Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of β-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series

Abstract

Objective: Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states.

Research design and methods: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT).

Results: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations.

Conclusions: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

Trial registration: ClinicalTrials.gov NCT01454973 NCT01663207 NCT01663207.

Figure 1

Mean ± SEM glucose, insulin, and C-peptide concentration time course profiles by stimulation test and glucose tolerance group. Squares, NGT; circles, PDM; triangles, T2DM.

Figure 2

Indices of BCF. Model predicted geometric means (95% CI) for AST and MMTT and arithmetic means (95% CI) for FSIGT. Note: lower CI suppressed for graphical purposes for FSIGT AIRg and DI in T2DM. GT, glucose tolerance. *P < 0.05, **P < 0.01, ***P < 0.001.