Red Pepper (Capsicum annuum L.) Seed Extract Improves Glycemic Control by Inhibiting Hepatic Gluconeogenesis via Phosphorylation of FOXO1 and AMPK in Obese Diabetic db/db Mice

Abstract

Obesity is a notable risk factor for developing type 2 diabetes, augmenting the concern of obese diabetes (ObD). Anti-obesity and antioxidant effects of red pepper seeds extract (RPSE) have increased our expectations that RPSE would also improve the pathological phenotypes of obese diabetes. Therefore, we hypothesized that RPSE would have an anti-diabetic effect in ObD mice. Animals were assigned either as follows: (1) db/+, (2) db/db control, (3) RPSE (200 mg/kg bw), or (4) a comparative control (metformin 150 mg/kg bw). RPSE was orally administered daily for 8 weeks. As a result, RPSE supplementation improved diabetic phenotypes, including fasting glucose, hemoglobin (HbA1c), and insulin levels. Pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), and triglycerides were reduced in RPSE-treated mice. RPSE supplementation also diminished the rate-limiting enzymes of gluconeogenesis, including glucose 6-phosphatas (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the liver. RPSE supplementation increased the phosphorylation of forkhead box protein O1 (FOXO1) and AMP-activated protein kinase (AMPK), which underlined the mechanism of the anti-diabetic effects of RPSE. Taken together, RPSE has the potential to improve glycemic control by repressing hepatic gluconeogenesis via the phosphorylation of FOXO1 and AMPK in ObD mice.

Protein Targeting to Glycogen (PTG): A Promising Player in Glucose and Lipid Metabolism

“…It is generally believed that phosphorylation or dephosphorylation of proteins is one of the initial steps in the coordination of cell and organ functions, such as regulation of glycolipid metabolism, cell proliferation, apoptosis, inflammation, and other important physiological processes. Protein kinases and protein phosphatases catalyze this process [ 24 , 25 , 26 , 27 ]. Therefore, kinases and phosphatases are promising targets for regulating this reaction, and many inhibitors against these proteins have been developed [ 30 ].…”

“…Protein phosphorylation and dephosphorylation can regulate signal transduction in a variety of ways, including by activating or inhibiting conformational changes to create binding sites for proteins containing specific domains, thereby affecting the conformation of proteins or protein–protein interactions, and controlling their cellular localization [ 22 , 23 ]. Numerous studies have shown that the phosphorylation/dephosphorylation of related signaling molecules plays a key role in the regulation of hepatic glucose and lipid metabolism [ 24 , 25 , 26 , 27 ]. Glycogen targeting protein (PTG) is a member of the protein phosphatase 1 (PP1) family and can play a role by catalyzing the dephosphorylation of phosphorylated protein molecules.…”

Composición y aplicaciones clínicas de especies de chiles (Capsicum spp.) domesticados

“…57 Por otro lado, la administración de 200 mg/kg peso de extractos de semillas de C. annuum en ratones C57BL/KsJ con diabetes, redujo significativamente (p<0.001) los niveles de glucosa en ayunas, glucosa posprandial (120 min después de la administración), insulina y la hemoglobina glicosilada (HbA1c) el 21 %, 30 %, 29 % y 22 %, respectivamente. 58 Los estudios señalan que el efecto antidiabético se atribuye a que la capsaicina ayuda a mejorar la acumulación de ácido tauro-𝛽-muricolato a nivel intestinal, antagonista del receptor fernesoide X (FXR), el cual actúa regulando el metabolismo de ácidos biliares, reduciendo la gluconeogénesis, y en conjunto mejoran la homeostasis de la glucosa 57 , mediante la activación del receptor TRPV1 y al incremento de expresión de genes implicados en el metabolismo de glúcidos en hígado y páncreas, por lo que hay menor absorción de azúcares en el intestino, que posteriormente serán excretados. 55 A su vez, los extractos de semillas de C. annuum aumentan la fosforilación de AMPK (Proteína implicada en el balance energético) y FOXO1 (factor de transcripción que aumenta la síntesis de glucosa en el hígado), que es un mecanismo importante en la mejora de los niveles de glucosa en ayuno y la sensibilidad a la insulina.…”

“…55 A su vez, los extractos de semillas de C. annuum aumentan la fosforilación de AMPK (Proteína implicada en el balance energético) y FOXO1 (factor de transcripción que aumenta la síntesis de glucosa en el hígado), que es un mecanismo importante en la mejora de los niveles de glucosa en ayuno y la sensibilidad a la insulina. 58…”

Establishment of blood glucose control model in diabetic mice

“…In addition, most animal models are type A study on blood glucose control model 1 diabetes mellitus (T1DM), while T2DM accounts for 90%-95% of all cases of diabetes mellitus [13] . Furthermore, some drug studies have improved glycemic control in db/db mice, but the exact level of glycemic control has not been specified [14] . Therefore, we aimed to establish a reproducible model of poor and stable blood glucose levels in diabetic mice, which is more reflective of the characteristics of blood glucose fluctuations in patients with diabetes in clinical practice.…”