Neuregulin improves response to glucose tolerance test in control and diabetic rats

Abstract

Neuregulin (NRG) is an EGF-related growth factor that binds to the tyrosine kinase receptors ErbB3 and ErbB4, thus inducing tissue development and muscle glucose utilization during contraction. Here, we analyzed whether NRG has systemic effects regulating glycemia in control and type 2 diabetic rats. To this end, recombinant NRG (rNRG) was injected into Zucker diabetic fatty (ZDF) rats and their respective lean littermates 15 min before a glucose tolerance test (GTT) was performed. rNRG enhanced glucose tolerance without promoting the activation of the insulin receptor (IR) or insulin receptor substrates (IRS) in muscle and liver. However, in control rats, rNRG induced the phosphorylation of protein kinase B (PKB) and glycogen synthase kinase-3 (GSK-3) in liver but not in muscle. In liver, rNRG increased ErbB3 tyrosine phosphorylation and its binding to phosphatidylinositol 3-kinase (PI3K), thus indicating that rNRG activates the ErbB3/PI3K/PKB signaling pathway. rNRG increased glycogen content in liver but not in muscle. rNRG also increased the content of fructose-2,6-bisphosphate (Fru-2,6-P2), an activator of hepatic glycolysis, and lactate in liver but not in muscle. Increases in lactate were abrogated by wortmannin, a PI3K inhibitor, in incubated hepatocytes. The liver of ZDF rats showed a reduced content of ErbB3 receptors, entailing a minor stimulation of the rNRG-induced PKB/GSK-3 cascade and resulting in unaltered hepatic glycogen content. Nonetheless, rNRG increased hepatic Fru-2,6-P2 and augmented lactate both in liver and in plasma of diabetic rats. As a whole, rNRG improved response to the GTT in both control and diabetic rats by enhancing hepatic glucose utilization.

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

“…Here, chronic NRG1 treatment did not alter basal and phosphorylated (Ser473 and Thr308) AKT level. These results are in accordance with the study by Lopez-Soldadό and colleagues who showed that acute injection of NRG1 does not activate AKT in skeletal muscle of lean and diabetic Zucker rats 46 . The other molecules evaluated (ERK1/2, AMPK, ACC and ACL) also were not affected by NRG1 treatment.…”

Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders

“…Nrg1 treatment improved whole body glucose metabolism in db/db mice and diabetic rats [41], [42]. Whether Nrg4 may act directly on skeletal muscle to promote glucose uptake and utilization remains an important question to be addressed in future studies.…”

ErbB4 deletion predisposes to development of metabolic syndrome in mice

“…All these ligands have been reported to play important roles in glucose transport, lipogenesis, or browning of the adipocytes, critical steps in glucose homeostasis and energy expenditure. Multiple studies have reported that NRG1 mediates glucose transport and improves glucose tolerance (14,26). Although NRG1 can bind to both ErbB3 and ErbB4, activation of ErbB4 was proven to be critical for the increased glucose uptake, as ErbB4-blocking antibodies impaired NRG1-induced glucose uptake (3).…”