The disposition index does not reflect β-cell function in IGT subjects treated with pioglitazone

Ralph A. Defronzo, Devjit Tripathy, Muhammad Abdulghani, Nicolas Musi, Amalia Gastaldelli

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Aims and Hypothesis: The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of (3-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide(ACP) (instead of Δ plasma insulin) was plotted against insulin sensitivity.

Methods: A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years.

Results: Pioglitazone reduced IGT conversion to diabetes by 72% (P<.0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism where in the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia.

Conclusions: These results demonstrate the validity of the disposition index when relating the plasma insulin responseto insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the plasma insulin response.

Original languageEnglish
Pages (from-to)3774-3781
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number10
DOIs
Publication statusPublished - 1 Oct 2014

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