Abstract
Insulin resistance (IR) links Alzheimer’s disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance.
Highlights
Insulin resistance is one of the core defects in type 2 diabetes mellitus (T2DM) and this defect leads to hyperinsulinemia that compensates for the reduced efficacy of insulin in peripheral tissues
We found that pioglitazone partly reversed the accumulation of b-amyloid and the activation of advanced glycosylation end products (AGEs)/ receptors for AGEs (RAGE) system in brains of fructose-drinking insulin resistance rats [24,25]
Reduced levels of reactive oxygen species (ROS) (P,0.05, P,0.05), TBARS (P,0.05, P,0.01) and carbonyl (P,0.05, P,0.05) in both hippocampus and cerebral coxtex were observed in pioglitazone-treated fructose-drinking rats compared with fructose-drinking insulin resistance rats
Summary
Insulin resistance is one of the core defects in type 2 diabetes mellitus (T2DM) and this defect leads to hyperinsulinemia that compensates for the reduced efficacy of insulin in peripheral tissues. In CNS, deterioration of cognitive function such as learning and memory impairment has been proven to be associated with insulin resistance [2,3,4]. Oxidative stress arises due to the imbalance of the production of free radicals and cellular antioxidant defense mechanism. The excessive production of free radicals in brain that has insulin resistance may attack many cellular components including membrane lipids and proteins, resulting in neuronal damage and dysfunction [7,8]. Accumulating evidences have demonstrated the link between free radical and neuronal degeneration, which highlights the importance of antioxidants in the treatment of neurodegenerative disorders including diabetes-associated cognitive decline [5]. It is thought that oxidative damage contributes to learning and memory impairments in rat models with insulin resistance [7,14]
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