title: Determining pancreatic β-cell compensation for changing insulin sensitivity using an oral glucose tolerance test.
abstract: Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index (DI(OGTT)) that is a measure of pancreatic β-cell insulin secretory compensation for changing insulin sensitivity. We conducted an observational study of n = 187 subjects, representing the entire glucose tolerance continuum from normal glucose tolerance to type 2 diabetes. OGTT-derived insulin sensitivity (S(I OGTT)) was calculated using a novel multiple-regression model derived from insulin sensitivity measured by hyperinsulinemic euglycemic clamp as the independent variable. We also validated the novel S(I OGTT) in n = 40 subjects from an independent data set. Plasma C-peptide responses during OGTT were used to determine oral glucose-stimulated insulin secretion (GSIS(OGTT)), and DI(OGTT) was calculated as the product of S(I OGTT) and GSIS(OGTT). Our novel S(I OGTT) showed high agreement with clamp-derived insulin sensitivity (typical error = +3.6%; r = 0.69, P < 0.0001) and that insulin sensitivity was lowest in subjects with impaired glucose tolerance and type 2 diabetes. GSIS(OGTT) demonstrated a significant inverse relationship with S(I OGTT). GSIS(OGTT) was lowest in normal glucose-tolerant subjects and greatest in those with impaired glucose tolerance. DI(OGTT) was sequentially lower with advancing glucose intolerance. We hereby derive and validate a novel OGTT-derived measurement of insulin sensitivity across the entire glucose tolerance continuum and demonstrate that β-cell compensation for changing insulin sensitivity can be readily calculated from clinical variables collected during OGTT.
authors.affiliation: Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark; Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark; thomas.solomon@sund.ku.dk.
authors.forename: Thomas P J
authors.initials: TP
authors.lastname: Solomon
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Steven K
authors.initials: SK
authors.lastname: Malin
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark;
authors.forename: Kristian
authors.initials: K
authors.lastname: Karstoft
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark;
authors.forename: Sine H
authors.initials: SH
authors.lastname: Knudsen
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Haus
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Laye
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark;
authors.forename: Maria
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark;
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Metabolic Translational Research Center, Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: John P
authors.initials: JP
authors.lastname: Kirwan
mesh_terms: D052636:Allostasis; D001786:Blood Glucose / Q000032:analysis; D015331:Cohort Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009820:Ohio; D011236:Prediabetic State / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin
keywords: disposition index; hyperinsulinemic euglycemic clamp; insulin resistance; insulin secretion; insulin sensitivity; insulin sensitivity index; obesity; oral glucose tolerance; type 2 diabetes; β-cell dysfunction; β-cell function