Mechanisms involved in the islet adaptation to insulin resistance were examined in mice of the C57BL/6J strain challenged with a high-fat (58%) diet for 8 weeks. Basal hyperglycemia commenced after 1 week, whereas hyperinsulinemia evolved after 8 weeks. Glucose elimination after an intravenous glucose challenge (1 g/kg) was significantly delayed after 1, 4, and 8 weeks on the high-fat diet compared with normal-diet-fed mice. This result was associated with unchanged insulin responses. However, glucose-stimulated insulin secretion from isolated islets was increased in a compensatory fashion at all glucose levels over a wide range (3.3-22 mmol/l) after 8 weeks on the high-fat diet, whereas no compensatory hypersecretion of insulin was evident after 1 or 4 weeks, except at 22 mmol/l glucose. Immunohistochemistry revealed that the islet architecture of insulin and glucagon cells remained intact in islets from mice fed a high-fat diet. However, the nuclear translocation of the homeobox transcription factor, pdx-1, and the plasma membrane translocation of GLUT2 were both impaired in high-fat-fed animals after 1 week. In contrast, the expression of the full-length leptin receptor (ObRb) was not affected by high-fat feeding. The study thus shows that 8 weeks are required for the development of a compensatory hypersecretion of insulin after high-fat feeding in mice, and even then the in vivo insulin secretion is insufficient to normalize impaired glucose tolerance. The early-onset islet dysfunction is accompanied by impaired -cell trafficking of two factors, pdx-1 and GLUT-2, which are involved in -cell proliferation and glucose recognition. The mechanisms compromising this -cell trafficking remain to be established. Diabetes 51 (Suppl. 1):S138 -S143, 2002 I nsulin resistance is associated with islet adaptation ensuring adequate hyperinsulinemia to maintain normoglycemia. However, if the islet adaptation is impaired, hyperinsulinemia is inadequate and metabolic perturbations such as hyperglycemia might ensue (1). A model to study the mechanisms of impaired islet adaptation in insulin resistance is the high-fat feeding of C57BL/6J mice, which are especially susceptible to highfat treatment with regard to the development of glucose intolerance compared with other strains (2,3). We have previously shown that this model is associated with obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia (4); increased insulin mRNA expression in islets (5); and exaggerated insulin response to challenges with -cell secretagogues (6,7). In contrast, the early islet changes after feeding these mice a high-fat diet are less well studied. Therefore, we have explored whether the development of glucose intolerance provoked by short-term feeding of a high-fat diet in C57BL/6J mice is associated with changes in insulin secretion, islet architecture of insulin and glucagon cells, and islet localization of factors thought to be of particular relevance for -cell adaptation to insulin resistance. One such factor is the homeobox transcript...