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.

Melatonin receptor 1B gene associated with hyperglycemia in bipolar disorder

“…Melatonin has been proposed to reduce response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time in type 2 diabetes . The MTNR1B receptor is a transmembrane G protein-coupled receptor, proposed to be a new pharmacological target for diabetes (Mulder et al, 2009;Kimple et al, 2014). The MTNR1B is expressed in β-cells, and β-cells from diabetic patients tended to have increased MTNR1B expression .…”

Evaluation of clenbuterol-induced changes in blood biochemical parameters in white mice

“…According to previous studies, after binding to β 2 -receptor, β 2 -agonists activated several sub-units of G protein family which consequently causes glucose-stimulated and hormone-stimulated insulin secretion 13,22 . When using at dosage of 10mg/kg and 100mg/kg consecutively in 30 days, clenbuterol induced a significant decline in glucose concentrations in mice 23 .…”

“…In these cases, it was reported that clenbuterol residues in eddible tissues were higher 2,000 times than MRLs, and the amount of clenbuterol consumed was estimated about 230-300µg 9 . Previous studies evaluated the prolonged effects of clenbuterol on animals (mice, rats, pigs) at high concentrations (20-2,000 µg/kg body weight) [11][12][13][14] , and the results showed that clenbuterol affected protein, glucose and lipid metabolism [15][16][17][18] . However, these studies were conducted for a short time.…”

Minireview: Role of Intracellular Scaffolding Proteins in the Regulation of Endocrine G Protein-Coupled Receptor Signaling

“…Targets for therapeutic interventions include several members of the GPCR superfamily and their ligands as well as various GPCR-scaffolding proteins (167). Ghrelin, with its critical role in energy homeostasis, and its receptor, the GH secretagogue receptor [ghrelin receptor (GHSR1)] are of great significance for the treatment of obesity (168).…”