Abstract
GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in db/db mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism.
Highlights
GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis
To compare the glucose-lowering efficacy of a combination of GPR40 and GPR120 against either monotherapy, 12-week-old db/db male mice were treated for 10 days with a GPR40 selective agonist MK-2305 [15], a GPR120 selective agonist cpd A [5], or the combination
Treatment with the GPR40 agonist MK-2305 resulted in a significant reduction of blood glucose, as evident on study days 4–7, the effect seemed to attenuate from treatment days 7–10, whereas treatment with the GPR120 agonist cpd A showed an initial trend for glucose lowering on study days 4–5, but this efficacy was not sustained (Fig. 1B)
Summary
GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Thiazolidinediones (TZDs) are generally acknowledged as the only class of antidiabetic drugs that work directly as insulin sensitizers in the clinic Adverse effects such as edema, weight gain, and increased cardiovascular and bone fracture risk have limited the use of this class of drugs in the treatment of T2DM [1]. GPR40 and GPR120 have each emerged as a potential target for T2DM in recent years [2, 3] They are both fatty acid-sensing G protein-coupled receptors (GPCRs) that play important roles in glucose and energy homeostasis.
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