Abstract
Orexigenic hormone ghrelin and anorexic hormone obestatin are encoded by the same preproghrelin gene. While it is known that ghrelin inhibits glucose-stimulated insulin secretion (GSIS), the effect of obestatin on GSIS is unclear. Ghrelin’s effect is mediated by its receptor Growth Hormone Secretagogue Receptor (GHS-R), but the physiologically relevant receptor of obestatin remains debatable. Here we have investigated the effect of obestatin on GSIS in vitro, in vivo and ex vivo, and tested whether obestatin regulates insulin secretion through GHS-R. We found that under hyperglycemic condition, obestatin augments GSIS in rat insulinoma cells (INS-1) and in pancreatic islets from ghrelin−/− mice. Surprisingly, obestatin-induced GSIS was absent in β-cells in which GHS-R was suppressed. Obestatin-induced insulin secretion was abolished in the circulation of Ghsr−/− mice, and in pancreatic islets isolated from Ghsr−/− mice. We also found that obestatin-induced GSIS was attenuated in islets isolated from β-cell-specific Ghsr knockout MIP-Cre/ERT;Ghsrf/f mice. Our data collectively demonstrate that obestatin is a potent insulin secretagogue under hyperglycemic condition, and obestatin’s effect on insulin secretion is mediated by GHS-R in pancreatic β-cells. Our findings reveal an intriguing insight that obestatin and ghrelin have opposing effects on insulin secretion, and both are mediated through ghrelin receptor GHS-R.
Highlights
Type 2 diabetes mellitus (T2DM) is a complex multifactorial disease that is characterized by insulin resistance, loss of pancreatic β-cell mass, and diminished β-cell function
When INS-1 cells were treated with different concentrations of obestatin, the levels of insulin secretion were similar to controls at 3.3 mM low glucose condition
Our results collectively show that exogenous obestatin treatment augments glucose-stimulated insulin secretion in β-cells and isolated pancreatic islets
Summary
Type 2 diabetes mellitus (T2DM) is a complex multifactorial disease that is characterized by insulin resistance, loss of pancreatic β-cell mass, and diminished β-cell function. To study the effects of obestatin on insulin secretion, we utilized rat insulinoma INS-1 cells, as well as mouse pancreatic islets from ghrelin−/− mice lacking both ghrelin and obestatin. We demonstrated that obestatin augments insulin secretion in pancreatic β-cells under hyperglycemic condition, and obestatin-induced stimulatory effect on insulin is mediated through GHS-R.
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