Unlocking Therapeutic Synergy: Tailoring Drugs for Comorbidities such as Depression and Diabetes through Identical Molecular Targets in Different Cell Types

Abstract

Research in the field of pharmacology aims to generate new treatments for pathologies. Nowadays, there are an increased number of chronic disorders that severely and durably handicap many patients. Among the most widespread pathologies, obesity, which is often associated with diabetes, is constantly increasing in incidence, and in parallel, neurodegenerative and mood disorders are increasingly affecting many people. For years, these pathologies have been so frequently observed in the population in a concomitant way that they are considered as comorbidities. In fact, common mechanisms are certainly at work in the etiology of these pathologies. The main purpose of this review is to show the value of anticipating the effect of baseline treatment of a condition on its comorbidity in order to obtain concomitant positive actions. One of the implications would be that by understanding and targeting shared molecular mechanisms underlying these conditions, it may be possible to tailor drugs that address both simultaneously. To this end, we firstly remind readers of the close link existing between depression and diabetes and secondly address the potential benefit of the pleiotropic actions of two major active molecules used to treat central and peripheral disorders, first a serotonin reuptake inhibitor (Prozac ^®) and then GLP-1R agonists. In the second part, by discussing the therapeutic potential of new experimental antidepressant molecules, we will support the concept that a better understanding of the intracellular signaling pathways targeted by pharmacological agents could lead to future synergistic treatments targeting solely positive effects for comorbidities.

Keywords: cell signaling; channel; depression; diabetes; pharmacology; receptor.

Figure 1

Specific molecular targets of fluoxetine on neurons and pancreatic β cells. Distribution of 5-HT transporters and receptors in neurons (upper panel) and in pancreatic β cells (lower panel). In neurons, 5-HT receptors are expressed mostly at the postsynaptic level, and they modulate signal transmission. β cells express 5-HT receptors similar to those of neurons. SSRIs are symbolized by blue, 5-HT by red and insulin by green dots. 5-HT1, 2, 4, 6 and 7 are 7-TM domain receptors (GPCRs). 5-HT3 is a cationic channel symbolized by blue. SERTs are in orange.

Figure 2

Summary of GLP-1 functions. Acting on several physiological functions, GLP-1 is a multitask hormone that regulates general body metabolisms.

Figure 3

GLP-1 signaling pathways in pancreatic beta cells. Secreted GLP-1 from enteroendocrine L cells in the small intestine epithelium acts on several target cells, such as pancreatic beta cells. GLP-1 receptor agonists are associated with cAMP-dependent pathways, which amplify regulated exocytosis and increase cell survival and proliferation. Amplification and survival pathways controlled by cAMP as a second messenger activate PKA and EPAC sensors. Once activated, these sensors maintain endocrine function by modulating CREB transcriptional activity.

Figure 4

PE signaling pathway in neurons and pancreatic beta cells. PE is present in the general circulation, being secreted by several cells, such as adipocytes, skeletal muscle and the intestinal epithelium. PE is a specific K₂P TREK-1 channel blocker, thus inducing partial plasma membrane depolarization. The subsequently induced calcium entry activates several signaling pathways: Akt, ERK and CaM-Kinases. The final resulting activation upregulates CREB transcriptional activity, maintaining cellular functions. As described, secreted peptides can modulate central and peripheral targets and provide co-benefits for different but related pathologies. In both cases, the target is a common molecular system that generates similar protective and functional improvements for the challenged organs.