Brain Mass (Energy) Resistant to Hyperglycaemic Oversupply: A Systematic Review

Cerebral energy supply is determined by the energy content of the blood. Accordingly, the brain is undersupplied during hypoglycaemia. Whether or not there is an additional cerebral energy demand that depends upon the energy content of the brain is considered differently in two opposing theoretical approaches. The Selfish-Brain theory postulates that the brain actively demands energy from the body when needed, while long-held theories, the gluco-lipostatic theory and its variants, deny such active brain involvement and view the brain as purely passively supplied. Here we put the competing theories to the test. We conducted a systematic review of a condition in which the rival theories make opposite predictions, i.e., experimental T1DM. The Selfish-Brain theory predicts that induction of experimental type 1 diabetes causes minor mass (energy) changes in the brain as opposed to major glucose changes in the blood. This prediction becomes our hypothesis to be tested here. A total of 608 works were screened by title and abstract, and 64 were analysed in full text. According to strict selection criteria defined in our PROSPERO preannouncement and complying with PRISMA guidelines, 18 studies met all inclusion criteria. Thirteen studies provided sufficient data to test our hypothesis. The 13 evaluable studies (15 experiments) showed that the diabetic groups had blood glucose concentrations that differed from controls by +294 ± 96% (mean ± standard deviation) and brain mass (energy) that differed from controls by -4 ± 13%, such that blood changes were an order of magnitude greater than brain changes (T = 11.5, df = 14, p < 0.001). This finding confirms not only our hypothesis but also the prediction of the Selfish-Brain theory, while the predictions of the gluco-lipostatic theory and its variants were violated. The current paper completes a three-part series of systematic reviews, the two previous papers deal with a distal and a proximal bottleneck in the cerebral brain supply, i.e., caloric restriction and cerebral artery occlusion. All three papers demonstrate that accurate predictions are only possible if one regards the brain as an organ that regulates its energy concentrations independently and occupies a primary position in a hierarchically organised energy metabolism. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=156816, PROSPERO, identifier: CRD42020156816.