Introduction: The novel hybrid GLP-1/GIP receptor agonist concept, with efficacy surpassing GLP-1 agonist medication, is promising for treatment of obesity. Nevertheless, its mechanism of action is not fully understood. Understanding gut hormonal control of motility and hunger/satiety is crucial for development of obesity therapies.

Methods: Healthy (n=41) and obese (n=28) fasted subjects consumed a mixed meal and SmartPill motility capsule. Active GLP-1, glucose-GIP, motilin, and active acyl-ghrelin were measured by multiplex ELISA up to 240 minutes postprandially. Data in which SmartPill recording was significantly interrupted was excluded. MotiliGI 3.0.2 and GIMS software were used to analyze motility data. Logistic regression, unpaired t-test, and correlations were performed in GraphPad Prism.

Results: Gastric emptying time was shorter in the obese vs. healthy (p<0.01; Fig. 1). Higher gastric motility index was associated with gastric emptying in healthy and obese (both p<0.0001).
Post-prandially, GIP (p<0.0001) and GLP-1 (p<0.0001) were lower in the obese. GIP negatively correlated with gastric motility index (p<0.01) in the healthy, but not the obese. Lower GIP and GLP-1 correlated with gastric emptying in both healthy (p<0.0001, p<0.05) and obese (p<0.0001, p<0.01) (Fig. 2).

Before gastric emptying, motility index including hunger contractions sharply increased in the obese (p<0.001) compared with healthy (p=0.313). Preceding emptying, the increased motility index correlated with high ghrelin in both healthy (p<0.0001) and obese (p<0.05), and with motilin in healthy (p<0.0001) but not the obese. Emptying occurred with high ghrelin (p<0.05) and motilin (p<0.05) along with low GIP (p<0.0001) and GLP-1 (p<0.05) in the healthy; in the obese emptying occurred at high ghrelin (p<0.05; Fig. 2) but not motilin, along with low GIP (p<0.0001 and GLP-1 (p<0.01).

In the healthy, ghrelin but not motilin, positively correlated with hunger (p<0.01) and negatively with satiety (p<0.0001), whereas GIP and GLP-1 correlated negatively with hunger (p<0.0001, p<0.05) and positively with satiety (both p<0.0001). In the obese, ghrelin and motilin did not correlate with hunger or satiety, while GLP-1 and GIP negatively correlated with hunger (both p<0.05) and positively with satiety (both p<0.05).

Conclusion: GIP may play a role in inhibiting gastric motility thereby suppressing hunger sensations and promoting satiety. Ghrelin and motilin correlated with gastric motility in the healthy but had an inconsistent pattern in the obese where ghrelin but not motilin correlated with motility index. Hastened gastric emptying in the obese is explained by an earlier rise in ghrelin prior to gastric emptying and less suppression of motility due to low GLP-1 and GIP. The lack of association between ghrelin and hunger in the obese may be a consequence of ghrelin resistance.

Gastric emptying time of SmartPill in healthy and obese.

Plasma profiles of gut hormones glucose-dependent insulinotropic peptide (GIP) and ghrelin after ingestion of a meal with SmartPill.

Per Hellström

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