Data suggest that the temporal sequence of carbohydrate ingestion during a meal has a significant impact on postprandial glucose (1–3), insulin, and glucagon-like peptide 1 (GLP-1) excursions (4) in type 2 diabetes, while the effects on ghrelin suppression and satiety have not been reported.
The study design and methods have previously been described in detail (4). Briefly, using a crossover design, 16 subjects with overweight/obesity and metformin-treated type 2 diabetes were assigned to consume the same meal on 3 days in random order:
Carbohydrate-first meal: carbohydrate (bread and orange juice), followed 10 min later by protein (chicken) and vegetables
Carbohydrate-last meal: protein and vegetables, followed 10 min later by carbohydrate
Sandwich: all meal components together, each half consumed over 10 min with a 10-min interval in between
Blood was sampled for glucose, insulin, active GLP-1, and total ghrelin measurements at baseline (just before meal ingestion) and at 30-min intervals up to 180 min. Participants rated their hunger and fullness levels using a visual analog scale (VAS) at the same time points.
Baseline glucose, insulin, GLP-1, and ghrelin concentrations, as well as hunger and satiety scores, were similar in the three meal conditions. At 180 min, ghrelin levels remained suppressed following the carbohydrate-last meal order, while the carbohydrate-first meal led to a rebound in ghrelin to preprandial levels (percent ghrelin change from baseline to 180 min −11.45 ± 3.86% vs. 4.13 ± 4.38%; P = 0.003) (Fig. 1). Decremental areas under the curve for 0–180 min were similar in the three meal conditions. There was an inverse correlation between percent change in ghrelin and percent change in glucose from baseline when assessing all participants in the three meal conditions at the evaluated time points (r = −0.204; P < 0.001). We did not observe a significant effect of food order on subjective VAS appetite measures.
We have previously demonstrated that the carbohydrate-last meal pattern reduces postprandial glucose excursions compared with other meal patterns. Controlling for carbohydrate amount, this meal pattern stimulates lower insulin and higher GLP-1 response compared with the carbohydrate-first pattern (4). Taken together with our new findings on ghrelin suppression, this suggests that macronutrient order during a meal modifies the pattern of postprandial insulin and gut hormone secretion that could potentially impact satiety and weight regulation. However, similar to observations in previous studies that have investigated gut hormone excursions to isocaloric meal interventions (5,6), these disparate hormonal responses did not translate into any significant differences in hunger/satiety scores reported by participants in the three meal conditions. This result may reflect both the subjective nature of the VAS tool and the complexity of appetite regulation; ghrelin is the only known orexigenic peptide, whereas GLP-1 is one of several anorexigenic signaling gut hormones. Further study with an extended observation period, assessment of other gut hormones using meals with different macronutrient composition, and more objective measures of satiety is needed.
In conclusion, to our knowledge, this is the first study to demonstrate that manipulation of macronutrient order can impact gut hormone excursions. Its clinical implications for satiety and weight management require further study.
Acknowledgments. The authors acknowledge the support and contribution of Samir H. Touhamy and Jeselin Andono (Institute of Human Nutrition, Columbia University, New York, NY) toward subject recruitment and conduct of study procedures, Dr. David S. Ludwig (Boston Children’s Hospital, Boston, MA) for study design, and Dr. Ana Emiliano (Rockefeller University, New York, NY) for her critical review of the manuscript. The study was partially supported by grant UL1 TR000457-06 to the Clinical and Translational Science Center at Weill Cornell Medicine.
Funding. Funding for this study was provided by the Louis and Rachel Rudin Foundation and the Diane and Darryl Mallah Family Foundation.
Duality of Interest. L.J.A. reports receiving royalties for books on nutrition and obesity. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. A.P.S. and L.J.A. conceived and designed the study. A.P.S. drafted the manuscript. A.P.S., W.T., and A.C. conducted the study procedures and acquired the data. E.M. analyzed the data. A.P.S., L.I.I., R.B.K., K.H.S., and L.J.A. interpreted the data. All authors reviewed and edited the manuscript. A.P.S. and L.J.A. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this work were presented as a late-breaking abstract at the Obesity Society’s Annual Scientific Meeting, Obesity Week, Washington, DC, 29 October–2 November 2017.