Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes

Abstract

The worldwide prevalence of obesity is steadily increasing, nearly doubling between 1980 and 2008. Obesity is often associated with insulin resistance, a major risk factor for type 2 diabetes mellitus (T2DM): a costly chronic disease and serious public health problem. The underlying cause of T2DM is a failure of the beta cells of the pancreas to continue to produce enough insulin to counteract insulin resistance. Most current T2DM therapeutics do not prevent continued loss of insulin secretion capacity, and those that do have the potential to preserve beta cell mass and function are not effective in all patients. Therefore, developing new methods for preventing and treating obesity and T2DM is very timely and of great significance. There is now considerable literature demonstrating a link between inhibitory guanine nucleotide-binding protein (G protein) and G protein-coupled receptor (GPCR) signaling in insulin-responsive tissues and the pathogenesis of obesity and T2DM. These studies are suggesting new and emerging therapeutic targets for these conditions. In this review, we will discuss inhibitory G proteins and GPCRs that have primary actions in the beta cell and other peripheral sites as therapeutic targets for obesity and T2DM, improving satiety, insulin resistance and/or beta cell biology.

Figure 1

Summary of some of the proposed mechanisms of dysfunctional E prostanoid receptor 3 (EP3) and α2A-adrenergic receptor (α2A-AR) signaling in diabetic beta cells and how these receptors might be targeted in type 2 diabetes mellitus (T2DM) therapy. In a schematic of a diabetic beta cell, both expression and/or activity of both EP3 (left) and α2A-AR (right) have been shown to be dysfunctionally upregulated. Increased EP3 expression/activity is exacerbated by increased prostaglandin E2 (PGE2) production, acting in an autocrine/paracrine manner to further reduce cyclic AMP (cAMP) production by G_i subfamily member, G_z, signaling to adenylate cyclase (AC). In contrast, the release of α2A-AR agonists epinephrine and norepinephrine (Epi/NE) after stimulation by the parasympathetic nervous system (PNS) is not necessarily dysfunctionally upregulated in T2DM; rather, a specific ADRA2A single nucleotide polymorphism (SNP) confers increased stability of α2A-AR at the plasma membrane, allowing Epi/NE to tonically signal through α2A-AR and associated G_i subfamily proteins to reduce cAMP production by AC. Of note, cAMP is one of the only signaling pathways shown to positively impact on both beta cell mass (that is, growth, proliferation and survival) and beta cell function (that is, insulin secretion). Gray arrows and text indicate confirmed or potential downregulation of these effects with dysfunctional EP3 or α2A-AR signaling. The EP3 antagonist, L798,106, has been shown to reverse diabetic beta cell dysfunction in isolated islets in vitro, while DG-041 has gone through clinical trials for a different indication, indicating potential in vivo utility. Also suggested in this figure is the potential to target EP3 signaling by reducing PGE2 production with nutritional or pharmacological interventions. With regards to α2A-AR, a specific antagonist, yohimbine, improves insulin secretion from islets isolated from individuals with the specific ADRA2A SNP conferring α2A-AR stability. A clinical trial to confirm this finding in vivo has been initiated. Again, both EP3 and α2A-AR antagonists have the potential to improve beta cell mass, but this has yet to be confirmed.