Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

González,Nieves; Martín-Duce,Antonio; Martínez-Arrieta,Félix; Moreno-Villegas,Zaida; Portal-Núñez,Sergio; Sanz,Raúl; Egido,Jesús

doi:10.3892/ijmm.2015.2090

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

Authors:
- Nieves González
- Antonio Martín-Duce
- Félix Martínez-Arrieta
- Zaida Moreno-Villegas
- Sergio Portal-Núñez
- Raúl Sanz
- Jesús Egido
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Affiliations: Renal, Vascular and Diabetes Research Laboratory, IIS-Jiménez Díaz Foundation, The Autonomous University of Madrid, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain, Department of Nursery, Unit of Surgery, Alcalá University, Madrid, Spain, Department of General Surgery, Puerta de Hierro-Majadahonda University Hospital, The Autonomous University of Madrid, Madrid, Spain, Renal, Vascular and Diabetes Research Laboratory, IIS-Jiménez Díaz Foundation, The Autonomous University of Madrid, Madrid, Spain , Department of Bone and Mineral Metabolism, IIS-Jiménez Díaz Foundation, Cooperative Research Thematic Network on Aging and Frailty (RETICEF), Madrid, Spain, Department of Neurology, IIS-Jiménez Díaz Foundation, Madrid, Spain
Published online on: February 4, 2015 https://doi.org/10.3892/ijmm.2015.2090
Pages: 925-931
Copyright: © González et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein-coupled receptor (GPCR) member of the bombesin receptor family. Several studies have suggested an association between obesity, alterations in glucose metabolism, diabetes and the BRS-3 receptor. In this study, we focused on patients simultaneously diagnosed with obesity and type 2 diabetes (OB/T2D). The analysis of BRS-3 expression in the skeletal muscle of these patients revealed a marked decrease in the expression of BRS-3 at the mRNA (23.6±1.3-fold downregulation, p<0.0001) and protein level (49±7% decrease, p<0.05) compared to the normal patients (no obesity and diabetes). Moreover, in cultured primary myocytes from patients with OB/T2D, the synthetic BRS-3 agonist, [D-Try6,β‑Ala11,Phe13,Nle14]bombesin6-14, significantly increased the phosphorylation levels of mitogen-activated protein kinase (MAPK), p90RSK1, protein kinase B (PKB) and p70s6K. Specifically, the ligand at 10-11 M induced the maximal phosphorylation of MAPKs (p42, 159±15% of the control; p44, 166±11% of the control; p<0.0001) and p90RSK1 (148±2% of the control, p<0.0001). The basal phosphorylation levels of all kinases were reduced (p<0.05) in the patients with OB/T2D compared to the normal patients. Furthermore, the BRS-3 agonist stimulated glucose transport, which was already detected at 10-12 M (133±9% of the control), reached maximal levels at 10-11 M (160±9%, p<0.0001) and was maintained at up to 10-8 M (overall mean, 153±7%; p<0.007). This effect was less promiment than that attained with 10-8 M insulin (202±9%, p=0.009). The effect of the agonist on glycogen synthase a activity achieved the maximum effect at 10-11 M (165±16% of the control; p<0.0001), which did not differ from that observed with higher concentrations of the agonist. These results suggest that muscle cells isolated from patients with OB/T2D have extremely high sensitivity to the synthetic ligand, and the effects are particularly observed on MAPK and p90RSK1 phosphorylation, as well as glucose uptake. Moreover, our data indicate that BRS-3 may prove to be useful as a potential therapeutic target for the treatment of patients with OB/T2D.

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