Homocysteine: A Potential Molecular Link Between Alzheimer\u27s Disease and Type 2 Diabetes Mellitus

In order to elucidate some of the mechanisms through which Alzheimer’s disease (AD) and Type II Diabetes Mellitus (T2DM) are linked, this study investigated the effects of elevated plasma homocysteine levels – a risk factor for AD – in a rat model of T2DM. Both elevated plasma homocysteine levels and T2DM are associated with cognitive deficits and are recognized as strong risk factors for the development of AD. The present experiment examined the effects of diet-induced hyperhomocysteinemia on the development of cognitive impairments and insulin-resistance, as well as on the insulin signaling cascade, in a diet-induced obese rat model of T2DM. Hyperhomocyteinemia was induced in both control-fed and high-fat diet plus fructose-fed (T2DM) animals using dietary supplementation of 2% methionine. Homocysteine levels were dramatically elevated in animals receiving methionine supplementation and a high-fat diet plus fructose and were significantly increased in animals receiving either high methionine or high fat plus fructose. Behavioral impairments were observed in all groups receiving treatment. Impaired glucose tolerance was observed in animals receiving either high methionine or high fat plus fructose diets; glucose intolerance was observed in animals receiving both treatments. Akt phosphorylation was reduced by 50% in groups receiving high methionine, regardless of high fat plus fructose. These findings strongly suggest that there are mechanisms at work by which homocysteine modulates the insulin signaling pathway and/or vice versa