Meal and oral glucose tests for assessment of β-cell function: modeling analysis in normal subjects

Abstract

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

Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

“…Insulin secretion rates were calculated from plasma C-peptide concentrations by deconvolution, as previously described [18]. Parameters of beta cell function were derived from mathematical analysis of plasma glucose and C-peptide concentrations during the OGTT, using a previously developed model [13,14]. According to this method, glucose-stimulated insulin secretion [S(t)] is the sum of two components: S(t)=P(t)f(G)+ S d (t).…”

“…Glucose sensitivity represents the ability of the beta cell to respond to an increment in glucose concentration. It has been shown to have good reproducibility (24%) [13]. A characteristic parameter of the potentiation factor is the ratio between its value at the end of the OGTT (100-120 min) and its initial value (0-20 min).…”

“…A characteristic parameter of this secretion component is the constant k d , termed 'rate sensitivity'. This parameter has limited reproducibility (52%) [13].…”

“…This in turn will inform the development of targeted therapies to prevent progression. We have recently developed a mathematical model that uses data from a standard oral glucose tolerance test to measure insulin secretion rates, beta cell glucose sensitivity and beta cell potentiation (effects of glucose itself and non-glucose secretagogues to magnify the response to glucose), together with an estimate of wholebody insulin sensitivity [12][13][14]. In this study we used this model to identify predictors of deterioration in glucose tolerance in a longitudinal study of non-diabetic subjects of British extraction with or without a family history of type 2 diabetes.…”

Heritability of model-derived parameters of beta cell secretion during intravenous and oral glucose tolerance tests: a study of twins

“…Furthermore, the response of the beta cell to oral glucose is under the control of many important determinants not in play during an intravenous glucose stimulus, foremost among them being the gastrointestinal incretins [29]. Finally, OGTT beta index is a global parameter, which does not discriminate between the equivalents of first-and second-phase insulin secretion [15], both of which are also conceivably elicited by oral glucose administration [30,31]. The findings with respect to intraclass r and ctct-r were extended by a formal heritability analysis.…”