Effect of natural products on commercial oral antidiabetic drugs in enhancing 2-deoxyglucose uptake by 3T3-L1 adipocytes

Abstract

Abstract:Objective: The management of diabetes with insulin and synthetic oral hypoglycemic drugs (OHDs) can produce serious side effects and in addition fails to prevent diabetes-related complications in many patients. A new diabetes management strategy is needed that is more effective and has fewer side effects. Methods: This paper analyzes the dose-and time-dependent effect of three phytochemicals: berberine, arecoline and vanillic acid, and two antidiabetic drugs: 2,4-thiazolidinedione (TZD) and metformin, on the uptake of 2-deoxyglucose (2DG) by 3T3-L1 adipocytes. The interactions of the phytochemicals with the OHDs were analyzed with isobolograms and the combination index.Results: TZD and berberine increased 2DG uptake by 3.3-fold (with respect to control) at 15 mM and 25 mM, respectively. The same concentrations of arecoline and vanillic acid increased 2DG uptake by 3.2-and 2.9-fold, respectively, when compared with the basal level. Berberine and arecoline acted synergistically with both the OHDs, whereas vanillic acid had an additive interaction with TZD and an antagonistic interaction with metformin. Arecoline significantly increased the translocation of GLUT4 via the PPARg pathway, whereas berberine and vanillic acid did this via the AMPK-dependent pathway. Conclusions: These phytochemicals significantly reduced the expression of the enzymes involved in fatty acid and cholesterol synthesis, indicating that they might help prevent the secondary complications of diabetes. The current study suggests that berberine and arecoline could allow dosage reduction of OHDs, which could also lead to a reduction in the toxicity and side effects caused by OHDs.Keywords: berberine, 2-deoxyglucose, isobologram, synergy, vanillic acid Introduction Diabetes mellitus (DM) is a chronic endocrine metabolic disorder characterized by hyperglycemia. It is caused by inadequate insulin, either in its production or its function [Harris and Zimmet, 1997]. The disorder can be classified into type 1 (insulin-dependent DM) and type 2 (noninsulin-dependent DM). The latter accounts for more than 90% of all diabetes cases and is caused mainly by peripheral insulin resistance and impaired insulin secretion. It is often associated with lipid and lipoprotein disorders [Ciresi et al. 2007;Oh et al. 2005]. The metabolic disorder includes alterations in carbohydrates, lipids and protein metabolism.

Synthesis and Evaluation of Antidiabetic Properties of a Zinc Mixed Ligand Complex in High-Fat Diet - Low-Dose Streptozotocin-Induced Diabetic Rats

“…New chemical entities from natural sources have been explored for safer antidiabetic agents as they elicit relatively fewer side effects. Likewise, if the therapeutic dose of an oral hypoglycemic drug (OHD) could be partly reduced by replacing it with a biologically active phytochemical, the side effects caused by the former could be reduced to a greater extent [20]. However, the interactions between the OHD and the phytochemical in terms of stability, bioavailability, and metabolism have to be established for successful therapeutic strategies [21].…”

“…Vital organs were subjected to macroscopic observations. Similarly, the dosage fixation studies were also conducted using graded doses of the complex (5,10,20, and 50 mg/kg b.w/rat/day) for 30 days to fix the dose-dependent hypoglycemic effect in HFD fed low-dose STZinduced experimental T2D rats based on the fasting blood glucose levels.…”

Extended Intake of Mulberry Leaf Extract Delayed Metformin Elimination via Inhibiting the Organic Cation Transporter 2

“…Combinations of drugs with herbal medicine may reduce the unwanted side effects caused by drugs. For instance, cinnamic acid derivatives when combined with Met reduced the expression of fatty acid synthase and β-Hydroxy β-methylglutaryl-CoA (HMG CoA) reductase involved in the secondary complications of DM [18,19]. However, these combinations may produce three different types of effects-namely synergistic, additive, and antagonistic [5].…”

Network pharmacology-based assessment to elucidate the molecular mechanism of anti-diabetic action of Tinospora cordifolia

“…Type 2 diabetes mellitus (T2DM) is a metabolic disorder due to insulin insensitivity/insulin resistance; modern pharmacotherapy utilizes synthetic oral hypoglycaemic agents [1]. Although these molecules are effective in the management of elevated blood glucose level, they are not free from numerous side effects like genital mycosis, pancreatitis, ketoacidosis, nausea, vomiting, fractures, and neuropathy risk.…”