Insulin resistance contributes to aberrant stress responses in the Tg2576 mouse model of Alzheimer's disease

Abstract

We previously reported aberrant stress responses and impaired glucose tolerance in transgenic Tg2576 mice, a model of Alzheimer's disease (AD). Here we report that by 8 months of age, Tg2576 mice had lower basal serum insulin concentrations and exhibited a delayed insulin-induced reduction in blood glucose levels relative to wild-type mice. However, the basal levels of blood glucose and percent glycosylated hemoglobin (%HbA1c) were similar between the two groups of mice. While the basal levels of serum corticosterone were similar between Tg2576 and wild-type mice, an overnight fasting caused a greater rise in serum corticosterone levels and an excessive reduction in serum insulin concentrations in the transgenics. At 9 months of age, we began administering Tg2576 mice rosiglitazone, an agonist of peroxisome proliferator-activated receptor-γ that increases peripheral insulin sensitivity, and after 6 weeks of administration the Tg2576 mice had the same response to insulin and increase in serum corticosterone levels after an overnight fast as did wild-type mice. By 13 months of age, untreated Tg2576 mice had become hyperinsulinemic, in contrast to Tg2576 mice administered rosiglitazone for 4 months where the serum insulin concentrations were maintained at levels observed in wild-type mice. These results provide evidence for a relationship between insulin resistance, impaired regulation of insulin and glucose levels, and aberrant stress responses in Tg2576 mice.

Keywords

• Alzheimer's disease
• Anxiety
• Corticosterone
• Hypothalamic–pituitary–adrenal axis
• Insulin
• Stress response