Multimodal Imaging Analyses of Brain Hippocampal Formation Reveal Reduced Cu and Lipid Content and Increased Lactate Content in Non-Insulin-Dependent Diabetic Mice.

Non-insulin-dependent diabetes mellitus (NIDDM) is reported to increase the risk of cognitive impairment and dementia. However, the underlying mechanisms are not fully understood. While the brain homeostasis of metals and lipids is pivotal to maintaining energy metabolism and redox homeostasis for healthy brain function, no studies have reported hippocampal metal and biochemical changes in NIDDM. Therefore, we here utilized direct spectroscopic imaging to reveal the elemental distribution within the hippocampal subregions of an established murine model of NIDDM, db/db mice. In 26-week-old insulin resistant db/db mice, X-ray fluorescence microscopy revealed that the Cu content within the dentate gyrus and CA3 was significantly greater than that of the age-matched nondiabetic control mice. In addition, Fourier transform infrared (FTIR) spectroscopy analysis indicated a significant increase in the abundance of lactate within the corpus callosum (CC), dentate gyrus, CA1, and CA3 regions of diabetic db/db mice compared to that of the control, indicating altered energy metabolism. FTIR analysis also showed a significant decrease in the level of lipid methylene and ester within the CC of db/db mice. Furthermore, immunomicroscopy analyses demonstrated the increase in the level of glial fibrillary acidic protein expression and peri-vascular extravasation of IgG, indicating astrogliosis and blood-brain barrier dysfunction, respectively. These data suggest that astrogliosis-induced alterations in the supply of Cu, lipids, and energy substrates may be involved in the mechanisms of NIDDM-associated cognitive decline.