Abstract
Lipotoxicity plays an important role in exacerbating type 2 diabetes mellitus (T2DM) and leads to apoptosis of β cells. Recently dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as a useful tool in the treatment of T2DM. DPP-4 degrades type 1 glucagon-like peptide (GLP-1), and GLP-1 receptor (GLP-1R) signaling has been shown to protect β cells by modulating AMPK/mTOR, PI3K, and Bax. The anti-hyperglycemic effect of Abelmoschus esculentus (AE) is well known, however its mucilage makes it difficult to further examine this effect. In our recent report, a sequence of extraction steps was used to obtain a series of subfractions from AE, each with its own composition and property. Among them F1 (rich in quercetin glucosides and pentacyclic triterpene ester) and F2 (containing large amounts of carbohydrates and polysaccharides) were found to be especially effective in attenuating DPP-4 signaling, and to have the potential to counter diabetic nephropathy. Hence, the aim of the present study was to investigate whether AE subfractions can prevent the palmitate-induced apoptosis of β cells, and the putative signals involved. We demonstrated that AE, and especially 1 μg/mL of F2, decreased palmitate-induced apoptosis analyzed by flow cytometry. The result of western blot revealed that palmitate-induced decrease in GLP-1R and increase in DPP-4 were restored by F1 and F2. The DPP-4 inhibitor linagliptin decreased the expression of caspase 3, suggesting that DPP-4 is critically involved in apoptotic signaling. Analysis of enzyme activity revealed that palmitate increased the activity of DPP4 nearly 2 folds, while F2 especially inhibited the activation. In addition, AMPK/mTOR, PI3K and mitochondrial pathways were regulated by AE, and this attenuated the palmitate-induced signaling cascades. In conclusion, AE is useful to prevent the exacerbation of β cell apoptosis, and it could potentially be used as adjuvant or nutraceutical therapy for diabetes.
Highlights
Diabetes mellitus is a highly prevalent disease worldwide that is associated with significant morbidity and mortality [1]
Antibodies to GLP-1 receptor (GLP-1R) and DPP4 were provided by Abcam (Cambridge, UK), and antibodies to PI3K and pPI3K were products of from Cell Signaling (Danvers, MA, USA)
We demonstrated that Abelmoschus esculentus (AE) subfractions are effective in preventing palmitate-induced apoptosis of β cells, and that the mechanism of this effect appears to be via inhibiting the activity of dipeptidyl peptidase-4 (DPP-4)
Summary
Diabetes mellitus is a highly prevalent disease worldwide that is associated with significant morbidity and mortality [1]. Type 2 diabetes (T2DM), the most prevalent type of diabetes, is usually accompanied with obesity and characterized by insulin resistance [2]. Insulin signaling cascades have been shown to be altered in patients with T2DM [2]. Long-term exposure to diets high in glucose and fatty acids or over consumption of dietary sugar and fats has been reported to induce β cell apoptosis, leading to the exacerbation of T2DM [3]. Lipotoxicity is considered to be an underlying mechanism of T2DM [4]. The mechanism of action relies on inhibiting the degradation of type 1 glucagon-like peptide (GLP-1), an incretin with a short half-life that stimulates glucose-dependent insulin secretion from β cells and effectively suppresses glucagon release from α cells [5]. GLP-1 receptor (GLP-1R) agonists have been shown to efficiently protect β cells through various pathways, which include improving β-cell function, increasing β-cell mass, and enhancing an anti-apoptotic effect [4]
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