title: 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: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Sudha S
authors.initials: SS
authors.lastname: Shankar
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Adrian
authors.initials: A
authors.lastname: Vella
authors.affiliation: R-Squared Solutions, Skillman, NJ.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Raymond
authors.affiliation: Kelly Government Solutions for National Institute of Diabetes and Digestive and Kidney Diseases, Rockville, MD.
authors.forename: Myrlene A
authors.initials: MA
authors.lastname: Staten
authors.affiliation: Pfizer, Cambridge, MA, and Groton, CT.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Calle
authors.affiliation: Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, CA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.affiliation: Takeda Development Center Americas, Deerfield, IL.
authors.forename: Charlie
authors.initials: C
authors.lastname: Cao
authors.affiliation: Pfizer, Cambridge, MA, and Groton, CT.
authors.forename: Danny
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla Man
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Mark
authors.initials: M
authors.lastname: Deeg
authors.affiliation: Pfizer, Cambridge, MA, and Groton, CT.
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Dong
authors.affiliation: Pfizer, Cambridge, MA, and Groton, CT.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Janssen Research & Development, San Diego, CA.
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, WA Division of Endocrinology, Departments of Medicine and Pharmacology, University of Washington, Seattle, WA.
authors.forename: R Paul
authors.initials: RP
authors.lastname: Robertson
authors.affiliation: Sanofi, Paris, France.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ruetten
authors.affiliation: University of Pennsylvania, Philadelphia, PA.
authors.forename: Darko
authors.initials: D
authors.lastname: Stefanovski
authors.affiliation: Foundation for the National Institutes of Health, Bethesda, MD.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Vassileva
authors.affiliation: Joslin Diabetes Center, Boston, MA.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.affiliation: ROI Biopharma Consulting, East Lyme, CT dfryburg@roibiopharma.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Fryburg
mesh_terms: D000328:Adult; D001120:Arginine; D001786:Blood Glucose / Q000378:metabolism*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D005947:Glucose; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D062407:Meals; D008875:Middle Aged; D009316:National Institutes of Health (U.S.); D011236:Prediabetic State / Q000175:diagnosis / Q000378:metabolism*; D012015:Reference Standards; D015203:Reproducibility of Results; D014481:United States
chemical_list: D001786:Blood Glucose; D007328:Insulin; D001120:Arginine; D005947:Glucose