Interaction of GLP-1 and Ghrelin on Glucose Tolerance in Healthy Humans

Abstract

Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of 1) saline, 2) ghrelin, 3) the GLP-1 receptor antagonist exendin(9-39) (Ex9), or 4) combined ghrelin and Ex9. Similar to previous studies, infusion of ghrelin caused glucose intolerance, whereas Ex9 had a minimal effect. However, combined ghrelin and Ex9 resulted in greater postprandial glycemia than either alone, and this effect was associated with impaired β-cell function and decreased glucose clearance. These findings suggest that in the fed state, stimulation of GLP-1 mitigates some of the effect of ghrelin on glucose tolerance. This novel interaction between gastrointestinal hormones suggests a system that balances insulin secretion and glucose disposal in the fed and fasting states.

Trial registration: ClinicalTrials.gov NCT01729299.

Figure 1

Effects of ghrelin, Ex9, and combined ghrelin and Ex9 treatment on plasma glucose (A and B), insulin (C and D), ISR (E), and insulin corrected for glucose (F) during the 240-min MTT. Statistical comparisons were made between saline and ghrelin treatments and ghrelin and combined treatments. *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 2

Effects of ghrelin, Ex9, and combined ghrelin and Ex9 treatments on slope (A), K_d (B), insulin sensitivity (C and D), DI (E), and meal insulin clearance (F). AG, acyl ghrelin. With the exception of slope and DI, statistical comparisons were made between saline and ghrelin treatments and ghrelin and combined treatments. For slope and disposition index, an additional analysis was performed comparing saline and combined treatment in A and E. *P < 0.05; **P < 0.01; ****P < 0.0001.

Figure 3

Effects of ghrelin, Ex9, and combined ghrelin and Ex9 treatments on total R_a (A and B), exogenous R_a meal (C and D), and EGP (E and F) during the MTT. AG, acyl ghrelin. With the exception of EGP, statistical comparisons were made between saline and ghrelin treatments and ghrelin and combined treatments. For EGP (F) we performed an additional analysis comparing saline and combined treatment. *P < 0.05.

Figure 4

Effects of ghrelin, Ex9, and combined ghrelin and Ex9 treatments on R_d (A and B) and clearance (C and D) during the MTT. AG, acyl ghrelin. Statistical comparisons were made between saline and ghrelin treatments and ghrelin and combined treatments. *P < 0.05.