Badly controlled diabetes are known to affect the brain, causing memory and learning problems and even increased incidence of dementia. How this occurs is not clear but a study in mice with type 2 diabetes has discovered how diabetes affects the hippocampus, causing memory loss, and also how caffeine can prevent this. 

Curiously, the neurodegeneration that Rodrigo Cunha,  from the Centre for Neuroscience and Cell Biology of the University of Coimbra in Portugal, sees as result of  diabetes is the same that occurs at the first stages of several neurodegenerative diseases, including Alzheimer’s and Parkinson’s, suggesting that caffeine (or drugs with similar mechanisms) could help them too.

 Type 2 diabetes, which accounts for about 90%of all diabetic cases, is a full-blown public health disaster – 285 million people affected worldwide - 6.4% of the world population - with numbers expected to almost double by 2030, without counting pre-diabetic individuals. The problem is that the disease is triggered by obesity, sedentary lifestyle and bad eating habits (although there is also a genetic predisposition), all of which are increasingly widespread. 

Diabetes is caused by high levels of sugar in the blood, and in type 2 this occurs because the body becomes increasingly resistant to insulin –the hormone that allows cells to take sugar from the blood to use as “fuel” – resulting in toxic high levels of sugar  in the blood that damage nerves and blood vessels and, with time, cause severe complications

In the new study, João Duarte, Rodrigo Cunha and colleagues take advantage of a new mouse model of diabetes type 2, which, like humans, develops the disease in adults as result of a high-fat diet, to look at one of the least understood complications of diabetes – the disease effect on the brain, more specifically, on memory. They also investigate a possible protective effect by caffeine as this psychostimulant has been suggested to prevent memory loss in a series of neurodegenerative diseases, maybe even in diabetes, although how this happens is not known. when we consider that coffee is the world leading beverage right after water, with about 500 billion cups consumed annually, this effect, if true, needs to be better understood.

With that aim the researchers compared 4 groups of mice - diabetic or normal animals without or with caffeine (equivalent to 8 cups of coffee a day) in their water – to find that long-term consumption of caffeine not only diminished the weight gain and the high levels of blood sugar typical of diabetes, but also prevented the mice's memory loss (diabetic animals had significantly poorer memory than normal ones). This confirmed that caffeine seems to, in fact, protect against diabetes as well as prevent memory impairment, probably by interfering with the neurodegeneration caused by toxic sugar levels.

Obese rat with diabetes (Image by Joanna Servaes)

To investigate that, next the researchers looked at the brain region linked to memory and learning, which is often atrophied in diabetics -  hippocampus. Diabetic mice had abnormalities in this area showing synaptic degeneration (synapses are the structures at the end of each neuron used to communicate between neurons) and astrogliosis (an abnormal increase of the cells that surround neurons normally as result of the deathof nearby neurons). Both phenomena are known to affect memory and  caffeine consumption  prevented the abnormalities.

But to be able to develop drugs based on caffeine’s protective effect, it was necessary to understand its molecular mechanism first. So next the researchers looked at the only brain molecules known to respond to caffeine – the adenosine receptors A1R and A2AR - in the hippocampus. And here, A2AR seemed to be the key for caffeine’s memory rescue since its density - which increases with noxious insults - was high in diabetic animals but normal in those treated with caffeine. This agreed with other studies that showed that A2AR inhibition protected against synaptic degeneration and memory dysfunction.

In conclusion, Duarte and Cunha’s work – using an animal model of diabetes type 2 that closely mimics the human form of the disease – suggests that diabetes affects memory by causing synaptic degeneration, astrogliosis and increased levels of A2AR, and that chronic consumption of caffeine can prevent the neurodegeneration and the memory impairment. And since synaptic degeneration and astrogliosis are part of a cascade of events common to several neurodegenerative diseases it is probable too that caffeine (or similar drugs) could help them through the same mechanisms.

So does this means that we should drink eight cups of coffee a day to prevent memory loss in old age or diabetes? 

Not really as Rodrigo Cunha, the team leader explains: “Indeed, the dose of caffeine shown to be effective is just too excessive. All we can take from here is that a moderate consumption of caffeine should afford a moderate benefit, but still a benefit. Such experimental design is common in pre-clinical studies: in order to highlight a clear benefit, one dramatizes the tested doses. But it's an important  first step. Our ultimate goal is the design of a drug more potent and selective (i.e. with less potential side effects) than caffeine itself; animal studies enable us to pinpoint the likely target of caffeine with protective benefits in type 2 diabetes. So now we will be testing chemical derivates of caffeine, which act as selective adenosine A2A receptor antagonists,to try to prevent diabetic encephalopathy. It might turn out to be a therapeutic breakthrough for this devastating disease”. 

And a breakthrough in a disease that is already affecting 6.4% of the population and growing can never come too soon.

Citation: Duarte JMN, Agostinho PM, Carvalho RA, Cunha RA, 'Caffeine Consumption Prevents Diabetes-Induced Memory Impairment and Synaptotoxicity in theHippocampus of NONcZNO10/LTJ Mice', PLoS One 7(4): e21899.doi:10.1371/journal.pone.0021899 (2012)