Abstract
Alpha (α)-mangostin, a yellow crystalline powder with a xanthone core structure, is isolated from mangosteen (Garcinia mangostana), which is a tropical fruit of great nutritional value. The aim of the present study was to investigate the anti-diabetic effects of α-mangostin and to elucidate the molecular mechanisms underlying its effect on pancreatic beta (β)-cell dysfunction. To assess the effects of α-mangostin on insulin production, rat pancreatic INS-1 cells were treated with non-toxic doses of α-mangostin (1–10 μM) and its impact on insulin signaling was examined by Western blotting. In addition, the protective effect of α-mangostin against pancreatic β-cell apoptosis was verified by using the β-cell toxin streptozotocin (STZ). Our results showed that α-mangostin stimulated insulin secretion in INS-1 cells by activating insulin receptor (IR) and pancreatic and duodenal homeobox 1 (Pdx1) followed by phosphorylation of phospho-phosphatidylinositol-3 kinase (PI3K), Akt, and extracellular signal regulated kinase (ERK) signaling cascades, whereas it inhibited the phosphorylation of insulin receptor substrate (IRS-1) (Ser1101). Moreover, α-mangostin was found to restore the STZ-induced decrease in INS-1 cell viability in a dose-dependent manner. In addition, treatment of INS-1 cells with 50 μM STZ resulted in an increase in intracellular reactive oxygen species (ROS) levels, which was represented by the fluorescence intensity of 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA). This oxidative stress was decreased by co-treatment with 5 μM α-mangostin. Similarly, marked increases in the phosphorylation of P38, c-Jun N-terminal kinase (JNK), and cleavage of caspase-3 by STZ were decreased significantly by co-treatment with 5 μM α-mangostin. These results suggest that α-mangostin is capable of improving insulin secretion in pancreatic β-cells and protecting cells from apoptotic damage.
Highlights
Diabetes is a chronic metabolic disorder whose prevalence is increasing annually
Α-mangostin at concentrations up to 5 μM has no effect on insulin secretion in the absence of glucose (Figure 1C), whereas it led to an increase in Glucose-Stimulated Secretion of Insulin (GSIS) in a concentration-dependent manner (Figure 1D)
The GSIS levels, calculated by glucose stimulation index values, were 27.6 ± 0.7, 32.8 ± 1.0, and 37.0 ± 0.5 for 1, 2.5, and 5 μM α-mangostin for 1 h, respectively (Figure 1D). This stimulatory effect of α-mangostin on insulin secretion was significantly higher than that of the positive control group (Figure 1E). These results indicate that α-mangostin stimulates insulin secretion in INS-1 cells for 1 h without inducing cytotoxicity
Summary
Diabetes is a chronic metabolic disorder whose prevalence is increasing annually. It represents a major social issue associated with modern lifestyle worldwide [1,2,3]. Type 1 diabetes is an autoimmune disorder caused by pancreatic β-cells loss, while type 2 diabetes is a heterogeneous disease which is caused by pancreatic β-cells dysfunction and insufficient insulin release in response to glucose in peripheral tissues such as skeletal muscle (glucose disposal), liver (glucose production), and adipose tissue (lipolysis) [3,4,5,6,7]. The combination of failed metabolic response in skeletal muscle and pancreatic β-cells dysfunction causes an increase of glucose production by the liver [8]. Chronic hyperglycemia decreases insulin secretion from pancreatic β-cells and increases insulin resistance [10,11]
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