title: Bombesin receptor subtype-3 (BRS-3) regulates glucose-stimulated insulin secretion in pancreatic islets across multiple species.
abstract: Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, and BRS-3 agonism is being explored as a possible therapy for obesity. Here we study the role of BRS-3 in the regulation of glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. We quantified BRS-3 mRNA in pancreatic islets from multiple species and examined the acute effects of Bag-1, a selective BRS-3 agonist, on GSIS in mouse, rat, and human islets, and on oral glucose tolerance in mice. BRS-3 is highly expressed in human, mouse, rhesus, and dog (but not rat) pancreatic islets and in rodent insulinoma cell lines (INS-1 832/3 and MIN6). Silencing BRS-3 with small interfering RNA or pharmacological blockade with a BRS-3 antagonist, Bantag-1, reduced GSIS in 832/3 cells. In contrast, the BRS-3 agonist (Bag-1) increased GSIS in 832/3 and MIN6 cells. The augmentation of GSIS by Bag-1 was completely blocked by U73122, a phospholipase C inhibitor. Bag-1 also enhanced GSIS in islets isolated from wild-type, but not Brs3 knockout mice. In vivo, Bag-1 reduced glucose levels during oral glucose tolerance test in a BRS-3-dependent manner. BRS-3 agonists also increased GSIS in human islets. These results identify a potential role for BRS-3 in islet physiology, with agonism directly promoting GSIS. Thus, in addition to its potential role in the treatment of obesity, BRS-3 may also regulate blood glucose levels and have a role in the treatment of diabetes mellitus.
authors: Department of Diabetes and Obesity, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors: Yue
authors: Y
authors: Feng
authors: Xiao-Ming
authors: XM
authors: Guan
authors: Jing
authors: J
authors: Li
authors: Joseph M
authors: JM
authors: Metzger
authors: Yonghua
authors: Y
authors: Zhu
authors: Kirstine
authors: K
authors: Juhl
authors: Bei B
authors: BB
authors: Zhang
authors: Nancy A
authors: NA
authors: Thornberry
authors: Marc L
authors: ML
authors: Reitman
authors: Yun-Ping
authors: YP
authors: Zhou
mesh_terms: D000818:Animals; D004285:Dogs; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008253:Macaca mulatta; D051379:Mice; D051381:Rats; D018004:Receptors, Bombesin / Q000378:metabolism*
chemical_list: D007328:Insulin; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; D005947:Glucose