Neuron-glia interactions in patients with type 2 diabetes

This thesis investigates neurons and glial cells in several areas of the forebrain of patients with type 2 diabetes mellitus (T2DM). These investigations focused on the brain areas involved in the control of energy homeostasis, circadian rhythms and learning and memory. The proopiomelanocortin (POMC) and neuropeptide-Y (NPY) expressing neurons of the hypothalamic infundibular nucleus (IFN) are at the core of energy homeostasis. In the IFN of subjects with T2DM we discovered highly selective, treatment-dependent changes in POMC and NPY neurons and in microglial cells.
In humans, circadian rhythm is controlled by the suprachiasmatic nucleus (SCN). In the SCN, we discovered selective changes in different cell types in patients with T2DM, providing the first evidence that chronic T2DM pathogenesis is substantially linked to a dysfunction of the biological clock machinery in humans.
The nucleus basalis of Meynert (NBM) is vital for the proper functioning of memory and learning abilities. The NBM is one of the first areas of the brain affected by Alzheimer’s disease (AD) pathology, exemplified by the loss of cholinergic neurons and increased hyper phosphorylation of the tau protein. In the NBM of T2DM subjects we found no difference in these pathological changes compared to their non-diabetic controls. However, these pathological changes were significantly reduced when T2DM patients were treated with insulin. These data emphasize the role of impaired insulin signaling in AD development and, maybe even more important, it implies that insulin replacement may be effective in lowering the progression of this disease.