title: 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.
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.
authors: 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.
authors: Nieves
authors: N
authors: González
authors: Department of Nursery, Unit of Surgery, Alcalá University, Madrid, Spain.
authors: Antonio
authors: A
authors: Martín-Duce
authors: Department of General Surgery, Puerta de Hierro-Majadahonda University Hospital, The Autonomous University of Madrid, Madrid, Spain.
authors: Félix
authors: F
authors: Martínez-Arrieta
authors: Renal, Vascular and Diabetes Research Laboratory, IIS-Jiménez Díaz Foundation, The Autonomous University of Madrid, Madrid, Spain.
authors: Zaida
authors: Z
authors: Moreno-Villegas
authors: Department of Bone and Mineral Metabolism, IIS-Jiménez Díaz Foundation, Cooperative Research Thematic Network on Aging and Frailty (RETICEF), Madrid, Spain.
authors: Sergio
authors: S
authors: Portal-Núñez
authors: Department of Neurology, IIS-Jiménez Díaz Foundation, Madrid, Spain.
authors: Raúl
authors: R
authors: Sanz
authors: 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.
authors: Jesús
authors: J
authors: Egido
mesh_terms: D001692:Biological Transport; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism*; D006442:Glycated Hemoglobin; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D018004:Receptors, Bombesin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005947:Glucose; D051246:Glucose Transport Proteins, Facilitative; D006442:Glycated Hemoglobin; D006006:Glycogen Synthase; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3
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