No abstract

OBJECTIVE-To examine whether changes characteristic of Alzheimer's disease occur in two rat models with spontaneous onset of type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS-The frontal cortices of 8-month-diabetic rats were examined with respect to neuronal densities, neurite degeneration, expression, and/or immunolocalization of amyloid precursor protein (APP), ␤-secretase, ␤-amyloid, COOH-terminal fragment (CTF), insulin receptor, IGF-1 receptor, glycogen synthase kinase 3-␤ (GSK-3␤), protein kinase B (Akt), phosphorylated (phospho-), synaptophysin, and phosphorylated neurofilaments (SMI-31).RESULTS-Neuronal loss occurred in both models, significantly more so in type 2 diabetic BBZDR/Wor rats compared with type 1 diabetic BB/Wor rats and was associated with a ninefold increase of dystrophic neurites. APP, ␤-secretase, ␤-amyloid, and CTF were significantly increased in type 2 diabetic rats, as was phospho-. The insulin receptor expression was decreased in type 1 diabetes, whereas IGF-1 receptor was decreased in both models, as were Akt and GSK-3␤ expression. CONCLUSIONS-The data show that ␤-amyloid and phosphoaccumulation occur in experimental diabetes and that this is associated with neurite degeneration and neuronal loss. The changes were more severe in the type 2 diabetic model and appear to be associated with insulin resistance and possibly hypercholesterolemia. The two models will provide useful tools to unravel further mechanistic associations between diabetes and Alzheimer's disease.

C-peptide in the presence of insulin exerts synergistic effects on cell proliferation, neurite outgrowth and has in the presence of insulin an antiapoptotic effect on high glucose-induced apoptosis but less so on hyperosmolar-induced apoptosis. These effects are likely to be mediated via interactions with the insulin signaling pathway.

Peripheral nerve expresses predominantly the high affinity IR, which is localized to strategic structures associated with the blood-nerve barrier and the paranodal ion-channel barrier.

The more severe molecular, functional and morphometric abnormalities of nociceptive C-fibers in type 1 insulinopenic rats compared to type 2 hyperinsulinemic rats suggest that impaired insulin action may play a more important pathogenetic role than hyperglycemia per se.