The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice Bo Ahre ´n, Maria So ¨ rhede Winzell and Giovanni Pacini 1 Department of Clinical Sciences, Lund University, BMC B11, SE-221 84 Lund, Sweden 1 Metabolic Unit, Institute of Biomedical Engineering (ISIB-CNR), Padova, Italy (Correspondence should be addressed to B Ahre ´n; Email: bo.ahren@med.lu.se) Abstract To study whether the incretin effect is involved in adaptively increased insulin secretion in insulin resistance, glucose was infused at a variable rate to match glucose levels after oral glucose (25 mg) in normal anesthetized C57BL/6J female mice or in mice rendered insulin resistant by 8 weeks of high- fat feeding. Insulin response was markedly higher after oral than i.v. glucose in both groups, and this augmentation was even higher in high-fat fed than normal mice. In normal mice, the area under the curve (AUC insulin ) was augmented from 4 . 0G0 . 8 to 8 . 0G1 . 8 nmol/l!60 min by the oral glucose, i.e. by a factor of 2 (PZ0 . 023), whereas in the high- fat fed mice, AUC insulin was augmented from 0 . 70G0 . 4 to 12 . 4G2 . 5 nmol/l!60 min, i.e. by a factor of 17 (P!0 . 001). To examine whether the incretin hormone glucagon-like peptide-1 (GLP-1) is responsible for this difference, the effect of i.v. GLP-1 was compared in normal and high-fat fed mice. The sensitivity to i.v. GLP-1 in stimulating insulin secretion was increased in the high-fat diet fed mice: the lowest effective dose of GLP-1 was 650 pmol/kg in normal mice and 13 pmol/kg in the high-fat diet fed mice. We conclude that 1) the incretin effect contributes by w50% to insulin secretion by the oral glucose in normal mice, 2) this effect is markedly exaggerated in insulin-resistant mice fed a high-fat diet, and 3) this augmented incretin contribution in the high-fat fed mice may partially be explained by GLP-1. Journal of Endocrinology (2008) 197, 181–187 Introduction The entero–insular axis represents the physiological regulation of islet function by the gut (Unger & Eisentraut 1969). A key component of this axis is the incretin effect, which augments increase in insulin secretion following oral versus i.v. glucose (Elrick et al. 1964, Perley & Kipnis 1967). This effect is partially achieved by gastrointestinal hormones that are released during meal ingestion and augment glucose-stimulated insulin secretion; the two most important being glucagon-like peptide-1 (GLP-1) and glucose-depen- dent insulinotropic polypeptide (GIP; Vilsboll & Holst 2004, Drucker 2006). The effect is, however, also partially achieved by autonomic nerves activated by oral glucose. Thus, cholinergic nerves activated during meal ingestion may stimulate insulin secretion (Ahre ´n 2000). In humans, a study with careful matching of glucose levels after oral versus i.v. administration has shown that the incretin effect contributes to 70–90% of the insulin response to oral glucose (Nauck et al. 1986). Similarly, also in pigs, the incretin effect contributes to a large degree of the insulin response to oral glucose (Lindkaer- Jensen et al. 1975). Insulin resistance upregulates insulin secretion, and if this adaptation fails, impaired glucose tolerance or type 2 diabetes develops (Ahre ´n & Pacini 2005). The mechanisms of upregulated insulin secretion in insulin resistance may include slight elevation of glucose or free fatty acids (Ahre ´n & Pacini 2003). Whether the upregulation of insulin secretion also involves the incretin effect is, however, not known. To study this possibility, incretin contribution to the insulin response to oral glucose was examined in the animal model of high-fat feeding of mice. In this model, insulin resistance develops, and on a long-term basis, this is compensated by increased insulin secretion (Pacini et al. 2001, Ahre ´n & Pacini 2002, Winzell & Ahre ´n 2004). Previous studies have inferred that there is an upregulation of the insulin response also to non-glucose stimuli such as carbachol (cholinergic agonist), 2-deoxy- glucose (activating autonomic nerves), and GLP-1 in this model (Ahre ´n et al. 1997, Simonsson & Ahre ´n 1998). However, these studies have used exogenous administration of secretory agents and, therefore, whether the endogenous incretin effect per se is altered in insulin resistance is still not known. In this study, we have therefore examined the incretin contribution to insulin secretion during oral glucose in normal and high-fat fed insulin-resistant mice. We estimated insulin secretion after oral and i.v. glucose administration when the glucose levels were matched in these two conditions. We also examined the GLP-1 response to the oral glucose load and the insulin response to low-dose GLP-1 in the model for examining 181 Journal of Endocrinology (2008) 197, 181–187 DOI: 10.1677/JOE-07-0460 0022–0795/08/0197–181 q 2008 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org