Ghrelin directly stimulates glucagon secretion from pancreatic alpha-cells

CHUANG J-C; SAKATA I; KOHNO D.; PERELLÓ M; OSBORNE-LAWRENCE S; REPA JR; ZIGMAN JM

MOLECULAR ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2011 vol. 25 p. 1600 - 1611

0888-8809

Previous work has demonstrated that the peptide hormone ghrelin raises blood glucose. Such hasbeen attributed to ghrelin’s ability to enhance GH secretion, restrict insulin release, and/or reduceinsulin sensitivity. Ghrelin’s reported effects on glucagon have been inconsistent. Here, bothanimal- and cell-based systems were used to determine the role of glucagon in mediating ghrelin’seffects on blood glucose. The tissue and cell distribution of ghrelin receptors (GHSR) was evaluated by quantitative PCR and histochemistry. Plasma glucagon levels were determined following acute acyl-ghrelin injections and in pharmacological and/or transgenic mouse models of ghrelin overexpression and GHSR deletion. Isolated mouse islets and the alpha-cell lines TC1 and InR1G9 were used to evaluate ghrelin’s effects on glucagon secretion and the role of calcium and ERK in this activity. GHSR mRNA was abundantly expressed in mouse islets and colocalized with glucagon in alpha-cells. Elevation of acyl-ghrelin acutely (after sc administration, such that physiologically relevant plasma ghrelin levels were achieved) and chronically (by slow-releasing osmotic pumps and as observed in transgenic mice harboring ghrelinomas) led to higher plasma glucagon and increased blood glucose. Conversely, genetic GHSR deletion was associated with lower plasma glucagon and reduced fasting blood glucose. Acyl-ghrelin increased glucagon secretion in a dosedependent manner from mouse islets and alpha-cell lines, in a manner requiring elevation of intracellular calcium and phosphorylation of ERK. Our study shows that ghrelin’s regulation of blood glucose involves direct stimulation of glucagon secretion from alpha-cells and introduces the ghrelin-glucagon axis as an important mechanism controlling glycemia under fastingconditions.