Insulin resistance has been found to be a strong risk factor in the development of Alzheimer's disease and other age related neurological disorders. We have shown that reduced muscle mitochondrial oxidative metabolism plays a key role in the etiology of insulin resistance in aging, pre-diabetes, and diabetes. However it is not known whether there is a similar decrease in the brain. Mitochondrial dysfunction has been implicated in the cognitive decline with aging, Alzheimer's disease and other neurodegenerative disorders. In this proposal we will test whether reduced mitochondrial metabolism is a risk factor for age related neurological disorders in insulin resistance. We will combine 13C MRS to measure the rate of the neuronal TCA cycle with 31P MRS to measure energetic stress. 13C MRS has the unique capability to measure the rates of the neuronal and glial TCA cycles - a direct measure of in vivo mitochondrial oxidative energy production. We and others have used MRS to show that 80% of neuronal mitochondrial energy production supports neuronal signaling, with the implication that even small impairments in mitochondrial capacity could compromise brain function. Recently we applied these methods to study healthy elderly subjects. We found profound alterations in energy metabolism in the occipital lobe, including a 28% reduction in the neuronal TCA cycle. Our general hypothesis is that healthy non-diabetic, insulin-resistant subjects have a reduced capacity of neuronal mitochondria to support energetic requirements of brain function which may predispose them to age-related neurological disorders. We will test our hypothesis in otherwise healthy non-obese, insulin-resistant subjects who are the offspring of at least one parent with type 2 diabetes. In our metabolic studies we have extensively phenotyped a large cohort of these subjects because they allow the etiology and health impacts of chronic insulin resistance to be studied independent of the complications of diabetes and obesity.
Insulin resistance has been shown to be a major risk factor for Alzheimer's disease and other dementias, however the mechanism for this increased risk is unknown. The proposed studies will use 13C MRS to study in human brain whether mitochondrial oxidative metabolism is reduced in the prefrontal cortex of subjects with insulin resistance. A positive finding will implicate alterations in brain mitochondrial function in the increased risk conferred by insulin resistance and potentially lead to new treatment strategies.