SIRT1/AMPK-mediated pathway: Ferulic acid from sugar beet pulp mitigating obesity-induced diabetes-linked complications and improving metabolic health.

Obesity-induced type 2 diabetes (T2D) increases the risk of metabolic syndrome due to the high calorie intake. The role of sugar beet pulp (SBP) in T2D and the mechanism of its action remain unclear, though it is abundant in phenolics and has antioxidant activity. In this study, we isolated and purified ferulic acid from SBP, referred to as SBP-E, and studied the underlying molecular mechanisms in the regulation of glucose and lipid metabolism developing high glucose/high fat diet-induced diabetic models in vitro and in vivo. SBP-E showed no cytotoxicity and reduced the oxidative stress by increasing glutathione (GSH) in human liver (HepG2) and rat skeletal muscle (L6) cells. It also decreased body weight gain, food intake, fasting blood glucose levels (FBGL), glucose intolerance, hepatic steatosis, and lipid accumulation. Additionally, SBP-E decreased the oxidative stress and improved the antioxidant enzyme levels in high-fat diet (HFD)-induced T2D mice. Further, SBP-E reduced plasma and liver advanced glycation end products (AGEs), malondialdehyde (MDA), and pro-inflammatory cytokines, and increased anti-inflammatory cytokines in HFD-fed mice. Importantly, SBP-E significantly elevated AMPK, glucose transporter, SIRT1 activity, and Nrf2 expression and decreased ACC activity and SREBP1 levels in diabetic models. Collectively, our study results suggest that SBP-E treatment can improve obesity-induced T2D by regulating glucose and lipid metabolism via SIRT1/AMPK signalling and the AMPK/SREBP1/ACC1 pathway.

trans-ferulic acid attenuates hyperglycemia-induced oxidative stress and modulates glucose metabolism by activating AMPK signaling pathway in vitro.

Adenosine monophosphate-activated protein kinase (AMPK) is a potent metabolic regulator and an attractive target for antidiabetic activators. Here we report for the first that, trans-ferulic acid (TFA) is a potent dietary bioactive molecule of hydroxycinnamic acid derivative for the activation of AMPK with a maximum increase in phosphorylation (2.71/2.67 ± 0.10; p < .001 vs. high glucose [HG] control) in hyperglycemia-induced human liver cells (HepG2) and rat skeletal muscle cells (L6), where HG suppresses the AMPK pathway. It was also observed that TFA increased activation of AMPK in a dose- and time-dependent manner and also increased the phosphorylation of acetyl-CoA carboxylase (ACC), suggesting that it may promotes fatty acid oxidation; however, pretreatment with compound C reversed the effect. In addition, TFA reduced the level of intracellular reactive oxygen species (ROS) and nitric oxide (NO) induced by hyperglycemia and subsequently increased the level of glutathione. Interestingly, TFA also upregulated the glucose transporters, GLUT2 and GLUT4, and inhibited c-Jun N-terminal protein kinase (JNK1/2) by decreasing the phosphorylation level in tested cells under HG condition. Our studies provide critical insights into the mechanism of action of TFA as a potential natural activator of AMPK under hyperglycemia. PRACTICAL APPLICATIONS: Hydroxycinnamic acid derivatives possess various pharmacological properties and are found to be one of the most ubiquitous groups of plant metabolites in almost all dietary sources. However, the tissue-specific role and its mechanism under hyperglycemic condition remain largely unknown. The present study showed that TFA is a potent activator of AMPK under HG condition and it could be used as a therapeutic agent against hyperglycemia in type 2 diabetes.