Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans

Abstract

Aims: Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB).

Materials and methods: We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg^-1 min^-1 ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp.

Results: Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion.

Conclusions: These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.

Keywords: bariatric surgery; ghrelin; glucose metabolism; insulin resistance.

Figure 1. Acyl (A,B) and total (C,D) ghrelin levels during the basal (A,C) and insulin (B,D) periods of the hyperinsulinemic-euglycemic clamp procedure with saline or ghrelin infusion

Data are expressed are the mean ± SEM for n=9 per group. **P<0.01, ***P<0.001, and ****P ≤ 0.0001 for Lean vs. Obese and Obese/Pre-RYGB vs. Post-RYGB.

Figure 2. Effect of ghrelin infusion on growth hormone (GH) and pancreatic polypeptide (PP) secretion

A–F: Time courses for GH (A–C) and PP (D–F) responses to ghrelin and saline infusion over 150 minutes in Lean (A,D), Obese Pre-RYGB (B,E), and Post-RYGB (C,F) subjects. Data are mean ± SEM for 7–9 subjects per time point. G,H: Area under the curves for GH (G) and PP (H) responses to saline and ghrelin infusions for panels A-F. Data are mean ± SEM for nine lean subjects and nine subjects before and after RYGB. ***P < 0.001 and ****P ≤ 0.0001 for Saline vs. Ghrelin; ^#P <0.05 and ^###P < 0.001 for group × treatment or time × treatment interactions.

Figure 3. Liver and muscle insulin sensitivity in response to ghrelin infusion

A: HISI, Hepatic insulin sensitivity index. B: M/I, glucose infusion rate/plasma insulin concentrations during hyperinsulinemic euglycemia as a measure of peripheral (mostly muscle) insulin sensitivity. Data are mean ± SEM for nine lean subjects and nine subjects before and after RYGB. **P<0.01 and ***P<0.001 for Saline vs. Ghrelin. #P < 0.05 for group × treatment interaction.