Background and Significance: The peptide hormone ghrelin drives hunger and feeding behavior,
making it a focus of obesity research. Released mainly by the stomach and proximal small
intestine, ghrelin peaks prior to meals, potentially priming the gut for anticipated
nutrients. After eating, ghrelin abruptly declines, with levels varying 2- to 3-fold between
the fasted and fed states. Interestingly, in obesity and type 2 diabetes (T2D), this pattern
is disrupted. Individuals with these disorders have chronically suppressed ghrelin levels and
little variation before and after meals.
Although ghrelin's preprandial rise and postprandial fall is a well-established phenomenon,
its role in regulating glucose metabolism is unclear. In mice, increasing preprandial ghrelin
levels improves glucose tolerance through enhanced glucagon-like peptide-1 (GLP-1) secretion.
Ghrelin also stimulates GLP-1 secretion from mouse and human intestinal L-cells in vitro.
These findings suggest enhanced postprandial GLP-1 as a novel role for the preprandial
ghrelin surge. A ghrelin-incretin enteroendocrine axis could also explain the poor
postprandial GLP-1 secretion and glucose tolerance in subjects with T2D, given their
The investigators' preliminary data demonstrate that in humans, increasing circulating
ghrelin to a supraphysiologic range worsened glucose tolerance, despite increased GLP-1
secretion. The discrepancy between these findings and the ones from rodents could be due to
difference in study design and/or species. For example, the investigators' study used a
continuous ghrelin infusion, which resulted in elevated levels of ghrelin pre- and
postprandially. Elevated postprandial ghrelin likely mitigated the positive effects of
increased GLP-1 secretion by raising levels of glucagon and other counter-regulatory
This study seeks to delineate the interactions between ghrelin and GLP-1 in the regulation of
glucose tolerance, beta-cell function, and insulin sensitivity. The investigators hypothesize
that increased preprandial ghrelin will enhance GLP-1 secretion and consequently improve
glucose tolerance in healthy subjects and those with T2D. Confirmation of these hypotheses
would advance the investigators understanding of the control of glucose homeostasis and have
important clinical and therapeutic implications. Modulating ghrelin levels may provide a
novel therapeutic strategy to improve glucose tolerance in individuals with T2D, which
affects an estimated 350 million people worldwide.