How Ghrelin Suppresses Insulin Secretion
In the intricate symphony of our body's metabolic orchestra, ghrelin has long been celebrated as the "hunger hormone"—a powerful chemical messenger that signals our brain to eat.
Discovered in 1999, this gastric-derived peptide quickly gained fame for its ability to stimulate appetite and growth hormone release. But beneath this well-known persona lies a more mysterious identity: ghrelin as a potent regulator of insulin secretion.
Ghrelin is primarily produced by specialized cells in the lining of the stomach, though smaller amounts are also synthesized in other tissues including the pancreas itself 5 .
This 28-amino-acid peptide circulates in our bloodstream, with levels that rhythmically rise before meals and fall after eating, creating a chemical timer for our hunger patterns .
What makes ghrelin biologically active is a unique modification—the addition of an octanoyl group to one of its serine residues—a process facilitated by a specific enzyme called ghrelin O-acyltransferase (GOAT) 5 .
Ghrelin levels throughout the day
The research team recruited 16 healthy men and women with normal body weight and insulin sensitivity. In a carefully designed crossover study, each participant underwent three separate testing sessions:
-45 to 0 minutes: Begin ghrelin or saline infusion
0 minutes: Intravenous glucose bolus administration
0-180 minutes: Frequent blood sampling (29 samples total)
20 minutes: Insulin infusion (0.025 U/kg over 5 minutes)
| Parameter | Saline Control | Low-Dose Ghrelin | High-Dose Ghrelin |
|---|---|---|---|
| Acute Insulin Response (AIRg) | 520 ± 110 pM·min | 384 ± 75 pM·min | 354 ± 65 pM·min |
| Insulin Sensitivity (SI) | Unaffected | Unaffected | Unaffected |
| Disposition Index | 3339 ± 705 | 2238 ± 421 | 2067 ± 396 |
Ghrelin binds to GHSR receptor
Activates Gαi protein
Reduces cAMP production
Inhibits insulin secretion
Growth hormone secretagogue receptor that ghrelin binds to on pancreatic β-cells 5 .
Cyclic AMP is a crucial intracellular signaling molecule that normally amplifies insulin secretion 5 .
| Reagent/Solution | Function |
|---|---|
| Synthetic acylated ghrelin | Bioactive form used in experimental infusions |
| GHSR antagonists | Block ghrelin receptors to study function |
| LEAP2 | Endogenous antagonist used in regulation studies |
| GOAT inhibitors | Experimental tools to block ghrelin activation |
No hormone operates in isolation, and ghrelin is no exception. In 2018, researchers identified liver-enriched antimicrobial peptide 2 (LEAP2) as ghrelin's endogenous counterpart—an endogenous antagonist that competes for the same receptor (GHSR) and opposes ghrelin's actions 5 .
LEAP2 levels rise after eating and fall during fasting, creating a mirror image of ghrelin's secretion pattern 5 .
Elevated in obese individuals
Typically lower in obese individuals
LEAP2 administration improves glucose tolerance 5
The story of ghrelin and insulin secretion illustrates the beautiful complexity of our endocrine system. What began as a simple narrative about a hunger hormone has evolved into a sophisticated understanding of a dual-function regulator that coordinates feeding behavior with nutrient handling.
The experimental evidence clearly demonstrates that physiologically relevant ghrelin concentrations suppress insulin secretion in humans, likely representing an adaptive mechanism to prevent hypoglycemia during fasting 4 .
The clinical relevance of this phenomenon is still being unraveled, but current evidence suggests that modulating the ghrelin system holds promise for metabolic disease therapy. The discovery of LEAP2 as ghrelin's endogenous counterpart adds both complexity and opportunity to this landscape.
As research continues to decipher the nuanced language of ghrelin signaling, we move closer to harnessing this knowledge for therapeutic benefit—potentially offering new hope for those struggling with metabolic disorders.