Islet perturbations in rats fed a high-fat diet

The islet response to a high-fat diet, which induces insulin resistance, wa s investigated in Sprague-Dawley rats. It was found that the insulin respon se to glucose (15 or 25 mg/min, i.v.) was not different between rats given a high-fat diet and control rats after 2 weeks but was significantly reduce d in rats fed high-fat diets after 4 (by 46 +/- 9%; p < 0.001) and 8 weeks (by 68 +/- 12%; p < 0.001). However, after 2 weeks of a high-fat diet, stim ulated insulin secretion from isolated islets incubated for 60 min in 5.6, 8.3, and 11.1 mM glucose was impaired. When islets isolated from rats given a high-fat diet for 2 weeks were perifused, it was evident that the first- phase insulin secretion was impaired (seen during the first 6 min after inc rease of glucose from 3.3 to 8.3 mM). Insulin gene expression, examined by quantitative in situ hybridization, was impaired after 2 weeks of high-fat diet (52% decrease in mRNA-labeling; p < 0.001). Islet hypertrophy was not evident in rats given high-fat diet, as determined by areas of either islet profiles in dark-field images or isolated islets. Islet innervation, as re vealed by immunostaining for vasoactive intestinal peptide (VIP) and neurop eptide Y (NPY), was increased after 2, 4, and 8 weeks of high-fat diet. Thu s induction of insulin resistance by high-fat diet in Sprague-Dawley rats r esults after 2 weeks in impaired glucose-stimulated insulin secretion in vi tro, impaired insulin gene expression, and hyperinnervation of the islets w ithout any sign of islet hypertrophy, whereas the in vivo insulin response to glucose, although normal after 2 weeks, is impaired after 4 weeks.