Increased Aβ production prompts the onset of glucose intolerance and insulin resistance

Type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) are two prevalent
diseases with comparable pathophysiological features and genetic predisposition. 
Patients with AD are more susceptible to develop T2D. However, the molecular
mechanism linking AD and T2D remains elusive. In this study, we have generated a 
new mouse model to test the hypothesis that AD would prompt the onset of T2D in
mice. To test our hypothesis we crossed Alzheimer transgenic mice APPswe/PS1dE9
(APP/PS1) with mice partially deficient in leptin signaling (db/+). Body weight, 
plasma glucose and insulin levels were monitored. Phenotypic characterization of 
glucose metabolism was performed using glucose, and insulin tolerance test.
Beta-cell mass, islet volume and islet number were analyzed by histomorphometry. 
APP/PS1 coexpression in mice with intact leptin-receptor signaling did not show
any metabolic perturbations in glucose metabolism or insulin sensitivity. In
contrast, APP/PS1 coexpression in db/+ mice resulted in non-fasting
hyperglycemia, hyperinsulinemia and hypercholesterolemia without changes in body 
weight. Conversely, fasting blood glucose and cholesterol levels remained
unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in
db/+ mice resulted in glucose intolerance, insulin resistance and impaired
insulin signaling. In addition, histomorphometric analysis of pancreata revealed 
augmented beta-cell mass. Taken together, these findings provide experimental
evidence to support the notion that aberrant Aβ production might be a mechanistic
link underlying the pathology of insulin resistance and T2D in AD.