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Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE
Marwa E Abdelmageed1, George S Shehatou1, Rami A Abdelsalam2
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Abstract:
Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder considered to be the most predominant form of diabetes throughout the world. This study aimed to investigate the possible effects of cinnamaldehyde (CIN) on insulin signaling pathways in STZ-induced T2D rat model. T2D was originated by feeding rats with a high-fat diet (HFD) plus 25% fructose solution plus streptozotocin (STZ) (35 mg/kg, i.p.). CIN effects were investigated on fasting blood glucose, insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), liver biomarkers, lipid profile, oxidative stress biomarkers, serum advanced glycation end products (AGEs) and its receptors (RAGE) in the aorta, and histopathology of the liver and aorta. Additionally, the mRNA expression of hepatic insulin signaling pathway genes, phosphorylated AKT (serine 473) (P-AKT ser473) level, and aortic nitric oxide synthase3 (eNOS) and NADPH oxidase4 (NOX4) were determined. CIN treatment for 30 days significantly decreased OGTT, ITT, fasting blood glucose, insulin, and HOMA-IR and increased HOMA-β index when compared to diabetic rats. CIN also improved lipid profile and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, serum AGEs, and aortic RAGE. Additionally, CIN treatment significantly decreased hepatic malondialdehyde (MDA), increased hepatic and aortic glutathione (GSH) and superoxide dismutase (SOD), and decreased steatosis and inflammation observed in liver tissue of rats. Additionally, significant elevation in mRNA expression of insulin receptor substrate1 (IRS1), phosphatidylinositol 3-kinase regulatory subunit1 (PI3K-P85 subunit), and AKT serine/threonine kinase2 (AKT2); increased levels of P-AKT ser473 and aortic eNOS; and decrease in mRNA expression of NOX4 were detected in CIN-treated group when compared to diabetic group. This study suggests antidiabetic and antioxidant effects of CIN probably through upregulation of eNOS and IRS1/PI3K/AKT2 signaling pathway and alleviating AGEs, RAGE, and NOX4 elevation.
Insights
Cinnamaldehyde (CIN) shows significant antidiabetic and antioxidant effects in a rat model of type 2 diabetes. It improves glucose control, lipid profiles, and reduces oxidative stress, likely by enhancing insulin signaling pathways.
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Type 2 diabetes mellitus (T2D) is a prevalent chronic metabolic disorder globally.
- Insulin resistance and impaired insulin signaling are key features of T2D.
- Exploring natural compounds for T2D management is an active research area.
Purpose of the Study:
- To investigate the effects of cinnamaldehyde (CIN) on insulin signaling pathways in a streptozotocin-induced T2D rat model.
- To evaluate CIN's impact on glucose metabolism, lipid profiles, oxidative stress, and related molecular markers.
Main Methods:
- Type 2 diabetes was induced in rats using a high-fat diet, fructose, and streptozotocin (STZ).
- Cinnamaldehyde (CIN) was administered for 30 days to assess its effects on various physiological and biochemical parameters.
- Key molecular markers including hepatic insulin signaling genes, phosphorylated AKT (P-AKT), eNOS, and NOX4 were analyzed.
Main Results:
- CIN treatment significantly improved glucose tolerance (OGTT, ITT), reduced fasting blood glucose and insulin levels, and improved HOMA-IR.
- CIN enhanced lipid profiles, reduced liver enzymes (ALT, AST), decreased advanced glycation end products (AGEs) and their receptor (RAGE).
- CIN exhibited antioxidant effects by increasing GSH and SOD, decreasing MDA, and improving liver histopathology. It also upregulated IRS1/PI3K/AKT2 and eNOS while downregulating NOX4.
Conclusions:
- Cinnamaldehyde demonstrates significant antidiabetic and antioxidant properties in a T2D rat model.
- CIN likely exerts its beneficial effects by upregulating the eNOS and IRS1/PI3K/AKT2 signaling pathways.
- CIN alleviates AGEs, RAGE, and NOX4, contributing to its therapeutic potential in managing type 2 diabetes.
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