punicalagin and Diabetes-Mellitus--Type-2

Over the last decade, various studies have linked pomegranate (Punica granatum Linn), a fruit native to the Middle East, with type 2 diabetes prevention and treatment. This review focuses on current laboratory and clinical research related to the effects of pomegranate fractions (peels, flowers, and seeds) and some of their active components on biochemical and metabolic variables associated with the pathologic markers of type 2 diabetes. This review systematically presents findings from cell culture and animal studies as well as clinical human research. One key mechanism by which pomegranate fractions affect the type 2 diabetic condition is by reducing oxidative stress and lipid peroxidation. This reduction may occur by directly neutralizing the generated reactive oxygen species, increasing certain antioxidant enzyme activities, inducing metal chelation activity, reducing resistin formation, and inhibiting or activating certain transcriptional factors, such as nuclear factor κB and peroxisome proliferator-activated receptor γ. Fasting blood glucose levels were decreased significantly by punicic acid, methanolic seed extract, and pomegranate peel extract. Known compounds in pomegranate, such as punicalagin and ellagic, gallic, oleanolic, ursolic, and uallic acids, have been identified as having anti-diabetic actions. Furthermore, the juice sugar fraction was found to have unique antioxidant polyphenols (tannins and anthocyanins), which could be beneficial to control conditions in type 2 diabetes. These findings provide evidence for the anti-diabetic activity of pomegranate fruit; however, before pomegranate or any of its extracts can be medically recommended for the management of type 2 diabetes, controlled, clinical studies, are needed.

Topics: Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Type 2; Ellagic Acid; Flowers; Fruit; Humans; Hydrolyzable Tannins; Hypoglycemic Agents; Lipid Peroxidation; Lythraceae; Middle East; NF-kappa B; Oleanolic Acid; Plant Extracts; Polyphenols; PPAR gamma; Seeds; Triterpenes; Ursolic Acid

Diabetic liver injury has received increasing attention as a serious complication of type 2 diabetes. Punicalagin (PU), a major component of pomegranate polyphenols, has various biological activities such as antioxidant, anti-inflammatory, and lipid metabolism regulation. In this study, we observed the protective effect of punicalagin on a high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic liver injury in mice and revealed the underlying mechanism. The results showed that fasting blood glucose (FBG), fasting serum insulin (FINS), and homeostasis model assessment for insulin resistance (HOMA-IR) in diabetic liver injury mice were significantly decreased after punicalagin intervention. Simultaneously, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFA), malondialdehyde (MDA), and total superoxide dismutase (T-SOD) in the serum and liver were significantly decreased, with reductions in fat lesions and inflammatory cells. Mitophagy is a selective autophagy that maintains a balance between the quality and quantity of intracellular mitochondria. Studies have shown that mitophagy is closely related to the occurrence and development of diabetic liver injury. In our study, the mitochondrial membrane potential (MMP) was significantly increased in mice with diabetic liver injury after punicalagin intervention; the protein expression of Pink1, Parkin, Bnip3, LC3b, P62, manganese superoxide dismutase (MnSOD), and catalase (CAT) was significantly increased in the liver; and the activities of MnSOD and CAT in the serum and liver were significantly increased, which is consistent with the results of in vitro experiments. In summary, our study provided evidence that punicalagin could reduce the level of oxidative stress in the liver by upregulating mitophagy and the activities of antioxidant enzymes, thus having a certain protective effect against diabetic liver injury.

Topics: Animals; Antioxidants; Cholesterol, LDL; Diabetes Mellitus, Type 2; Hydrolyzable Tannins; Liver; Mice; Mitophagy; Oxidative Stress; Superoxide Dismutase

Type 2 diabetes has a series of metabolic aberrations accompanied by chronic hyperglycemia, along with various comorbidities. In recent reports, punicalagin from pomegranate has been reported to exert hypoglycemic effects against diabetes. The goal of the current research was to investigate the therapeutic effectiveness and elucidate the mechanisms of punicalagin underlying type 2 diabetes. Type 2 diabetes was induced by a high-fat diet (HFD) combined with streptozotocin (STZ) injection in C57BL/6J mice. Punicalagin was administered daily by oral gavage for 4 weeks. The results indicated that high FBG (fasting blood glucose), dyslipidemia and associated islet, liver and kidney injury were observed in the model group mice. Through metabolomics analysis, it was found that the administration of punicalagin could regulate 24 potential biomarkers and their related metabolic pathways. Moreover, the pathological changes in the liver and kidney were mainly mediated by reducing gluconeogenesis and increasing glycogenesis via stimulation of the PI3K/AKT signaling pathway and regulation of the HMGB-1/TLR4/NF-κB signaling pathway, which simultaneously interrelated to ten main pathological pathways. In addition, we confirmed the positive role of punicalagin in glucosamine-induced HepG2 cells and HG-induced HK-2 cells through related mechanistic studies in vitro. In conclusion, these findings suggested that the multi-effect and multi-target action mode of punicalagin had a significant hypoglycemic effect and a protective effect on diabetes mellitus. Punicalagin might serve as an alternative functional food or as a clinical supplemental therapy for the diabetic population to ameliorate metabolic syndrome.

Topics: Animals; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dyslipidemias; Hep G2 Cells; Humans; Hydrolyzable Tannins; Hyperglycemia; Hypoglycemic Agents; Kidney; Liver; Metabolic Syndrome; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Signal Transduction; Streptozocin

The aim of this study was to investigate the protective effect of punicalagin (PU), which is a main component of pomegranate polyphenols, against liver injury induced by Type 2 diabetes mellitus (T2DM) and to explore the molecular mechanism based on autophagy in vivo and in vitro. In T2DM mice, we found that PU significantly improved liver histology, reversed serum biochemical abnormalities, and increased the autophagosome number in the liver. In HepG2 cells cultured in a high-glucose environment, PU upregulated the glucose uptake level. Both in vivo and in vitro, PU upregulated the expression of autophagy-related proteins, such as LC3b and p62, and reduced the phosphorylated Akt/total Akt and phosphorylated FoxO3a/total FoxO3a protein ratios, and these effects were enhanced by LY294002 (a PI3K/Akt inhibitor). In summary, our current findings suggest that PU protects against liver injury induced by T2DM by restoring autophagy through the Akt/FoxO3a signaling pathway.

Topics: Animals; Autophagy; Diabetes Mellitus, Type 2; Forkhead Box Protein O3; Humans; Hydrolyzable Tannins; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Protective Agents; Proto-Oncogene Proteins c-akt; Signal Transduction

Nowadays, medicinal plants have been widely used everywhere to provide essential care for many disorders including diabetes. Recent reports assumed that the antidiabetic activities of pomegranate aril juice (PAJ) may be ascribed to its punicalagin (PCG). Therefore, the present study evaluated and compared the antidiabetic activities of PAJ and its PCG, and monitored some mechanisms of their actions in streptozotocin-nicotinamide (STZ-NA) type 2 diabetic rats. STZ-NA diabetic rats were given, orally/daily, PAJ (100 or 300 mg/kg body weight, containing 2.6 and 7.8 mg of PCG/kg body weight, respectively), pure PCG (2.6 or 7.8 mg/kg body weight), or distilled water (vehicle) for 6 weeks. PAJ (especially at the high dose) alleviated significantly (P < 0.05-0.001) most signs of type 2 diabetes including body-weight loss, insulin resistance (IR) and hyperglycemia through decreasing serum tumor necrosis factor-α concentration and the expression of hepatic c-Jun N-terminal kinase, and increasing the skeletal muscle weight and the expression of hepatic insulin receptor substrate-1 in STZ-NA diabetic rats. Also, it decreased significantly (P < 0.001) the oxidative liver injury in STZ-NA diabetic rats through decreasing the hepatic lipid peroxidation and nitric oxide production, and improving the hepatic antioxidant defense system. Although the low dose of PCG induced some modulation in STZ-NA diabetic rats, the high dose of PCG did not show any valuable antidiabetic activity, but induced many side effects. In conclusion, PAJ was safer and more effective than pure PCG in alleviating IR and oxidative liver injury in STZ-NA diabetic rats.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Hydrolyzable Tannins; Hyperglycemia; Insulin Receptor Substrate Proteins; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Lipid Peroxidation; Liver; Male; Muscle, Skeletal; Niacinamide; Nitric Oxide; Pomegranate; Rats; Streptozocin; Tumor Necrosis Factor-alpha