Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases

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   Figure 1

   Insulin signalling in neurons. The insulin receptor (IR) is expressed on neurons and activates growth factor-type cell signalling pathways. The IR plays an important role in neuronal growth, synaptic development and control of neurotransmitter release at the synapse. Its role in glucose uptake is limited in neurons, as the insulin-dependent GLUT-4 glucose uptake transporter is only expressed in a sub-population of large excitatory neurons (Benomar et al. 2006, Grillo et al. 2009). Insulin binds to the α-subunit of the receptor. This activates the tyrosine kinase phosphorylation of the β-subunit. This activates second messenger pathways. (1) Activation of the insulin receptor MAP kinase pathway activates growth-related gene expression required for the control of cell metabolism and energy homeostasis, cell growth, synapse growth and for cell repair and maintenance (Hoyer 1997, Biessels et al. 2006). (2) Insulin also modulates synaptic neurotransmission and primes synapses for induction of long-term potentiation of synaptic transmission (LTP; Biessels et al. 2004). This pathway most probably involves binding of IRS1 to activate the phosphatidylinositol 3-kinase (PI3K; Zhao et al. 2000). This may prime the synapse for increased neurotransmitter vesicle release (de la Monte & Wands 2006). Modulation of neurotransmission may be the basis for memory formation and information processing in the CNS (Hölscher 1999).
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   Figure 2

   Overview of the main pathways induced by GLP-1 in neurons. The GLP-1 receptor is a member of a different classes of receptors compared with the IR. Activation of the GLP-1R activates an adenylyl cyclase and increases cAMP levels. This activates PKA and other downstream kinases that are related to growth factor signalling. This may be the reason why GLP-1 mimetics can compensate for insulin desensitisation in diabetics and in AD. For more details, see Holscher (2010) and Holscher & Li (2010).

• © 2014 Society for Endocrinology