Ghrelin and insulin secretion in humans: not a tale of two hormones?

Abstract

Failure of pancreatic β-cells to secrete adequate amounts of insulin is a fundamental defect in type 1 and type 2 diabetes, and the search for innovative strategies to improve β-cell mass and function is a major priority in diabetes research. Ghrelin, a 28-amino acid peptide hormone predominantly secreted by the stomach, was identified as ligand of the growth hormone secretagogue receptor type-1a (GHSR-1a) (1). The Ser3-octanoylated ghrelin form (acylated ghrelin [AG]) also was soon recognized to act as a hypothalamic orexigenic signal (2) and to modulate tissue pathways and functions as a potential contributor to metabolic adaptation to low nutrient availability. Experimental AG administration commonly causes weight gain and hyperglycemia by enhancing food intake, fat deposition, and hepatic gluconeogenesis (3–5). A more comprehensive understanding of the metabolic impact of ghrelin has been recently allowed by the increasing appreciation of the independent, and generally more favorable, effects of its unacylated form (UAG), which does not increase food intake or circulating glucose in vivo (3,4,6). Although no specific UAG receptor has been yet identified, UAG coadministration may counteract the glucogenic effects of AG as well as AG-induced hyperglycemia (3,4,7), and positive or negative associations have been respectively reported in humans between AG or UAG and markers of whole-body insulin resistance (8). Modulating the AG–UAG balance by inhibiting the acylating enzyme ghrelin O-acyltransferase (9) or by …