Assessing insulin sensitivity and postprandial triglyceridemic response phenotypes with a mixed macronutrient tolerance test

Authors: Newman, John; KRISHNAN, SRIDEVI - University Of California, Davis; BORKOWSKI, KAMIL - University Of California, Davis; ADAMS, SEAN - University Of California, Davis; Stephensen, Charles; Keim, Nancy

Submitted to: Frontiers in Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/25/2022
Publication Date: 5/11/2022
Citation: Newman, J.W., Krishnan, S., Borkowski, K., Adams, S.H., Stephensen, C.B., Keim, N.L. 2022. Assessing insulin sensitivity and postprandial triglyceridemic response phenotypes with a mixed macronutrient tolerance test. Frontiers in Nutrition. 9. Article 877696. https://doi.org/10.3389/fnut.2022.877696.
DOI: https://doi.org/10.3389/fnut.2022.877696

Interpretive Summary: The response of glucose, insulin and triglycerides after eating (i.e. postprandial changes) are important indicators of metabolic health. The use of meal challenge tests for the assessment of postprandial responses in carbohydrate and fat metabolism is gaining popularity in clinical nutrition research. However, challenge meal compositions and protocols remain variable. Here we validate a mixed macronutrient tolerance test (MMTT) comprised of ~60 g palm oil, ~60 g sucrose and ~30 g egg white protein for the parallel determination of insulin sensitivity and postprandial triglyceridemia in clinically healthy subjects. The MMTT was administered in a cohort of overweight to obese women (n =43) involved in an 8wk dietary intervention along with oral glucose tolerance tests (OGTTs) after 0, 2, and 8 wk of the dietary intervention. It was followed in another study of 340 men and women between 18 and 64 y of age, with BMI from 18-40 kg/m2. Blood was collected at 0, 0.5, 3, and 6 h after the MMTT and used to measure glucose, insulin, and clinical lipid panels. The insulin dependent glucose disposal after the MMTT was strongly correlated (r = 0.77, p <0.001) to the OGTT-dependent insulin sensitivity index. Analysis of the area under the triglyceride excursion curve provided cutoffs for mild to moderate hypertriglyceridemia, that matched stratification with a post-MMTT triglyceride concentration cutoff of >200 mg/dL. This postprandial assessment indicated an ~20% greater prevalence of hypertriglyceridemia relative to fasting measures. Analysis of the postprandial triglyceride kinetics showed that appearance and disappearance rates as a function of the triglyceride increase over baseline provided optimal subject stratification. Notably, ~2% of the population showed minimal triglyceride appearance by 6 h, while ~25% had increasing triglycerides through 6h. Ultimately, the described procedures using an MMTT prepared from commonly available food materials can substantially increase phenotypic information in clinical studies, while aiding in the identification of persons with insulin resistance and perturbations in daylong triglyceridemia, which are associated with increased cardiometabolic disease risk.

Technical Abstract: The use of meal challenge tests for the assessment of postprandial responses in carbohydrate and fat metabolism is gaining popularity in clinical nutrition research. However, challenge meal compositions and protocols remain variable. Here we validate a mixed macronutrient tolerance test (MMTT) comprised of ~60 g palm oil, ~60 g sucrose and ~30 g egg white protein for the parallel determination of insulin sensitivity and postprandial triglyceridemia in clinically healthy subjects. The MMTT was administered in two study populations. In one, a cohort of overweight to obese women (n =43) involved in an 8wk dietary intervention was administered oral glucose tolerance tests (OGTTs) and MMTTs within 2 d of each other after 0, 2, and 8 wk of the dietary intervention. In the other, 340 men and women between 18 and 64 y of age, with BMI from 18-40 kg/m2 completed the MMTT as part of a broad nutritional phenotyping effort. Postprandial blood collected at 0, 0.5, 3, and 6 h were used to measure glucose, insulin, and clinical lipid panels. The MMTT postprandial glucose to insulin dependent glucose disposal was evaluated by using the Matsuda Index algorithm and the 0 and 3h blood insulin and glucose measures. The resulting MMTT insulin sensitivity index (ISIMMTT) was strongly correlated (r = 0.77, p <0.001) to the OGTT-dependent 2hr composite Matsuda index (ISIComposite), being related by the following equation: Log (ISIComposite) = [0.8751 x Log(ISIMMTT)] – 0.2115. An area under the triglyceride excursion curve >11.15 mg/mL h 1calculated from the 0, 3 and 6 h blood draws established mild to moderate triglyceridemia, that matched stratification with a post-MMTT triglyceride concentration cutoff of >200 mg/dL. The postprandial assessment indicated an ~20% greater prevalence of hypertriglyceridemia relative to fasting measures. Analysis of the postprandial triglyceride kinetics showed that appearance and disappearance rates as a function of the triglyceride incremental area under the curve provided optimal subject stratification. Notably, ~2% of the population minimal triglyceride appearance by 6 h, while ~25% had increasing triglycerides through 6h. Ultimately, using three blood draws the MMTT allowed for the simultaneous determination of insulin sensitivity and postprandial triglycerideimia in clinically healthy individuals.