Insulin Resistance: A Bridge between T2DM and Alzheimer’s Disease

Abstract

T2DM is caused by insulin resistance in the tissues, no longer able to respond to the hormone action. It is most frequently associated with aging, a family history of diabetes, obesity, and failure of exercise.The insulin, ahormone produced by the beta-cells of the pancreas, is the key biomolecule for the regulation of carbohydrate and lipid metabolism. Although its action in body organs mainly concerns the glucose homeostasis, in Central Nervous System insulin performs several functions such as regulation of glucose metabolism, food intake and body weight, fertility and reproduction [1] and others not yet completely known. In particular, the high density of insulin receptors in the hippocampus and cerebral cortex regions has suggested its participation in learning and memory process. The administration of insulin to both humans and animal models has induced an enhancement of the memory function [2] and the treatment with insulin has given in several animal models beneficial effects to prevent memory loss after ischemia episodes whereas no effects are observed with glucose alone [3]. Insulin is also involved in the synaptic plasticity, for example, it as been show that insulin allows the long-lasting enhancement of GABA receptormediated synaptic transmission [4] and promote the internalization of AMPA receptors from the neuron synaptic membrane causing a long-term depression (LTD) of excitatory synaptic transmission in the hippocampus and cerebellum [5,6]. LTD is a process that, together with the opposite one, long-term potentiation has a great relevance for brain information storage and improvement of neurons links during development [7]. Furthermore, insulin receptor signaling regulates the maintenance of synapses and contributes to experience-dependent structural plasticity that is necessary for the recruitment of neurons into brain circuits [8]. Moreover, some studies suggest that insulin participates in neuronal differentiation of postnatal neural stem cell [9] and their culturing with both insulin and insulin-like growth factor (GF-1) causes a greater production of neurons during differentiation compared to culturesstimulated by IGF-1 alone [10]. Insulin also avoids the necrosis of rat embryonic neurons cultured in a serum-free medium; in fact the protein was capable to restore the cell viability by activation of Protein Kinase C, having the crucial role of controlling other proteins through the phosphorylation of their serine and threonine amino acid residues; on the contrary, insulinlike growth factor addition had no effect [11]. Clearly, in the insulin resistance state, these functions are impaired.