Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV.
Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
JAMA. 2009 Apr 15;301(15):1565-72.
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The work of Whitmer et al. on the relationship of hypoglycemia to dementia risk in elder type 2 diabetics is a fine investigation of an important topic. Given its necessarily correlational nature, the work is so well conceived, conducted, and reported that it makes for a worthwhile read. The discussion is excellent and indicates the likely molecular basis for the findings in as much detail as is possible at this stage of research with references to the appropriate literature. The section on strengths and weaknesses is honest and useful in qualifying the findings for the reader.
This paper fits with our hypothesis that glucose deprivation increases BACE1 mRNA translation and hence increases the risk of AD, as type 2 diabetes has been shown to do epidemiologically. However, the study has not investigated mechanism, so the jury is out as to the cause of the dementia associated with hypoglycemic events. It may be more likely that the dementia found in this study is due to direct neuronal damage caused by hypoglycemia rather than BACE1 or Aβ increases. That said, if those individuals continue to have chronic hypoglycemic events and later develop AD (they were an average age of only 65, so are too young for AD now) then the AD might be the result of glucose deprivation-induced BACE1 and Aβ increases. Clearly, this is speculative and much more mechanistic work needs to go into the association between diabetes and AD. Analyzing brain tissue from diabetic patients for BACE1 and Aβ would be one step in this direction.