I. Receptors at the surface of the beta cell: first step in cell signalling

A. Allosteric modulation as a unifying mechanism for receptor function and regulation
Allosteric regulation was described decades ago as the regulation of an enzyme by an effector molecule via binding at a different site than the active (orthosteric) site, ie, the allosteric site.3 The binding of an effector molecule results in a conformational change that affects protein dynamics; some effector molecules are allosteric activators (positive allosteric modulators) that enhance a protein’s activity, whereas others are allosteric inhibitors (negative allosteric modulators) that reduce a protein’s activity. Most allosteric effects can be explained by two models: (i) the concerted Monod-Wyman-Changeux model; and (ii) the sequential model. The Monod-Wyman-Changeux model postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is conferred to all subunits (thus all subunits are in the same conformation, ie, tensed or relaxed; Figure 1).4,5 The sequential model proposed by Koshland et al holds that the subunits do not necessitate the same conformation.6 It is now accepted that protein dynamics are especially important in cell signaling,7 and Jean-Pierre Changeux stressed the point that allosteric proteins are not only enzymes, but also ion channels, G-protein-coupled receptors (GPCRs), nuclear hormone receptors, and tyrosine kinase receptors. He suggested that allosteric modulation is a unifying mechanism for receptor function and regulation.8

Indeed, the signal transduction mediated by receptors needs a “communication over a distance” between the activating site and the locus of the biological response.8 Changeux and Christopoulos proposed the concept that the link between activation and response is allosteric, ie, proteins are organized into symmetrical oligomers that undergo discrete cooperative changes in the quaternary structure and switched from one state to another state as described in the Monod-Wyman-Changeux model (Figure 1). The recent advances in understanding the mechanisms of allosteric receptor transition represent an important opportunity for pharmacological applications in various domains, including diabetes. In particular, the allosteric modulation of the nicotinic acetylcholine receptor, GPCRs (for which lipids are allosteric modulators9), or ion channels could modulate β-cell function. Allosteric antibodies that bind to the insulin receptor tyrosine kinase have been discovered recently.10,11 In addition, a database of more than 72000 substances that could be considered as allosteric modulators (http://mdl.shsmu.edu.cn/ASD/) is promising for future applications.8

B. GPCRs as sensors of autocrine and paracrine metabolite signalling
GPCRs are seven-transmembrane domain receptors that can detect molecules outside the cell and activate intracellular signal transduction pathways (eg, cAMP, phosphatidylinositol, and -arrestin signaling pathways), thus leading to a cellular response. Numerous GPCRs are present at the surface of β-cells (eg, GPR120 or GPR40) and involved in insulin secretion.12,13 Husted et al defines the metabolites acting on these GPCRs as extracellular signalling molecules that could be compared with hormones and neurotransmitters.14 These “signalling metabolites” mainly come from nutrients, but they could also be produced by the gut microbiota, and they primarily target the gut mucosa and the liver. In contrast, metabolites from intermediary metabolism, such as acetate, propionate, or succinate, mainly act as metabolic stress-induced autocrine and paracrine signals in adipose tissue, the liver, and the endocrine pancreas (Figure 2).14
In islets, GPR40 and GPR120 recognize triglyceride-derived metabolites, such as long-chain fatty acids and 2-monoacylglycerol, produced by the action of the intracapillary lipoprotein lipase action. In particular, GPR40 mediates free fatty acid–induced insulin secretion in β-cells, and, currently, a partial GPR40 agonist is being tested in a clinical phase 1 proof-of-concept study in patients with type 2 diabetes.15 Fasiglifam (TAK-875), another selective partial GPR40 agonist that is orally available, reached phase 3 clinical trials for the potential treatment of type 2 diabetes; however, the drug development was stopped due to liver side effects.16,17 GPR142, another GPCR that is highly expressed in β-cells has been recently identified as a potential glucose-stimulated insulin secretion target, and several agonists belonging to the triazole family are under close investigation.18,19
G proteins, coupled with GPCRs, (also known as guanine nucleotide-binding protein) are a target in islet function. When they are bound to GTP, they are “on,” and, when they are bound to GDP, they are “off .” Anjaneyulu Kowluru reviewed the roles of several small G proteins in supporting glucose-induced insulin secretion (GSIS) (ie, Rac1, Cdc42, Arf6, Rab27A) by promoting cytoskeletal remodeling and in the transport and docking of insulin granules on the plasma membrane.20 Lipidation (farnesylation and geranylation) mediates the effects of G proteins by limiting their targeting to specific cellular compartments. For instance, defective prenylation leads to the mislocalization of G proteins, activation of stress kinases, and production of reactive oxygen species, which could ultimately lead to β-cell apoptosis.20,21

C. Sweet taste receptors and insulin secretion
Glucose is the primary stimulator of insulin secretion, which is not a matter of debate; however, Itaru Kojima questioned whether glucose solely exerts its effects on β-cells through its intracellular metabolism. Indeed, glucose induces rapid Ca2+ and cAMP signalling in beta cells that is independent of metabolism, which, as a proof of concept, can be reproduced with nonmetabolizable glucose analogs. Some cell surface receptors activated by glucose or glucose analogs have been discovered and named “sweet taste receptors.”22 In beta cells, Kojima et al recently showed that taste type 1 receptor 3 (T1R3), a subunit of the sweet taste receptor, functions as a glucose-sensing receptor23,24 by forming a heterodimer with the calcium sensing subunit CaSR.25 When this receptor is blocked, glucose metabolism is decreased and GSIS is inhibited (Figure 3A),26 demonstrating that sweet taste receptors may play a role in the beta cell response to glucose (Figure 3B).27,28

D. NMDA receptors
Pancreatic β-cells and central nervous system cells have common features; in particular, they share the expression of NMDA receptors. In his lecture, Eckhard Lammert recapitulated the recent evidence on NMDA receptors in beta cell function, and proposed that morphinan-based NMDA receptor antagonists, such as dextromethorphan, could be beneficial for insulin secretion, glucose tolerance, and islet cell survival.29 Figure 4 displays the proposed mechanism of physiological NMDA receptor–regulated insulin release, stating that NMDA receptors are part of a negative feedback loop that limits GSIS at stimulatory glucose concentrations (Figure 4A). The pharmacological use of dextromethorphan would allow for sustained membrane depolarization, thereby increasing insulin release (Figure 6B).

In addition to the beneficial effect of NMDA receptor antagonists in β-cells, they could act on the long-term complications of diabetes, such as nephropathy, retinopathy, and neuropathy.30,31