Insulin Resistance and Neurodegeneration: Type-2
Versus Type-3 Diabetes Mellitus
Growing evidence suggests that Alzheimer's disease (AD), like Type 2 diabetes mellitus (T2DM), is an insulin resistance disease. Human studies revealed that AD is associated with significant deficits in insulin and insulin-like growth factor (IGF) polypeptide and receptor gene expression, and impaired insulin/IGF receptor binding in brain. These abnormalities worsen as AD progresses, and correlate with cholinergic dyshomeostasis. Due to molecular, biochemical, and functional overlap with T1DM and T2DM, but confinement to the brain, we suggested that AD be regarded as T3DM. Correspondingly, experimental T3DM was produced by intracerebral injection of the pro-diabetes compound, Streptozocin, and the associated neurodegeneration and cognitive impairment were ameliorated by treatment with insulin sensitizer drugs. However, epidemiological correlations between obesity or T2DM and cognitive impairment or AD prompted us to clarify the role of T2DM in relation to neurodegeneration. Obesity with T2DM and non-alcoholic steatohepatitis (NASH) was found to be sufficient to cause brain atrophy, cognitive impairment, and brain insulin resistance with cholinergic deficits, but the structural and biochemical abnormalities were far less than in AD/T3DM. Therefore, obesity, T2DM, and NASH may contribute to AD progression, but do not alone cause AD. Recent work suggests roles for neurotoxic lipids, i.e. ceramides, generated in liver and capable of crossing the blood-brain barrier, as mediators of brain insulin resistance in obesity, T2DM, and NASH, and thereby establish a liver-brain axis of neurodegeneration. Therefore, the potential exists for using insulin sensitizer agents to target T2DM, NASH, and AD, despite possibly different mechanisms of neurodegeneration.