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Since the discovery of insulin and insulin receptors (IR) in the brain in 1978, numerous studies have revealed a fundamental role of IR in the central nervous system and its implication in regulating synaptic plasticity, long-term potentiation and depression, neuroprotection, learning and memory, and energy balance. Central insulin resistance has been found in diverse brain disorders including Alzheimer’s disease (AD). Impaired insulin signaling in AD is evident in the activation states of IR and downstream signaling molecules. This is mediated by Aβ oligomer-evoked Ca  2+  influx by activating N-methyl-D-aspartate receptors (NMDARs) with Aβ oligomers directly, or indirectly through Aβ-induced release of glutamate, an endogenous NMDAR ligand. In the present opinion article, we highlight evidence that IR and free intracellular Ca  2+  concentration [Ca  2+ ]   i   form a double-negative regulatory feedback loop controlling insulin sensitivity, in which mitochondria play a key role, being involved in adenosine triphosphate (ATP) synthesis and IR activation. We found recently that the glutamate-evoked rise in [Ca  2+ ]   i   inhibits activation of IR and, vice versa, insulin-induced activation of IR inhibits the glutamate-evoked rise in [Ca  2+ ]   i  . In theory, such a double-negative feedback loop generates bistability. Thus, a stable steady state could exist with high [Ca  2+ ]  i  and nonactive IR, or with active IR and low [Ca  2+ ]  i , but no stable steady state is possible with both high [Ca  2+ ]  i  and active IR. Such a circuit could toggle between a high [Ca  2+ ]  i  state and an active IR state in response to glutamate and insulin, respectively. This model predicts that any condition leading to an increase of [Ca  2+ ]  i  may trigger central insulin resistance and explains why central insulin resistance is implicated in the pathogenesis of AD, with which glutamate excitotoxicity is a comorbid condition. The model also predicts that any intervention aiming to maintain low [Ca  2+ ]  i  may be useful for treating central insulin resistance.

Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity