An in vitro evaluation of the efficacy of Agomelatine in combination with Thapsigargin and 2-Aminoethoxydiphenyl borate for the treatment of type 2 diabetes

Abstract

Background: Type 2 diabetes is a heterogeneous disorder characterized by defective insulin secretion and insulin sensitivity. Ca²⁺ mobilization regulates pancreatic β-cell synthesis, storage, and release of insulin in response to variations in circulating metabolite levels and intracellular glucose metabolism. Pineal gland melatonin synthesis regulates carbohydrate metabolism; melatonin is referred to as the “hormone of darkness,” and sleep deprivation is one of the risk factors for diabetes.

Methods: Melatonin receptor types 1A and 1B are two G-protein coupled receptors that mediate melatonin's function. The effect of agomelatine (a melatonin agonist) in combination with thapsigargin and 2-Aminoethoxydiphenyl borate (2-APB) on MIN 6 cells was investigated through dose-effect curves for each drug. The PLC/IP3 pathway via melatonin receptors on pancreatic β-cells was targeted.

Results: The three drugs and their combination exposure treatments were statistically analyzed for significant differences using one-way ANOVA. Dunnett's test was used to compare the different treatment groups. Mean insulin secretion responses were found to not be equal across groups, thus treatments had different effects on cells’ insulin regulation. The method of combination index (CI) predicted synergism in agomelatine and 2-APB, which may have therapeutic implications for diabetes.

Conclusion: As melatonin regulates circadian rhythm, incorporation of a melatonin agonist like agomelatine along with 2-APB may maintain both sleep/wake cycle conditions and insulin secretion by pancreatic cells. This combination of drugs may be a promising agent in the treatment of symptoms of depression and anxiety and thus the improvement of health-related behaviors in depressed patients with Type 2 diabetes.