Insulin-like growth factor 1 in diabetic neuropathy and amyotrophic lateral sclerosis.

Insulin-like growth factor 1 (IGF-1) is a pluripotent growth factor with multiple functions in the peripheral and central nervous system. It supports neuronal survival and axon growth, and also acts on myelinating Schwann cells and oligodendroglia. The biological functions of IGF-1 are modulated by IGF-binding proteins (IGFBPs). Expression of IGF-1 and its corresponding IGF-1 receptor (IGF-1R) are dysregulated in patients with diabetes and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). IGFBP5, an inhibitory binding protein for IGF-1, is also substantially increased in nerve biopsies of patients with sensorimotor diabetic neuropathy (DNP). We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which IGF-1R was conditionally depleted in motoneurons, indicating that reduced activity of IGF-1 on IGF-1R in motoneurons is responsible for the observed effect. The upregulation of IGFBP5 has possibly contributed to the lack of efficacy found in previous clinical trials with systemically administered IGF-1 in patients with other forms of motoneuron disease such as ALS. Thus, strategies aiming at circumventing these inhibitory effects could be of benefit for development of new therapies for ALS and DNP. However, these strategies have to be built on a better understanding of the metabolic processes that contribute to neurodegeneration, and on the role of IGF-1 in these metabolic processes that go beyond protection from axonal degeneration and cell death.