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β-Cell Dysfunction in Subjects With Impaired Glucose Tolerance and Early Type 2 Diabetes

Comparison of Surrogate Markers With First-Phase Insulin Secretion From an Intravenous Glucose Tolerance Test

¹ Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
² MSD Austria, Vienna, Austria
³ Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada

Corresponding author: Steven M. Haffner, MD, University of Texas Health Science Center, Department of Medicine (#7873), 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: haffner{at}uthscsa.edu

Abbreviations: AIR, acute insulin response; DM, newly diagnosed diabetes by both fasting and 2-h hyperglycemia and patients with established type 2 diabetes on diet only; DM2h, newly diagnosed type 2 diabetes based on 2-h oral glucose tolerance test levels; DMf, newly diagnosed type 2 diabetes based on fasting glucose levels; HOMA, homeostasis model assessment; HOMA-B, HOMA of β-cell function; HOMA-IS, HOMA of insulin sensitivity; IGT, impaired glucose tolerance; IRAS, Insulin Resistance Atherosclerosis Study; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; S_I, insulin sensitivity index; UKPDS, UK Prospective Diabetes Study

OBJECTIVE—Methods to assess β-cell function in clinical studies are limited. The aim of the current study was to compare a direct measure of insulin secretion with fasting surrogate markers in relation to glucose tolerance status.

RESEARCH DESIGN AND METHODS—In 1,380 individuals from the Insulin Resistance Atherosclerosis Study, β-cell function was assessed using a frequently sampled intravenous glucose tolerance test (first-phase insulin secretion; acute insulin response [AIR]), homeostasis model assessment of β-cell function (HOMA-B), proinsulin levels, and the proinsulin-to-insulin ratio. β-Cell function was cross-sectionally analyzed by glucose tolerance categories (normal glucose tolerance [NGT], n = 712; impaired glucose tolerance [IGT], n = 353; newly diagnosed diabetes by 2-h glucose from an oral glucose tolerance test [OGTT] [DM2h], n = 80; newly diagnosed diabetes by fasting glucose [DMf], n = 135; or newly diagnosed diabetes by fasting and 2-h glucose and established diabetes on diet/exercise only [DM], n = 100).

RESULTS—In Spearman correlation analyses, proinsulin and the proinsulin-to-insulin ratio were only modestly inversely related to AIR (r values from –0.02 to –0.27), and AIR was strongly related to HOMA-B (r values 0.56 and 0.58). HOMA-B markedly underestimated the magnitude of the β-cell defect across declining glucose tolerance, especially for IGT and new DM by OGTT compared with AIR. Analyses adjusting for insulin sensitivity showed that β-cell function was compromised in IGT, DM2h, DMf, and DM, relative to NGT, by 13, 12, 59, and 62% (HOMA-B) and by as much as 40, 60, 80, and 75%, using AIR.

CONCLUSIONS—Subjects with IGT and early-stage, asymptomatic type 2 diabetic patients have more pronounced β-cell defects than previously estimated from epidemiological studies using homeostasis model assessment.

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