Dataset Information

Longitudinal decline of ?-cell function: comparison of a direct method vs a fasting surrogate measure: the Insulin Resistance Atherosclerosis Study.

ABSTRACT: ?-Cell function (BCF) declines over the course of type 2 diabetes, but little is known about BCF changes across glucose tolerance status (GTS) categories, and comparisons of direct vs surrogate measures.To assess longitudinal changes in BCF across GTS.The Insulin Resistance Atherosclerosis Study is a multicenter, observational, epidemiologic study.Four clinical centers in the US that could identify subjects likely to have impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).We compared longitudinal changes in BCF in 1052 subjects over 5 years. Subjects were categorized according to baseline GTS: normal glucose tolerance (NGT: n = 547), impaired fasting glucose or impaired glucose tolerance (IFG/IGT: n = 341), and newly diagnosed type 2 diabetes (n = 164).None.BCF was assessed from a frequently sampled iv glucose tolerance test (AIR, acute insulin response), and the homeostasis model assessment of BCF (HOMA B).NGT and IFG/IGT subjects increased their insulin secretion over time, whereas those with type 2 diabetes experienced either decline or little change in BCF. After adjustment for demographic variables and change in insulin resistance, change in HOMA B underestimated the magnitude of changes in BCF, as assessed by change in AIR. Relative to NGT, the 5-year change in insulin secretion in IFG/IGT and type 2 diabetes was 31% and 70% lower (by HOMA B) and 50% and 80% lower (by AIR).The decline in BCF over time in IFG/IGT and type 2 diabetes may be more pronounced than previously estimated; HOMA B may underestimate this decline significantly.

SUBMITTER: Festa A

PROVIDER: S-EPMC3790620 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Longitudinal decline of β-cell function: comparison of a direct method vs a fasting surrogate measure: the Insulin Resistance Atherosclerosis Study.

Festa A A Haffner S M SM Wagenknecht L E LE Lorenzo C C Hanley A J G AJ

The Journal of clinical endocrinology and metabolism 20130724 10

<h4>Context</h4>β-Cell function (BCF) declines over the course of type 2 diabetes, but little is known about BCF changes across glucose tolerance status (GTS) categories, and comparisons of direct vs surrogate measures.<h4>Objective</h4>To assess longitudinal changes in BCF across GTS.<h4>Design</h4>The Insulin Resistance Atherosclerosis Study is a multicenter, observational, epidemiologic study.<h4>Setting</h4>Four clinical centers in the US that could identify subjects likely to have impaired ...[more]

PMID: 23884776

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Project description:Aims/hypothesisThe euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC.MethodsWe measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2).ResultsA standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2.Conclusions/interpretationA plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

Dataset Information

Longitudinal decline of ?-cell function: comparison of a direct method vs a fasting surrogate measure: the Insulin Resistance Atherosclerosis Study.

Publications

Longitudinal decline of β-cell function: comparison of a direct method vs a fasting surrogate measure: the Insulin Resistance Atherosclerosis Study.

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