Insulin resistance in the nervous system

Abstract

Metabolic syndrome is a cluster of cardiovascular risk factors including obesity, diabetes and dyslipidemia. Insulin resistance (IR) is at the core of metabolic syndrome. In adipose tissue and muscle, IR results in decreased insulin signaling, primarily affecting downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling. It was recently proposed that neurons can develop hyperinsulinemia-induced IR, which in turn results in injury to the peripheral and central nervous systems and is probably pathogenic in common neurological disorders such as diabetic neuropathy and Alzheimer's disease (AD). This review presents evidence indicating that, similarly to insulin-dependent metabolically active tissues such as fat and muscle, neurons also develop IR and thus cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury, subsequent dysfunction and disease states.

Figure 1

Insulin signaling pathways. The binding of insulin to InsR stimulates autophosphorylation of the receptor and recruits docking proteins Shc and IRS. IRS phosphorylation stimulates PI3K activation, and this leads to the generation of phosphatidylinositol-3,4,5-triphosphate (PIP3) by phosphorylating phosphatidylinositol-4,5-bisphosphate (PIP2). PDK1 and Akt are recruited to the plasma membrane by binding to PIP3 through their PH domains. PDK1 phosphorylates a threonine residue in the catalytic domain of Akt. Full activation of Akt requires a second phosphorylation of a serine residue by the mTORC2 complex. Alternatively, phosphorylated Shc recruits Grb2/SOS, which stimulates the MAPK signaling pathway. Substrates activated by the MAPK and PI3K/Akt pathways mediate various downstream biological responses of insulin, including cell survival and glucose metabolism.

Figure 2

Insulin action in the CNS and PNS. Even though neurons are generally not considered to be insulin-dependent, they are responsive to insulin, and InRs are widely distributed in both the PNS and CNS. Insulin signaling is important for various aspects of neuronal functions including energy homeostasis, learning and memory, peripheral glucose metabolism (PNS), and regeneration, reinnervation and survival (CNS).

Figure 3

Model of the development of neuronal IR. (a) Insulin-mediated signaling activates Akt and maintains normal neuronal function. (b) In the presence of MetS, as in insulin-dependent tissues, neurons develop IR, and in turn cannot respond to the neurotrophic properties of insulin. Neurons become more susceptible to neurotoxic stimuli, resulting in neuronal dysfunction and the onset and progression of neurologic disease states.