ group).

FIGURE 2

Effects of mango ginger (MG) supplementation on serum glucose (a), serum insulin (b), homeostasis model assessment of insulin resistance (HOMA‐IR, c), the β‐cell function (HOMA‐β, d), and quantitative insulin sensitivity check index (QUICKI, e) in high‐fat diet (HFD)/streptozotocin (STZ)‐induced type 2 diabetic rats. The error lines on the bars points out the standard deviation of the mean. Different symbols above the bars indicate statistical differences among the groups [ANOVA and Tukey's (for body weight, serum glucose, serum insulin) or Tamhane's T2 (for HOMA‐IR, HOMA‐β, and QUICKI) post‐hoc test; ***p < .001 and ****p < .0001 compared to the control group; ^## p < .01, ^### p < .001, and ^#### p < .0001 compared to the MG group; ^$ p < .05; ^$$ p < .01 and ^$$$$ p < .0001 compared to the HFD + STZ group].

FIGURE 3

Effects of mango ginger (MG) supplementation on serum malondialdehyde (MDA, a), liver MDA (b), and total antioxidant capacity (TAC, c) in high‐fat diet (HFD)/streptozotocin (STZ)‐induced type 2 diabetic rats. The error lines on the bars points out the standard deviation of the mean. Different symbols above the bars indicate statistical differences among the groups (ANOVA and Tukey's post‐hoc test; *p < .05 and ****p < .0001 compared to the control group; ^#### p < .0001 compared to the MG group; ^$$$$ p < .0001 compared to the HFD + STZ group).

FIGURE 4

Effects of mango ginger (MG) supplementation on liver GSK‐3β (a), Fyn (b), Nrf2 (c), Keap‐1 (d), and HO‐1 (e) in high‐fat diet (HFD)/streptozotocin (STZ)‐induced type 2 diabetic rats. β‐Actin was referenced to ensure equal protein loading. Blots were repeated at least three times (n = 3) and representative blots are shown (f). Data are demonstrated as a percent of the control value. The error lines on the bars points out the standard deviation of the mean. Different symbols above the lines indicate statistical differences among the groups (ANOVA and Tukey's post‐hoc test; *p < .05, **p < .01, and ****p < .0001 compared to the control group; ^# p < .05, ^## p < .01, ^### p < .001, and ^#### p < .0001 compared to the MG group; ^$ p < .05, ^$$ p < .01, and ^$$$$ p < .0001 compared to the HFD + STZ group).

FIGURE 5

Effects of mango ginger (MG) supplementation on histological alterations in the liver in high‐fat diet (HFD)/streptozotocin (STZ)‐induced type 2 diabetic rats (H&E, 200X). HFD/STZ‐induced rats had fat inclusions within hepatocytes (black arrows). (a) Control; (b) MG; (c) HFD + STZ and (d) HFD + STZ + MG.