G Protein-Coupled Receptors and the Rise of Type 2 Diabetes in Children

Abstract

The human genome counts hundreds of GPCRs specialized to sense thousands of different extracellular cues, including light, odorants and nutrients in addition to hormones. Primordial GPCRs were likely glucose transporters that became sensors to monitor the abundance of nutrients and direct the cell to switch from aerobic metabolism to fermentation. Human β cells express multiple GPCRs that contribute to regulate glucose homeostasis, cooperating with many others expressed by a variety of cell types and tissues. These GPCRs are intensely studied as pharmacological targets to treat type 2 diabetes in adults. The dramatic rise of type 2 diabetes incidence in pediatric age is likely correlated to the rapidly evolving lifestyle of children and adolescents of the new century. Current pharmacological treatments are based on therapies designed for adults, while youth and puberty are characterized by a different hormonal balance related to glucose metabolism. This review focuses on GPCRs functional traits that are relevant for β cells function, with an emphasis on aspects that could help to differentiate new treatments specifically addressed to young type 2 diabetes patients.

Keywords: GPCRs; diabetes in youth; glucose homeostasis; type 2 diabetes; β cells.

Figure 1

Light perception effects on glucose metabolism—Humans sense visible light primarily through cones and rods in the retina. However, additional opsins specialized to sense blue light are located in the 0.2% of RGCs or in subcutaneous white adipocytes. RGCs project to various areas of the brain to transmit visual information received from the retina. Projections directed to the SCN are instead important to synchronize the circadian clock by regulating melatonin production in the PG through the superior cervical ganglion (SCG). The PG is the most important source of circulating melatonin. Melatonin then regulates insulin release from β cells. 1–5% of the blue light can penetrate the human skin and reach the subcutaneous white adipocytes. Here, OPN4 and OPN3 melanopsin receptors are reported to promote lipolysis. Dotted arrows represent indirect effects of the molecules reported.

Figure 2

GPCR signaling should be seen as a dynamic equilibrium—Driven by spontaneous activation or driven by the basal concentration of ligand, GPCRs are constitutively internalized (A) and recycled (B). Fluctuations of endogenous ligand will stabilize ‘active’ conformations and thus promote the dissociation of the heterotrimeric G protein and the binding of arrestin to a phosphorylated receptor. Early endosomes can transfer GPCR to different intracellular compartments such as late endosomes (C) or perinuclear recycling compartment (D). The perturbation of the pre-existing balance will redistribute GPCR inside the cell, including nuclear (E) and mitochondrial (F) membranes. Membrane-permeable ligands such as melatonin or estrogens can diffuse inside the cell, directly promoting intracellular signaling (G). GPCR sense stimuli while directly interacting with other GPCRs, as dimers or oligomers, or with other receptors (H) and receptor like GLP1R can recognize multiple ligands, such as glucagon and GLP1 (I). Arrestins and other interactors can sense the activation of distinct receptors. From this description, it appears that coordinated stimuli such as combinations of incretins transmit detailed information about the composition of the meal that will be deciphered by β cells or by neurons in CNS based on the perturbation of an equilibrium that was established during fastening. This complex machinery evolved from prokaryotes will allow a coordinated response of the organism in terms of satiety, enzyme production, etc. Fasting glucose, insulin and insulin resistance change during childhood [114] and incretin levels may be titrated to favor growth during adolescence [115]. The design of pharmacological treatments should consider this level of complexity to achieve the best efficacy and minimize undesired effects during adolescence and puberty.