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1 Institute of Systems Science and Biomedical Engineering, Italian National Research Council, 35127 Padua, Italy; and 2 Department of Medicine, Lund University, S-221 84 Lund, Sweden
To study the
contributions of insulin-dependent vs. insulin-independent
mechanisms to intravenous glucose tolerance (KG), 475 experiments in mice were performed. An intravenous glucose bolus was
given either alone or with exogenous insulin or with substances
modulating insulin secretion and sensitivity. Seven samples were taken
over 50 min. Insulin [suprabasal area under the curve
(
AUCins)] ranged from 0 to 100 mU · ml
1 · 50 min. After validation
against the euglycemic hyperinsulinemic clamp, the minimal model of net
glucose disappearance was exploited to analyze glucose and insulin
concentrations to measure the action of glucose per se independent of
dynamic insulin (SG) and the combined effect of insulin
sensitivity (SI) and secretion. Sensitivity analysis showed
that insulin [through disposition index (DI)] contributed to glucose
tolerance by 29 ± 4% in normal conditions. In conditions of
elevated hyperinsulinemia, contribution by insulin increased on average
to 69%. KG correlated with DI but was saturated for
AUCins above 15 mU · ml1 · 50 min. Insulin sensitivity
related to AUCins in a hyperbolic manner, whereas
SG did not correlate with the insulin peak in the
physiological range. Thus glucose tolerance in vivo is largely mediated
by mechanisms unrelated to dynamic insulin and saturates with high insulin.
insulin sensitivity; insulin secretion; glucose tolerance; glucose effectiveness; mathematical modeling; intravenous glucose tolerance test
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