‘Type 3’ diabetes: a brain insulin‐resistant state linked to Alzheimer's disease

Over the years, identifying novel sub-type variants of diabetes has always provided a measure of academic interest as well as an engaging area for debate and discussion. Having established the relatively clear-cut classification of type 1 and type 2 diabetes, it was perhaps inevitable that a further category of type 3 diabetes would in due course emerge. Indeed, a number of putative candidates has been put forward, including ‘Double Diabetes’ (a combination of type 1 diabetes and insulin resistance), MODY3 and more recently type 3c (pancreatogenic) diabetes. But the most intriguing remains the proposal by Suzanne de la Monte and colleagues1 that the term type 3 diabetes could be appropriately applied to an association between a state of brain insulin resistance and dementia, including Alzheimer’s disease. Diabetes itself transcends into every aspect of clinical medicine, with familiar consequences to a legion of other specialist disorders. For good reason, a major focus of diabetes in recent years has been directed towards its long-term adverse cardiovascular effects, with clinical trials of new therapeutic interventions designed to evaluate potential benefits, or otherwise, in respect of reducing the substantial risk to the heart, the circulation and to overall mortality. In the same context, the effects of diabetes on the brain should now be considered with comparable concern. Although it may still seem difficult to justify the precise terminology of ‘type 3’ diabetes, given that hyperglycaemia itself is not an absolute prerequisite, the concept, nonetheless, of a brain insulin-resistant state, associated with increased risk of developing dementia, has not been unduly challenged. Certainly, it has engendered a stimulating two-way perspective on underlying pathogenic mechanisms shared between type 2 diabetes and Alzheimer’s disease. This fascinating notion of a new sub-type of diabetes prompted an editorial review in Practical Diabetes some four years ago,2 outlining the emerging evidence of cerebral metabolic dysfunction, characteristic of a central insulin resistance, linked to a process of progressive neuronal stress, neurodegeneration, cognitive decline and eventual dementia. Although acknowledging the proposal was somewhat speculative at the time, the possibility of such pathogenic mechanisms contributing to the process of dementia, with or without underlying diabetes, seemed sufficiently plausible to warrant further studies and potential therapeutic opportunities.