Insulin-like growth factor-1-dependent maintenance of neuronal metabolism through the phosphatidylinositol 3-kinase-Akt pathway is inhibited by C2-ceramide in CAD cells.

Ceramide is a lipid second-messenger generated in response to stimuli associated with neurodegeneration that induces apoptosis, a mechanism underlying neuronal death in Parkinson's disease. We tested the hypothesis that insulin-like growth factor-1 (IGF-1) could mediate a metabolic response in CAD cells, a dopaminergic cell line of mesencephalic origin that differentiate into a neuronal-like phenotype upon serum removal, extend processes resembling neurites, synthesize abundant dopamine and noradrenaline and express the catecholaminergic biosynthetic enzymes tyrosine hydroxylase and dopamine beta-hydroxylase, and that this process was phosphatidylinositol 3-kinase (PI 3-K)-Akt-dependent and could be inhibited by C(2)-ceramide. The metabolic response was evaluated as real-time changes in extracellular acidification rate (ECAR) using microphysiometry.

Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons.

We tested the hypothesis that neurotrophic factors control neuronal metabolism by directly regulating mitochondrial function in the absence of effects on survival. Real-time whole cell fluorescence video microscopy was utilized to analyze mitochondrial inner membrane potential (Delta Psi(m)), which drives ATP synthesis, in cultured adult sensory neurons. These adult neurons do not require neurotrophic factors for survival.

Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy.

Symmetrical sensory polyneuropathy, the most common form of diabetic neuropathy in humans, is associated with a spectrum of structural changes in peripheral nerve that includes axonal degeneration, paranodal demyelination, and loss of myelinated fibers--the latter probably the result of a dying-back of distal axons. Mitochondrial dysfunction has recently been proposed as an etiological factor in this degenerative disease of the peripheral nervous system. Lack of neurotrophic support has been proposed as a contributing factor in the etiology of diabetic neuropathy based on studies in animal models of Type I diabetes.

Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons of type 1 diabetic rats in the presence of sustained hyperglycemia.

Mitochondrial dysfunction has been proposed as a mediator of neurodegeneration in diabetes complications. The aim of this study was to determine whether deficits in insulin-dependent neurotrophic support contributed to depolarization of the mitochondrial membrane in sensory neurons of streptozocin (STZ)-induced diabetic rats. Whole cell fluorescent video imaging using rhodamine 123 (R123) was used to monitor mitochondrial inner membrane potential (deltapsi(m)).