Jiménez-Palomares M, Ramos-Rodríguez JJ, López-Acosta JF, Pacheco-Herrero M, Lechuga-Sancho AM, Perdomo G, García-Alloza M, Cózar-Castellano I. Increased A production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab 302: E1373-E1380, 2012. First published March 13, 2012; doi:10.1152/ajpendo.00500.2011.-Type 2 diabetes (T2D) mellitus 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 APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/ϩ). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. -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/ϩ mice resulted in nonfasting 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/ϩ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented -cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant A production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD. type 2 diabetes; Alzheimer's disease; -amyloid peptide; APPswe/PS1dE9 mouse; db/db mouse; -cell mass ALZHEIMER'S DISEASE (AD) and type 2 diabetes (T2D) are two prevalent diseases in developed countries with comparable pathological features and genetic predisposition (3, 4, 7). Several clinical and epidemiological studies have shown a relationship between AD and T2D. Patients with T2D exhibit an increased risk for developing dementia and AD (1,11,12,14,15,19). On the other hand, patients suffering AD are more vulnerable to develop T2D (10). Patients with AD show a remarkable deposition of -amyloid peptide (A) in brain, whereas patients with T2D present islet amyloid polypeptide deposition in pancreatic -cells (6). On the other hand, patients with T2D are glucose intolerant and insulin resistant, revealing decreased insulin signaling in peripheral tissues, whereas patients with AD show signs of impaired insulin signaling in the brain (16). Taken together, these observations have spurred the hypothesis that these pathological alterations may underline the mecha...