Mechanisms Underlying the Pathogenesis of Isolated Impaired Glucose Tolerance in Humans.
Prediabetes is a heterogeneous disorder classified on the basis of fasting glucose concentrations and 2-hour glucose tolerance.



We sought to determine the relative contributions of insulin secretion and action to the pathogenesis of isolated impaired glucose tolerance (IGT).



The study consisted of an oral glucose tolerance test and a euglycemic clamp performed in two cohorts matched for anthropometric characteristics and fasting glucose but discordant for glucose tolerance.



An inpatient clinical research unit at an academic medical center.



Twenty-five subjects who had normal fasting glucose (NFG) and normal glucose tolerance (NGT) and 19 NFG/IGT subjects participated in this study.



Subjects underwent a seven-sample oral glucose tolerance test and a 4-hour euglycemic, hyperinsulinemic clamp on separate occasions. Glucose turnover during the clamp was measured using tracers, and endogenous hormone secretion was inhibited by somatostatin.



We sought to determine whether hepatic glucose metabolism, specifically the contribution of gluconeogenesis to endogenous glucose production, differed between subjects with NFG/NGT and those with NFG/IGT.



Endogenous glucose production did not differ between groups before or during the clamp. Insulin-stimulated glucose disappearance was lower in NFG/IGT (24.6 ± 2.2 vs 35.0 ± 3.6 μmol/kg/min; P = .03). The disposition index was decreased in NFG/IGT (681 ± 102 vs 2231 ± 413 × 10-14dL/kg/min2per pmol/L; P < .001).



We conclude that innate defects in the regulation of glycogenolysis and gluconeogenesis do not contribute to NFG/IGT. However, insulin-stimulated glucose disposal is impaired, exacerbating defects in β-cell function.
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Ron T
RT
Varghese
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Chiara
C
Dalla Man
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Anu
A
Sharma
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Ivan
I
Viegas
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Cristina
C
Barosa
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Catia
C
Marques
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Meera
M
Shah
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
John M
JM
Miles
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Robert A
RA
Rizza
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
John G
JG
Jones
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Claudio
C
Cobelli
Division of Endocrinology, Diabetes, and Metabolism (R.T.V., A.S., M.S., J.M.M., R.A.R., A.V.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Department of Information Engineering (C.D.M., C.C.), Universitá di Padova, 35122 Padova, Italy; Center for Neurosciences and Cell Biology (I.V., C.B., C.M., J.G.J.), University of Coimbra, 3000-370 Coimbra, Portugal; and APDP-Portuguese Diabetes Association (J.G.J.), 1250-203 Lisbon, Portugal.
Adrian
A
Vella
D001786:Blood Glucose / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D008875:Middle Aged
D001786:Blood Glucose