Consumption of Terpenoids-Rich Padina pavonia Extract Attenuates Hyperglycemia, Insulin Resistance and Oxidative Stress, and Upregulates PPARγ in a Rat Model of Type 2 Diabetes

Abstract

Seaweeds are rich in structurally diverse bioactive compounds with promising therapeutic effects. This study aimed to isolate and identify terpenes from the brown alga Padina pavonia and to investigate its antidiabetic activity, pointing to the possible involvement of peroxisome proliferator-activated receptor (PPAR)γ. Type 2 diabetes was induced by feeding rats a high fat diet (HFD) for 4 weeks followed by injection of 35 mg/kg streptozotocin (STZ). The diabetic rats received P. pavonia extract (PPE; 50, 100 and 200 mg/kg) for 4 weeks and samples were collected for analyses. HFD/STZ-induced rats showed hyperglycemia, dyslipidemia, impaired glucose tolerance, decreased insulin, and increased HbA1c and HOMA-IR. PPE ameliorated hyperglycemia and dyslipidemia, and improved glucose tolerance and insulin sensitivity in diabetic rats. Treatment with PPE increased hepatic hexokinase activity and glycogen, suppressed glucose-6-phosphatase, fructose-1,6-biphosphatase, and glycogen phosphorylase, and attenuated oxidative stress, inflammation, and liver injury and lipid infiltration in HFD/STZ-induced rats. In addition, PPE boosted antioxidants and upregulated PPARγ gene and protein expression in the liver of diabetic rats. Phytochemical investigation resulted in the isolation of six terpenes from PPE and in silico analysis revealed their binding affinity toward PPARγ. In conclusion, P. pavonia-derived terpenes attenuated hyperglycemia, dyslipidemia, oxidative stress, and inflammation, and improved insulin sensitivity and carbohydrate metabolism in type 2 diabetic rats. These beneficial effects are mediated via PPARγ activation. However, further studies to explore the exact mechanisms underlying the antidiabetic effect of PPE are recommended.

Keywords: PPARs; diabetes; oxidative stress; seaweeds; terpenes.

Figure 1

Chemical structure of the isolated compounds.

Figure 2

P. pavonia extract (PPE) ameliorates hyperglycemia and insulin resistance (IR) in high fat diet/streptozotocin (HFD/STZ)-induced rats. PPE and pioglitazone (PIO) ameliorated blood glucose levels (A,B), glucose tolerance (C,D), and HbA1c% (E), increased serum insulin (F) and decreased HOMA-IR (G) in STZ/HFD-induced rats. Data are mean ± SEM, n = 6. *** P < 0.001 versus control and ^# P < 0.05, ^## P < 0.01 and ^### P < 0.001 versus diabetic.

Figure 3

PPE improves liver glucose-metabolizing enzymes and glycogen in HFD/STZ-induced rats. PPE and PIO increased hexokinase activity (A), suppress glucose-6-phosphatase (B), fructose-1,6-biphosphatase (C) and glycogen phosphorylase (D), and improved glycogen content (E) in diabetic rats. Data are mean ± SEM, n = 6. *** P < 0.001 versus control and ^### P < 0.001 versus diabetic.

Figure 4

PPE attenuates hyperlipidemia in HFD/STZ-induced rats. PPE and PIO decreased serum triglycerides (A), total cholesterol (B), LDL-C (C), vLDL-C (D) and atherogenic index of plasma (F), and increased HDL-C (E) in diabetic rats. Data are mean ± SEM, n = 6. *** P < 0.001 versus control and ^# P < 0.05 and ^### P < 0.001 versus diabetic.

Figure 5

PPE and PIO decreased serum ALT (A) and alanine aminotransferase (AST) (B), and liver cholesterol (C) and triglycerides (D) in diabetic rats. Data are mean ± SEM, n = 6. *** P < 0.001 versus Control and ^### P < 0.001 versus diabetic.

Figure 6

Photomicrographs of H&E-stained liver sections in liver of control and PPE-supplemented rats showing normal structure of hepatic lobule, hepatocytes, and central vein. HFD/STZ-induced rats showed centrilobular hepatic vacuolation of round border and clear vacuoles consistent with fatty changes (arrows). Diabetic rats treated with 50, 100, and 200 mg/kg PPE or PIO showed remarkable improvement of liver structure.

Figure 7

PPE attenuates oxidative stress and enhances antioxidants in HFD/STZ-induced rats. PPE and PIO decreased ROS (A), MDA (B), and NO (C), and increased GSH (D), SOD (E), and CAT (F) in liver of diabetic rats. Data are mean ± SEM, n = 6. *** P < 0.001 versus control and ^### P < 0.001 versus diabetic.

Figure 8

PPE and PIO decreased serum TNF-α (A) and IL-6 (B) in HFD/STZ-induced rats. Data are mean ± SEM, n = 6. *** P < 0.001 versus control and ^### P < 0.001 versus diabetic.

Figure 9

PPE upregulates hepatic PPARγ in HFD/STZ-induced rats. PPE and PIO increased mRNA abundance (A) and protein expression (B) levels of PPARγ in the liver of diabetic rats. Data are mean ± SEM, n = 6. *** P < 0.001 versus control and ^### P < 0.001 versus diabetic. (C) Molecular docking analysis showing the binding between P. pavonia-derived terpenes (Compounds 1–6) and PPARγ. Compounds 1, 5, and 6 interact with Arg288 and Glu343, compounds 2 and 3 interact with Arg288 and compound 4 binds Arg288 and Glu295 in PPARγ.

Figure 10

A schematic diagram showing the antidiabetic properties of P. pavonia terpenoids-rich extract.