Species-specific effects of neuregulin-1β (cimaglermin alfa) on glucose handling in animal models and humans with heart failure

Abstract

Neuregulin-1β is a member of the neuregulin family of growth factors and is critically important for normal development and functioning of the heart and brain. A recombinant version of neuregulin-1β, cimaglermin alfa (also known as glial growth factor 2 or GGF2) is being investigated as a possible therapy for heart failure. Previous studies suggest that neuregulin-1β stimulation of skeletal muscle increases glucose uptake and, specifically, sufficient doses of cimaglermin alfa acutely produce hypoglycemia in pigs. Since acute hypoglycemia could be a safety concern, blood glucose changes in the above pig study were further investigated. In addition, basal glucose and glucose disposal were investigated in mice. Finally, as part of standard clinical chemistry profiling in a single ascending-dose human safety study, blood glucose levels were evaluated in patients with heart failure after cimaglermin alfa treatment. A single intravenous injection of cimaglermin alfa at doses of 0.8 mg/kg and 2.6 mg/kg in mice resulted in a transient reduction of blood glucose concentrations of approximately 20% and 34%, respectively, at 2 hours after the treatment compared to pre-treatment levels. Similar results were observed in diabetic mice. Treatment with cimaglermin alfa also increased blood glucose disposal following oral challenge in mice. However, no significant alterations in blood glucose concentrations were found in human heart failure patients at 0.5 and 2 hours after treatment with cimaglermin alfa over an equivalent human dose range, based on body surface area. Taken together, these data indicate strong species differences in blood glucose handling after cimaglermin alfa treatment, and particularly do not indicate that this phenomenon should affect human subjects.

Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure

“…Glucose metabolism is a complex process modulated by NRG-1 signaling. [31][32][33][34] Administration of NRG-1 acutely reduces blood glucose in pigs and mice, with effects on both hepatic glucose utilization and glucose uptake by skeletal muscle. 33 For instance, NRG-1 influences glucose transporter translocation in skeletal myoblasts 35 activates the ErbB3/protein kinase B (Akt) signaling pathway in hepatocytes.…”

“…[31][32][33][34] Administration of NRG-1 acutely reduces blood glucose in pigs and mice, with effects on both hepatic glucose utilization and glucose uptake by skeletal muscle. 33 For instance, NRG-1 influences glucose transporter translocation in skeletal myoblasts 35 activates the ErbB3/protein kinase B (Akt) signaling pathway in hepatocytes. 32,34 Also, insulin deficiency reduces expression of ErbB3 in liver cells, suggesting an interaction between insulin and the NRG-1/ ErbB3 pathway in maintenance of glucose homeostasis.…”

“…32 In conclusion, a growing number of studies indicate that NRG-1 signaling induces glucose tolerance, but the effect may be species specific and needs to be confirmed in humans. 33…”