ABSTRACT
The increase in obesity within populations across the globe is driving diabetes mellitus to an epidemic level. The most common complication of this disease is neuropathy, which affects at least 50% of diabetic individuals during their lifetime, and this condition causes significant levels of mortality and morbidity, such as through heart disease and non-traumatic amputations, respectively. Distal axonal degeneration is a hallmark of the disease, and mitochondrial dysfunction likely plays a key role in its manifestation. Hyperglycemia in diabetes can cause a nutrient surplus in neurons, and this excess alters the energy-sensing signaling pathway that critically controls mitochondrial biogenesis and regeneration. The AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) proteins are central to this pathway, and changes in their signaling can result in the loss of expression and activity of respiratory chain components. The net effect of reduction of oxidative phosphorylation capacity in these mitochondria means that the neurons cannot readily adjust to rapid changes in ATP demands, which can increase to extremely high levels in the peripheral nervous system. Due to this constraint on mitochondrial function, the energy supply in the distal nerve compartment of the neuron may then become exhausted, resulting in distal degeneration of peripheral neurons and nerve fiber dissolution. Recent findings have identified the muscarinic 1 receptor (M1R) as another critical component to this bioenergetics-signaling pathway, where it appears that peripheral neurons are under a cholinergic constraint that functions through M1R, and which limits neurite growth. Release of this M1R-mediated constraint permits the mitochondria to increase the cellular energy supply and allow for neuronal regrowth. As currently there is no treatment for diabetic peripheral neuropathy in the US that has been approved by the FDA, there is much excitement around this discovery because known M1R antagonists could act as first-in-class therapies.
