The Effect of a Subcutaneous Infusion of GLP-1, OXM, and PYY on Energy Intake and Expenditure in Obese Volunteers

Abstract

Background: Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment of obesity, although limited by availability and operative risk. The gut hormones Glucagon-like peptide-1 (GLP-1), Peptide YY (PYY), and Oxyntomodulin (OXM) are elevated postprandially after RYGB, which has been postulated to contribute to its metabolic benefits.

Objective: We hypothesized that infusion of the three gut hormones to achieve levels similar to those encountered postprandially in RYGB patients might be effective in suppressing appetite. The aim of this study was to investigate the effect of a continuous infusion of GLP-1, OXM, and PYY (GOP) on energy intake and expenditure in obese volunteers.

Methods: Obese volunteers were randomized to receive an infusion of GOP or placebo in a single-blinded, randomized, placebo-controlled crossover study for 10.5 hours a day. This was delivered subcutaneously using a pump device, allowing volunteers to remain ambulatory. Ad libitum food intake studies were performed during the infusion, and energy expenditure was measured using a ventilated hood calorimeter.

Results: Postprandial levels of GLP-1, OXM, and PYY seen post RYGB were successfully matched using 4 pmol/kg/min, 4 pmol/kg/min, and 0.4 pmol/kg/min, respectively. This dose led to a mean reduction of 32% in food intake. No significant effects on resting energy expenditure were observed.

Conclusion: This is, to our knowledge, the first time that an acute continuous subcutaneous infusion of GOP, replicating the postprandial levels observed after RYGB, is shown to be safe and effective in reducing food intake. This data suggests that triple hormone therapy might be a useful tool against obesity.

Figure 1.

Study protocol.

Figure 2.

Food intake on GOP vs 0.9% saline (n = 10). (a) Food intake at lunch, dinner, and lunch plus dinner as measured on the GOP infusion day, compared with the 0.9% saline infusion day. Lunch and dinner served at t = 4 and t =10 hours, respectively. Mean ± SEM plotted. Paired Student t test shows significant differences between saline and GOP arms for lunch, dinner, and total (lunch plus dinner) food intake. (b) Individual total food intake on GOP vs 0.9% saline infusion.

Figure 3.

Change in VASs between GOP (dashed line, triangle symbols) and 0.9% saline (solid line, square symbols) infusion. Mean ± SEM plotted. (a) “How sick do you feel?” score. (b) “How hungry do you feel?” score. (c) “How much can you eat?” score. (d) “How full do you feel?” score. No significant differences observed between the two infusions on two-way repeated-measures ANOVA with Bonferroni post hoc test.

Figure 4.

GLP-1, OXM, and PYY levels achieved following GOP and 0.9% saline infusion. (a) GLP-1 levels. Peak postprandial levels of GLP-1 in RYGB group matched by GOP infusion. (b) OXM levels. Peak postprandial levels of OXM in RYGB matched by GOP infusion. (c) Total PYY levels. Peak postprandial levels of PYY in RYGB matched by GOP infusion.

Figure 5.

The effects of GOP (dashed line, triangle symbols) and 0.9% saline infusion (solid line, square symbols) on glucose and insulin profile. (a) Glucose levels at 6 hours significantly higher on 0.9% saline infusion. (b) Insulin levels at 6 hours significantly higher on 0.9% saline infusion. Mean ± SEM plotted with two-way repeated-measures ANOVA with Bonferroni post hoc test: ***P < 0.001. (c and d) No significant difference observed between glucose and insulin AUCs over the first 4 hours. Paired Student t test applied to compare AUCs calculated for glucose and insulin over the first 4 hours of infusion (fasted state).