Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance resulting in glucose intolerance and hyperglycaemia .
Since insulin effectiveness is reduced in diabetes, research into other signalling pathways that support insulin actions or that reduce blood glucose is ongoing. One of these strategies focus on the use of the incretins, a class of peptide hormones that helps to normalise insulin signaling and also improves blood sugar levels. Incretins increase the release of insulin during high blood sugar levels, the so-called 'incretin effect'. Drugs that mimic incretin hormones can maintain glucose homeostasis and improve multiple symptoms of type 2 diabetes like the risk of hypoglycaemia, inadequate post-prandial blood glucose control, glucose fluctuations, β-cell failure, and weight gain [1, 2].
GLP-1 is an endogenous 30-amino acid peptide hormone. Numerous novel long-lasting GLP-1 receptor agonists have been developed by several companies. Exendin-4 (Byetta) has been on the market as a T2DM treatment for several years . Liraglutide (Victoza) also has been released onto the market several years ago . A third drug is lixisenatide (Lyxumia), which will be released onto the market soon .
T2DM has been identified as a risk factor for AD, indicating that insulin signaling failure may be a factor in initiating or accelerating the development of AD. Epidemiological studies found a clear correlation between T2DM and the risk of developing AD [6–8]. It was also shown that insulin receptors in the brain are desensitised in AD patients [9, 10]. Therefore, a promising strategy to treat AD is the use of such GLP-1 analogues . GLP-1 receptors are found on neurons in the brains of rodents and humans [12, 13]. The GLP-1 receptor agonists exendin-4, liraglutide, lixisenatide, and (Val8)GLP-1 have neuroprotective properties. The protease resistant and long-lasting GLP-1 analogue Val(8)GLP-1 enhanced synaptic plasticity in acute and chronic application and preserved synaptic functionality in the brains of a mouse model of AD [14, 15]. The novel GLP-1 analogue liraglutide lowered plaque formation, protected memory and synaptic plasticity, and reduced inflammation in the brains of a mouse model of Alzheimer disease . All of these effects in the brain were observed after peripheral injection. Therefore, it is likely that these peptides have to be able to cross the blood brain barrier (BBB).
The focus of this study was to measure the kinetics of incretin drugs of crossing the blood brain barrier, activation of incretin receptors by measuring cAMP levels, and physiological effects in the brain on cell proliferation and neurogenesis.