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Impact of incretin hormones on -cell function in subjects with normal or impaired glucose tolerance

¹Department of Internal Medicine and Consiglio Nazionale delle Ricerche (CNR) Institute of Clinical Physiology, University of Pisa; ²CNR Institute of Biochemical Engineering, Padua, Italy; and ³Department of Medical Physiology, Panum Institute, Copenhagen, Denmark

Submitted 21 November 2005 ; accepted in final form 9 February 2006

The mechanisms by which the enteroinsular axis influences -cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate -cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 ± 0.18, P = 0.004] amounted to 18 ± 2 nmol/m² (32 ± 4% of oral response), and its time course matched that of total insulin secretion. The -cell glucose sensitivity (OGTT/IV ratio = 1.52 ± 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 ± 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, -cell glucose sensitivity (75 ± 14 vs. 156 ± 28 pmol·min^–1·m^–2·mM^–1 of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of -cell glucose sensitivity (OGTT/IV ratio = 1.73 ± 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of -cell function, particularly -cell glucose sensitivity. In IGT, -cell function is inherently impaired, whereas the incretin effect is only partially affected.

glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; insulin secretion

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