Fig. 2

Decreased production of adenosine triphosphate or decreased glucose metabolism in neurons and decreased glucose metabolism in the skeletal muscle may contribute to the hyperexcitability and selective degeneration of upper and lower motor neurons and muscle pathology/denervation in ALS, respectively. Insulin resistance and glucose intolerance may underpin an inability to efficiently use glucose as an energy substrate. Overall, an inabillity to use glucose in the periphery, in neurons and in skeletal muscle will result in an increased dependence on the use of fat as an energy substrate to offset energy deficit. With escalating metabolic pressure, the rapid depletion of endogenous energy stores will result in a catastrophic failure to meet increased metabolic demand. Thus, a vicious cycle of bioenergetic deficit may underpin or exacerbate disease pathogenesis in ALS