Insulin-like growth factor-1 promotes neuronal glucose utilization during brain development and repair processes

Abstract

Abstract We have reviewed several lines of evidence suggesting that IGF-1 augments neuronal glucose utilization during brain development. To briefly recapitulate, brain glucose utilization parallels IGF-1 receptor expression during brain development. In normal murine brain development, IGF-1 is produced in greatest abundance by growing cerebellar and sensory projection neurons during the time of dendrite elaboration and synaptogenesis. Glucose utilization is significantly reduced in developing IGF1 -/-brain, particularly in those sites where IGF-1 expression is normally most abundant. The defect in glucose utilization in IGF1 -/-brains is demonstrable at the terminal level in vitro , and is reversed by IGF-1. It appears that IGF-1 promotes glucose allocation to growing neurons in an autocrine manner, enabling the extraordinary elaboration of processes characterizing these complex information-processing systems. These sensory processing centers continue to exhibit high-level glucose utilization in the mature brain, after IGF-1 expression has receded, reflecting the extraordinary dendritic complexity and synaptic density achieved by these structures. IGF-1 is not likely to play a major role in the rapid, neural activity-based glucose utilization in the mature brain, as discussed in Section IV. It will be interesting to determine whether IGF-1 is involved in activity-induced synaptic remodelling, as a number of studies suggest ( Torres-Aleman, 2000 ). IGF-1 is highly expressed by reactive (GFAP-positive) astrocytes in various injury models ( Komoly et al. , 1992 ; Lee et al. , 1992 ; Lee and Bondy, 1993 ; Gehrmann et al. , 1994 ; Yao et al. , 1995 ; Walter et al. , 1997 ; Beilharz et al. , 1998 ; Li et al. , 1998 ). We have found that astrocytic IGF-1 expression several days after MCAO is closely correlated with increased glucose utilization in the injury site, as shown in Fig. 7 ( Lee et al. , 1992 ). The significance of this local increase in glucose utilization is unclear, but it may be attributed to increased anabolic activity by astrocytes synthesizing and secreting collagen and other extracellular proteins involved in scar formation. PKB/Akt and GSK3β appear to be central players in IGF signaling to the brain (Fig. 13). PKB/Akt phosphorylation in IGF-1-expressing neurons is associated with increased GLUT4 expression and translocation from intracellular to the plasma membrane. IGF1's apparent link with this “insulin-sensitive” transporter may represent a specific anabolic pathway, distinct from the glucose transport pathways involving GLUTs 1 and 3. PKB/Akt phosphorylation also leads to the inhibition of GSK3β in IGF-1-expressing neurons (Figs. 11 and 13). This inhibition is expected to facilitate glycogen and protein synthesis, as GSK3β normally inhibits both glycogen synthase and eIF2B (Fig. 13). As a result, there is accumulation of glycogen in IGF-1-expressing neurons ( Cheng et al. , 2000 ), which may serve to create a relative “sink” for G-6-P, promoting further glucose transport into the neuron. GSK3β also phosphorylates the microtubule-associated protein tau. Tau is hyper-phosphorylated in the IGF1 null brain, as expected if IGF-1 normally inhibits this multifunctional enzyme. Tau hyperphosphorylation is the mechanisms governing normal cell- and developmental stage-specific regulation of IGF-1 expression, and to attempt to restore normal patterns of expression in conditions such as fetal alcohol exposure and malnutrition, and possibly in other forms of mental retardation.