15. Acyl Ghrelin Is a “Negative Incretin Hormone” Responsible for Improved Acute Glucose Responses following Roux-en-Y Gastric Bypass (RYGB) (161-OR)

Abstract

Ghrelin stimulates appetite, promotes adiposity, and worsens glucose metabolism. Ghrelin levels vary according to both chronic and acute nutritional status, but the regulation of ghrelin secretion is not well understood. The primary site of production of ghrelin is the stomach; however, evidence suggests that there is post-gastric regulation of ghrelin secretion. A reduction in fasting and postprandial ghrelin levels is implicated in the efficacy of RYGB to produce metabolic improvements in the immediate postoperative period. In this study, we determined if the enhanced postprandial ghrelin suppression observed after RYGB could be attributed to more rapid intestinal nutrient stimulation. We studied 9, Class III obese, non-diabetic but insulin resistant subjects on two occasions, where we simulated pre- and post-RYGB nutrient delivery by administering a 50 g glucose load either to the stomach or to proximal jejunum, in random order. The next day, plasma glucose excursions for each was replicated with an isoglycemic IV glucose clamp. Gastric administration of glucose produced a ~35% suppression of ghrelin, which was equally matched by the isoglycemic clamp. Jejunal administration of glucose caused a ~65% suppression of plasma ghrelin, while in the concurrent isoglycemic clamp ghrelin was only suppressed ~35%, matching the suppression observed with gastric glucose. These data demonstrate that acyl ghrelin suppression with gastric glucose delivery is primarily due to the elevated post-absorptive glucose levels. However, the suppression seen with administration of a glucose load directly to the proximal jejunum is due to additional suppression of acyl ghrelin that is independent of circulating glucose levels. In conclusion, it appears that the postprandial ghrelin suppression observed after RYGB could be attributed to a ‘negative incretin response’ resulting from rapid intestinal nutrient stimulation.