Expression of insulin and GLP-1 receptors in interneurons of the cerebral cortex

Abstract

The action of insulin is not restricted to peripheral organs. Insulin receptors and signal transduction pathways described in the periphery are involved in a wide array of functions in the central nervous system. It is generally accepted that insulin produced by pancreatic beta cells in physiological conditions or applied intranasally with a therapeutic purpose for mild to moderate Alzheimer’s disease finds its way to neurons of the cerebral cortex. The timescale of external insulin transport to the vicinity of neurons is relatively slow, consistent with long-term homeostatic regulation of neural networks. Recent work has overwhelmingly shown that insulin is also synthesised locally in the cerebral cortex. Neuron-derived insulin is capable of rapid modulation of synaptic and microcircuit mechanisms and is suggested to regulate on-demand energy homeostasis of neural networks. Our results provide evidence for functional expression of GLP-1 receptors in neurons known to release insulin in the cerebral cortex. Hyperglycemia increases the expression of GLP-1 receptors in neurogliaform cells suggesting that endogenous incretins and therapeutic GLP-1 receptor agonists might have effects on these neurons similar to that of pancreatic beta cells. We suggest that novel therapeutic strategies might include modulation of neural insulin production in the brain by GLP-1 agonists for counteracting diabetes, obesity and neurodegenerative diseases. Recent experiments in which lost pancreatic beta cells were replaced by autologous transplants of insulin-producing neural progenitor cells signal the immense therapeutic potential of this approach for diabetes.