Supplementation of scopoletin improves insulin sensitivity by attenuating the derangements of insulin signaling through AMPK.

Scopoletin (SPL), a phenolic coumarin, is reported to regulate glucose metabolism. This study is initiated to substantiate the action of SPL on the regulation of insulin signaling in insulin resistant RIN5f cells and high fat, high fructose diet (HFFD)-fed rat model. Adult male Sprague Dawley rats were fed HFFD for 45 days to induce type 2 diabetes and then treated or untreated with SPL for the next 45 days. The levels of glucose, insulin, lipid profile, oxidative stress markers along with insulin signaling and AMPK protein expressions were examined at the end of 90 days. SPL lowered the levels of plasma glucose, insulin, and lipids which were increased in HFFD-fed rats. HFFD intake suppressed the activities of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase; however, they were reversed by SPL supplementation, which reduced TBARS, lipid hydroperoxide, and protein carbonyl levels both in plasma and pancreas. SPL supplementation significantly activated insulin receptor substrate 1 (IRS1), phosphatidyl inositol 3-kinase (PI3K), and protein kinase B (Akt) phosphorylation which was suppressed in HFFD rats due to lipotoxicity. Moreover, SPL significantly activated AMPK and enhanced the association of IRS1-PI3K-Akt compared to the control group. The results revealed that SPL alleviated T2D induced by HFFD by escalating the antioxidant levels and through insulin signaling regulation. We conclude that SPL can improve insulin signaling through AMPK, thereby confirming the role of SPL as an AMPK activator.

Scopoletin intervention in pancreatic endoplasmic reticulum stress induced by lipotoxicity.

Endoplasmic reticulum (ER), a dynamic organelle, plays an essential role in organizing the signaling pathways involved in cellular adaptation, resilience, and survival. Impairment in the functions of ER occurs in a variety of nutritive disorders including obesity and type 2 diabetes. Here, we hypothesize that (scopoletin) SPL, a coumarin, has the potential to alleviate ER stress induced in vitro and in vivo models by lipotoxicity. To test this hypothesis, the ability of SPL to restore the levels of proteins of ER stress was analyzed. Rat insulinoma 5f (RIN5f) cells and Sprague Dawley rats were the models used for this study. Groups of control and high-fat, high-fructose diet (HFFD)-fed rats were treated with either SPL or 4-phenylbutyric acid. Status of ER stress was enumerated by quantitative RT-PCR, Western blot, electron microscopic, and immunohistochemical studies. Proximal proteins of ER stress inositol requiring enzyme 1 (IRE1), protein kinase like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) were reduced in the ß-cells by SPL. The subsequent signaling proteins X-box binding protein 1, eukaryotic initiation factor2α, activating transcription factor 4, and C/EBP homologous protein were also suppressed in their expression levels when treated with SPL. IRE1, PERK signaling leads to c-Jun-N-terminal kinases phosphorylation, a kinase that interrupts insulin signaling, which was also reverted upon scopoletin treatment. Finally, we confirm that SPL has the ability to suppress the stress proteins and limit pancreatic ER stress which might help in delaying the progression of insulin resistance.

Antioxidative and hypolipidemic efficacy of alcoholic seed extract of Swietenia macrophylla in streptozotocin diabetic rats.

The present study was designed to examine the antioxidative potential and antihyperlipidemic activity of Swietenia macrophylla in streptozotocin diabetic rats. The experimental groups were rendered diabetic by intraperitoneal injection of a single dose of streptozotocin (STZ; 40 mg/kg body weight, BW). Rats with glucose levels >200 mg/dL were considered diabetic and were divided into five groups. Three groups of diabetic animals were orally administered daily with seed extract (SME) at a dosage of 50, 100 and 200 mg/kg BW. One group of STZ rats was treated as diabetic control and another group orally administered 600 µg/kg BW glibenclamide daily. Repeated daily oral administration of S. macrophylla significantly reduced blood glucose levels after 45 days of treatment. The lipid peroxidation products such as thiobarbituric acid reactive substances and lipid hydroperoxides of SME treated rats decreased in the plasma, liver and kidney. Glutathione peroxidase, superoxide dismutase and catalase activity were significantly increased in SME treated rats. Antioxidants such as reduced glutathione level in the plasma, liver and kidney and vitamins C and E levels in the plasma increased in SME treated rats. Total cholesterol, triglycerides, phospholipids and free fatty acids and lipoproteins levels increased. Altered lipid profile of treated rats lead to normality with treatment of S. macrophylla. Thus, our results indicate that the administration of 100 mg/kg BW SME restores near normal blood glucose, redox status and lipid profile in STZ-diabetic rats.