Alzheimer's disease-related brain insulin resistance and the prospective therapeutic impact of metformin.

Abstract

Besides COVID-19, two of the most critical outbreaks of our day are insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer's disease (AD). Each disease's pathophysiology is well established. Furthermore, a substantial overlap between them has coexisted. Uncertainty remains on whether T2DM and AD are parallel illnesses with the same origin or separate illnesses linked through violent pathways. The current study was aimed at testing whether the insulin resistance in the brain results in AD symptoms or not. Insulin resistance was induced in the brains of rats using a single intracerebroventricular streptozotocin (STZ) dose. We then measured glucose, insulin receptor substrate 2 (IRS-2), amyloid β (Aβ) deposition, and tau phosphorylation in the brain to look for signs of insulin resistance and AD. The results of this study indicated that a single dose of STZ was able to induce insulin resistance in the brain and significantly decline IRS-2. This resistance was accompanied by obvious memory loss, Aβ deposition, and tau phosphorylation, further visible diminishing in neurotransmitters such as dopamine and acetylcholine. Furthermore, oxidative stress was increased due to the antioxidant system being compromised. Interestingly, the pancreas injury and peripheral insulin resistance coexisted with brain insulin resistance. Indeed, the antidiabetic metformin was able to enhance all these drastic effects. In conclusion, brain insulin resistance could lead to AD and vice versa. These are highly linked syndromes that could influence peripheral organs. Further studies are required to stabilize this putative pathobiology relationship between them.