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Insulin signaling via PKCδ isoforms in the diabetic brain promotes cognitive function

People with type II diabetes have significantly lower cognitive function. Strong links between insulin and cognitive function supported by epidemiological data from humans and animal studies and in vitro research. The consequences of protein kinase C (PKC) activation by insulin in the CNS influence memory, cognition, synaptogenesis, and neuronal repair. In addition, PKCδ, a novel PKC is implicated in memory, neuronal survival and proliferation. Insulin regulates the alternative splicing of mouse PKCδ splice variants: PKCδI promotes apoptosis while PKCδII is a pro‐survival protein. In vitro and in vivo studies demonstrated that apoptosis accounted for the neuronal loss and cognitive decline in the diabetic mouse models. Our data in mouse neural cells derived from the hippocampus demonstrates that insulin increases the expression of PKCδII and is not influenced by high glucose or thiazolidinediones. We used inhibitors of several pathways targeted by insulin to determine which pathways are involved in PKCδ alternative splicing in neuronal cells and show that insulin increases PKCδII expression via PI3K‐Akt pathway. Constitutively active Akt2 kinase mimicked insulin effects in increasing PKCδII levels while WT‐Akt2 kinase had no effect. Further, using over‐expression and siRNA we show that PKCδII increases expression of pro‐survival proteins Bcl‐2 and Bcl‐xL thereby increasing neurogenesis.