Meal and oral glucose tests for assessment of ␤-cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 283: E1159-E1166, 2002. First published August 6, 2002 10.1152/ajpendo.00093.2002We investigated ␤-cell function and its relationship to insulin sensitivity in 17 normal volunteers. For insulin secretion (derived by C-peptide deconvolution), a mathematical model was applied to 24-h triple-meal tests (MT) as well as oral glucose tolerance tests (OGTT); insulin sensitivity was assessed by the euglycemic insulin clamp technique. The ␤-cell model featured a glucose concentration-insulin secretion dose response (characterized by secretion at 5 mM glucose and slope), a secretion component proportional to the glucose concentration derivative, and a time-dependent potentiation factor (modulating the dose response and accounting for effects of sustained hyperglycemia and incretins). The ␤-cell dose-response functions estimated from the whole 24-h MT, the first 2 h of the MT, and the OGTT differed systematically, because a different potentiation factor was involved. In fact, potentiation was higher than average during meals (1.6 Ϯ 0.1-fold during the first meal) and had a different time course in the MT and OGTT. However, if potentiation was accounted for, the 24-and 2-h MT and the OGTT yielded similar dose responses, and most ␤-cell function parameters were intercorrelated (r ϭ 0.50-0.86, P Յ 0.05). The potentiation factor was found to be related to plasma glucose-dependent insulin-releasing polypeptide concentrations (r ϭ 0.49, P Ͻ 0.0001). Among ␤-cell function parameters, only insulin secretion at 5 mM glucose from MT correlated inversely with insulin sensitivity (24-h MT: r ϭ Ϫ0.74, P Ͻ 0.001; 2-h MT: r ϭ Ϫ0.52, P Ͻ 0.05), whereas the dose-response slope and the OGTT parameters did not. In nine other subjects, reproducibility of model parameters was evaluated from repeated MTs. Coefficients of variation were generally ϳ20%, but the derivative component was less reproducible. We conclude that our model for the multiple MT yields useful information on ␤-cell function, particularly with regard to the role of potentiation. With cautious interpretation, a 2-h MT or a standard OGTT can be used as surrogates of 24-h tests in assessing spontaneous ␤-cell function. insulin secretion; glucose-induced insulin release; potentiation of glucose-induced insulin release; insulin sensitivity

Turner's syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness. Sex hormone administration causes a deterioration in glucose tolerance, increases FFM and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance may be mediated by norethisterone, a gestagen known to have androgenic effects.

Detection of insulin secretory bursts in peripheral blood is hampered by hepatic insulin extraction, dilution in the systemic insulin pool, and time-delayed damping of secretory burst amplitude. Previous studies in dogs in vivo and other experiments in vitro have shown that ∼70% of all insulin is released within distinct insulin secretory bursts. To establish a method for detection and quantification of pulsatile insulin release in humans on the basis of peripheral insulin concentration measurements, we used a high-sensitivity, -specificity, and -precision insulin enzyme-linked immunosorbent assay (ELISA) and optimized an established deconvolution methodology to quantify the frequency, mass, and amplitude of insulin secretory bursts as well as to estimate the relative contribution of pulsatile insulin release to overall insulin secretion. By use of minutely sampled serum insulin concentrations measured by a highly sensitive insulin ELISA, and insulin kinetics of 2.8 min (first half-life), 5.0 min (second half-life), and a fractional slow component of 0.28, the deconvolved insulin secretion rates in 20 healthy subjects during glucose infusion (4.5 mg ⋅ kg−1 ⋅ min−1) could be resolved into a series (4.7 ± 0.1 min/pulse) of approximately symmetric insulin secretory bursts with a mean mass of 87 ± 12 pmol ⋅ l−1 ⋅ pulse−1and a mean amplitude (maximal release rate) of 35 ± 4.7 pmol ⋅ l−1 ⋅ min−1. The relative contribution of pulsatile to overall insulin secretion was 75 ± 1.6% (range 59–85%). We conclude that in vivo insulin secretion in humans during nominal glucose stimulation consists of a series of punctuated insulin secretory bursts accounting for ≥75% of total insulin secretion.

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