Insulin receptors in the brain play an important role in a variety of physiologic functions (memory, cognitive function, control of appetite, energy homeostasis, and endogenous glucose production). Cerebral insulin receptors seem to be involved in neurodegenerative diseases such as Alzheimer's disease and metabolic diseases such as obesity and type 2 diabetes. The prevalence of these diseases increases 
and, especially for obesity and diabetes, has reached epidemic proportions in western populations. Cerebral insulin resistance (i.e. reduced availability and/or effectiveness of insulin in the brain) might contribute to the pathogenesis of these diseases and, therefore, strategies to improve or overcome cerebral insulin resistance may become relevant for the therapy and prevention of obesity, type 2 diabetes and neurodegenerative diseases.
In a previous study, in which we established the detection of insulin effects on cerebrocortical activity with MEG, we have shown that human obesity is characterized by a reduced cerebral insulin response 
. In the current study we designed a hyperinsulinemic euglycemic clamp with i.v. application of insulin detemir. As we hypothesized increased cerebrocortical action of the insulin analogue, it was necessary to achieve a similar or slightly lower effect on peripheral glucose metabolism than in the experiment using human insulin. Furthermore the time-profile of the plasma insulin concentrations had to be mimicked. First, 10 overweight subjects were investigated, and consistent with our previous findings human insulin did not change cortical activity. However, insulin detemir increased beta activity considerably, and therefore seems to improve the cerebrocortical response in beta activity. It is of note that the increase of the cerebrocortical effect was achieved despite lower peripheral effects, which justifies the conclusion of a brain-specific effect of insulin detemir in humans. Furthermore, the effect of insulin detemir in these overweight subjects was comparable to the effect of human insulin in the lean.
As proposed in the mouse study 
, an increased effect of insulin detemir in the brain may be explained by differences in albumin binding. In the brain, albumin concentrations are 200-fold lower than in the circulation 
, while in skeletal muscle they are only 5-fold lower 
. In contrast to the brain, in skeletal muscle a considerable proportion of insulin detemir is bound to interstitial albumin. While in the circulation the albumin-bound insulin detemir appears to be metabolically inactive, it is unclear whether the local albumin concentrations in the skeletal muscle further reduces binding of insulin detemir to the receptor. In dogs, human insulin and insulin detemir induced a similar glucose uptake when interstitial concentrations of both insulins were similar, while the serum concentrations of insulin detemir were much higher than those of human insulin 
. This finding indicates that in the circulation albumin-bound insulin detemir is metabolically inactive because it does not contribute to the passive transport to the interstitial fluid of the skeletal muscle while albumin-bound insulin detemir in the interstitial fluid contributes to receptor binding and is metabolically active. The main reason for the increased effect of insulin detemir in the brain is probably an increased transport across the blood-brain barrier. Insulin crosses the blood-brain barrier via an insulin receptor mediated active transport which is located on the vascular endothelium of brain blood vessels 
. Like the insulin receptor in the skeletal muscle cell, this receptor is exposed to free and albumin-bound insulin detemir, however, in a much higher concentration (up to 40-fold higher). In contrast to the passive transport in peripheral tissues, the albumin-bound insulin detemir contributes to the active transport across the blood-brain barrier which leads to higher brain tissue concentrations as observed in mice 
Beta activity and other frequency bands are very unspecific measures of cerebrocortical activity. Changes in this parameter may reflect multiple functions and at the current stage no specific function can be assigned to the insulin effect. Therefore, it is unclear whether the increase of beta activity by insulin in lean subjects or by insulin detemir in overweight subjects is directly involved in body weight regulation, glucose tolerance or neuroprotection and whether it reflects a beneficial effect on brain function. However, we have some circumstantial evidence of a functional link as we recently found that a polymorphism in the FTO
gene, which is related to obesity, is associated with a decreased insulin effect on cerebrocortical beta activity 
. Though FTO is expressed in the brain, its function in humans is unclear. However, a decreased insulin response of the brain beta activity may contribute to the obesity effect of variation in this gene locus. Another interesting aspect is that insulin detemir has favorable effects on body weight development. Throughout all phase III studies, patients receiving insulin detemir displayed no weight gain or even weight loss, while patients receiving NPH insulin displayed weight gain 
. This difference was observed under comparable glycemic control, strengthening the assumption of a specific weight-lowering effect of insulin detemir. Therefore, one may speculate that the increased cerebrocortical effect of insulin detemir in presence of comparable peripheral effects might be involved in the beneficial effects of insulin detemir on body weight development during insulin treatment.
In conclusion, we demonstrate that insulin detemir acts in the human brain more efficiently than human insulin at comparable or even lower peripheral metabolic effects. This tissue selectivity has already been demonstrated in mice and might be explained by the pharmacokinetic properties of insulin detemir. In the present study we could stimulate cerebrocortical beta activity in subjects who displayed no effect of human insulin in the brain. Therefore, insulin detemir seems to be a tool to restore at least in part the cerebrocortical insulin response in overweight humans. This principle may become a new therapeutic paradigm in obesity, type 2 diabetes and neurodegenerative diseases and might be applicable to other peptides which act in peripheral tissues and the brain.