Diabetic neuropathy (DN) is the most common cause of peripheral neuropathy in the United States, yet the pathogenesis remains unknown. Although diabetes can affect all peripheral neurons, sensory neurons are most commonly affected, possibly because dorsal root ganglion (DRG) neurons reside outside the blood-nerve barrier. Hyperglycemia has been implicated in both animal and human studies in the pathogenesis of DN and recent clinical trials have shown a reduction in the progression of DN with careful control of blood glucose an intensive insulin therapy. However even excellent glycemic control fails to prevent or reverse DN. Insulin-alike growth factor I (IGF-I) can improve glycemic control in diabetes and is able to promote neuronal growth, development, and regeneration of neurons. In ongoing preliminary studies, we find that hyperglycemia leads to impaired rat DRG sensory neuronal growth and programmed cell death (PCD). In both paradigms, IGF-I is neuroprotective. Our initial investigations of IGF-I neuroprotection reveal that 1) IGF-I acts trough the type I IGF receptor (IGF-IR activation results in downstream phosphorylation of focal adhesion proteins involved in organization of the actin cytoskeleton and neurite formative, and 3) IGF-IR activation of phosphatidylinositol-3 kinase (PI-3K) is essential for rescue of neuronal cells from PCD. We have developed a novel hypothesis to explain hyperglycemic coupled neurotoxicity. We speculate that high glucose alters IGF-IR activation in DRG neurons. This result in changes in the phosphorylation of focal adhesion proteins which results in disruption of the actin cytoskeleton and impairs DGR neurite growth. We believe subsequent cytoskeletal changes alone, or in conjunction with direct glucose toxicity, induce PCD in DRG neurons. Activation of IGF-IR 1) prevents PCD by enhancing focal adhesion protein phosphorylation and stabilizing the cytoskeleton, and/or 2) blocks PCD by activating PI 3K pathways, which may effect PCD regulatory proteins like bcl-2 and/or death proteases. In this proposal we will test each component of the model. We have 2 aims: 1. Examine the effect of high glucose on DRG neurons. In DRG neurons, in response to high glucose, examine: a) DRG neuronal morphology and neurite growth b) IGF-IR transcription, cell surface abundance, and autophosphorylation c) Phosphorylation of focal adhesion proteins and the DRG cytoskeleton and d) PCD in DRG 2. Characterize IGF-IR protection of DRG neurons following glucose exposure. In DRG neuron, in response to high glucose, examine the effect of IGR-I on: a) DRG neuronal morphology and neurite growth b) IGF-IR transcription, cell surface abundance, and autophosphorylation c) Phosphorylation of focal adhesion proteins and the DRG cytoskeleton 3. Investigate the components underlying IGF-IR rescue of DRG from glucose-induced PCD. a) Determine the association between the observed changes in focal adhesion proteins, the cytoskeleton, an PCD pathways in response to high glucose b) Examine the effect of high glucose and IGF-I on IGF-IR activation of PI-3K c) Ascertain if IGF-IR activation prevents PCD by promoting expression of regulatory proteins that suppress cell death, like bcl-2 d) Determine if high glucose promotes PCD by activation of death proteases, and the role of IGF-IR activation in modulating this PCD pathway. IGF-I is currently undergoing evaluation in clinical trails of diabetic neuropathy. The current proposal will help elucidate the mechanisms underlying the role of IGF-I in preventing changes in neuronal morphology and PCD in diabetic neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001938-05
Application #
6330372
Study Section
NST-2 Subcommittee (NST)
Program Officer
Nichols, Paul L
Project Start
1996-12-01
Project End
2001-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
5
Fiscal Year
2001
Total Cost
$99,252
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cowell, Rita M; Blake, Kathryn R; Inoue, Tatsuya et al. (2008) Regulation of PGC-1alpha and PGC-1alpha-responsive genes with forskolin-induced Schwann cell differentiation. Neurosci Lett 439:269-74
Vincent, Andrea M; Brownlee, Michael; Russell, James W (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368-83
Russell, James W; Golovoy, David; Vincent, Andrea M et al. (2002) High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 16:1738-48
Russell, J W; Gill, J S; Sorenson, E J et al. (2001) Suramin-induced neuropathy in an animal model. J Neurol Sci 192:71-80
Delaney, C L; Russell, J W; Cheng, H L et al. (2001) Insulin-like growth factor-I and over-expression of Bcl-xL prevent glucose-mediated apoptosis in Schwann cells. J Neuropathol Exp Neurol 60:147-60
Cheng, H L; Steinway, M L; Russell, J W et al. (2000) GTPases and phosphatidylinositol 3-kinase are critical for insulin-like growth factor-I-mediated Schwann cell motility. J Biol Chem 275:27197-204
Russell, J W; Cheng, H L; Golovoy, D (2000) Insulin-like growth factor-I promotes myelination of peripheral sensory axons. J Neuropathol Exp Neurol 59:575-84
Smith, A G; Urbanits, S; Blaivas, M et al. (2000) Clinical and pathologic features of focal myositis. Muscle Nerve 23:1569-75
Feldman, E L; Russell, J W; Sullivan, K A et al. (1999) New insights into the pathogenesis of diabetic neuropathy. Curr Opin Neurol 12:553-63
Russell, J W; Feldman, E L (1999) Insulin-like growth factor-I prevents apoptosis in sympathetic neurons exposed to high glucose. Horm Metab Res 31:90-6

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