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Designing a late-stage type 2 diabetes mellitus model with brain insulin resistance and oxidative stress
* 1, 2 , 1, 2 , 1, 3 , 1 , 4 , 4 , 4 , 1 , 2 , 1
1  Department of Pharmacology, Pharmacognosy and Botany. Faculty of Pharmacy. Complutense University of Madrid
2  Departmental Section of Physiology. Faculty of Pharmacy, Complutense University of Madrid.
3  Brain Mapping Unit, Pluridisciplinary Institute. Complutense University of Madrid.
4  Department of Nutrition and Fodd Science (Nutrition). Faculty of Pharmacy. Complutense University of Madrid
Academic Editor: Jean Jacques Vanden Eynde

Published: 03 November 2021 by MDPI in 7th International Electronic Conference on Medicinal Chemistry session General

The impairment in insulin-signaling pathway induces neurological damage [e.g., Alzheimer’s disease (AD)]. When AD and type 2 diabetes mellitus (T2DM) coexists, it is known as type 3 diabetes mellitus (T3DM). The mitochondrial dysfunction promotes oxidative stress and plays an important role in brain insulin resistance (BIR) instauration, which finally leads to T3DM. This study aimed to reveal the suitability of a late-stage T2DM model induced by high-saturated fat and hypercholesterolemic diet (HFHCD) and streptozotocin-nicotinamide (STZ-NAD) injection as a T3DM model. We used an early-stage T2DM rat model as control group (C) induced by a high-saturated-fat diet; and a late-stage T2DM rat model (D) induced by a HFHCD and a low dose of STZ-NAD (65 and 225 mg/kg b.w) injection. Frontal cortex were dissected and proteins were extracted. The levels of antioxidant enzymes (SOD1, SOD2, CAT, GPx and GR), the insulin-signaling pathway markers (InsRβ, IRS-1, AKT and GSK3β) and GLUT3 were measured by Western Blotting. D rats showed significant lower levels of SOD1, SOD2 and GR, contributing to oxidative stress instauration. Moreover, D rats presented an altered insulin-signaling pathway respect to C counterparts as indicated by decreased InsRβ and IRS-1 levels and downstream signaling (AKT-GSK3β). Finally, GLUT3 levels increased in D rats improving insulin-independent glucose uptake. Our findings support that this late-stage T2DM model represents an appropriate experimental tool to study the progression of BIR in T3DM as well as evaluate the efficacy of potential neuroprotective drugs.

Keywords: Brain insulin resistance; experimental animal model; insulin-signalin pathway; type 2 diabetes mellitus; type 3 diabetes mellitus.