Objective: The hormone ghrelin both regulates and is regulated by food intake and blood glucose. Yet, the mechanisms restricting ghrelin release after meals or upon glucose delivery have remained elusive. Here, we tested whether meal and glucose-associated rises in plasma insulin act via ghrelin cell-expressed insulin receptors to suppress ghrelin release.

Methods: We generated ghrelin cell-selective insulin receptor-knock out (GIRKO) mice by crossing ghrelin-Cre mice with floxed-insulin receptor mice. We examined ghrelin release using hyperinsulinemic-hypoglycemic clamps, glucose tolerance tests (GTTs), a fast-refeed protocol, and gastric mucosal cell primary cultures.

Results: During clamps, plasma ghrelin fell in WT control groups (by 85%) but not in GIRKO mice, leading to a 29% lower glucose infusion rate in GIRKO mice. During GTTs, plasma ghrelin was suppressed in controls (by 42%) but not in GIRKO mice. During the refeed phase of a fast-refeed protocol, plasma ghrelin fell in controls (by 49%) but not in GIRKO mice. Also, insulin suppressed ghrelin release in isolated ghrelin cells of controls (by 19%) but not of GIRKO mice.

Conclusions: These data suggest that insulin, acting via ghrelin cell-expressed insulin receptors, is a key mediator of ghrelin release in response to meals, glucose administration, and insulin infusion. Further, suppressed ghrelin release resulting from direct insulin action on ghrelin cells restricts ghrelin’s capacity to protect against hypoglycemia during over-insulinization.

Disclosure

K. Shankar: None. S. Takemi: None. D. Gupta: None. B.K. Mani: None. S. Osborne-Lawrence: None. N. Metzger: None. E. Berglund: None. J.M. Zigman: Stock/Shareholder; Self; Medtronic.

Funding

National Institutes of Health (R01DK119341-01A1, R01DK103884 to J.M.Z.), (R01DK109408 to E.B.), (R01DK119341 to J.M.Z., E.B.); David and Teresa Disiere Foundation (to J.M.Z.); Diana and Richard C. Strauss Professorship in Biomedical Research; Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine; Kent and Jodi Foster Distinguished Chair in Endocrinology (to J.M.Z.); Uehara Memorial Foundation (to S.T.)

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