Figure 2. Insulin signaling counterbalances glucocorticoid signaling to maintain neuroplasticity, and impairment of insulin signaling increases neuronal vulnerability to stress.

(A), Under normal physiological circumstances, hippocampal insulin signaling protects against the negative effects of exposure to moderately elevated glucocorticoid hormones. Glucocorticoids act via the hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), facilitating HPA axis shutoff. While activation of GR in particular leads to transcription of genes that attenuate plasticity (Morsink et al., 2006), concurrent insulin receptor (IR) activation would counteract this effect by promoting survival signaling. Similarly, neuronal utilization of glucose and lactate would suppress the energetic stress associated with glucocorticoid receptor activation. (B), In the diabetic hippocampus, GR expression is compromised (Campbell et al., in press), leading to impairment of HPA axis shutoff. Moreover, insulin receptor signaling is impaired, and neuronal access to energy substrates is diminished. This creates a scenario in which the effects of exposure to elevated corticosterone levels, in the context of reduced insulin signaling and impaired metabolism, lead to neuronal endangerment. This model is a reductionist view of how insulin signaling and the availability of energy substrates might interact with the stress response. In the interests of space, other factors such as 11β-hydroxysteroid dehydrogenase 1, which locally modulates glucocorticoid actions in the hippocampus, and feeding-related peptides such as ghrelin and leptin, are not included in the diagram but could potentially contribute to the relationship between metabolism and stress.