Insulin and brain glucose handling
It has long been known that the brain abundantly expresses insulin receptors in all its major areas, indicating that this vital hormone controlling general glucose metabolism is important for brain function. However, mechanisms of neuro-vascular coupling at the blood-brain barrier (BBB) whereby active brain regions locally increase glucose and oxygen uptake are not considered to involve insulin under physiological circumstances. In other words, the brain has been considered the only organ in the body that is not dependent on insulin to modulate its glucose handling. Working with in vitro cultures of cells forming the BBB we found that insulin does modulate brain glucose metabolism by acting onto astrocytes, a cell type recently recognized to be a main player in brain glucose uptake. The reason the active role of insulin in brain glucose physiology was overlooked for so many years probably strives in that insulin acts in concert with insulin-like growth factor I (IGF-I), a closely related hormone that share many biological functions with insulin. They are so similar that even their respective receptors in cells can form hybrids that are also abundantly found in brain.
Using a set of pharmacological and molecular tools in vivo and in vitro to manipulate the function of these specialized brain cells, we determined that the concerted action of these two hormones in astrocytes recruits glucose transporter 1 (GluT1), the main brain glucose transporter. Although we still do not know many details of the mechanisms involved, a series of complex protein-protein interactions -not only of the insulin receptor, but naturally also the IGF-I receptor take place in response to the concerted action of insulin and IGF-I. The latter is triggered by neuronal activity and eventually results in the translocation of GluT1 to the cell membrane to facilitate glucose capture. Because neurons require extra glucose when they are active, this mechanism links insulin with neuronal activation. An intriguing aspect that was a byproduct of our observations is that the cooperative action of insulin and IGF-I abrogates an intrinsic negative regulation of the IGF-I receptor on glucose uptake by modifying its interactions with GluT1.
While it is early to predict the impact of these observations, the fact that insulin also regulates brain glucose supports many new avenues of research for key diseases such as diabetes, where central nervous system disturbances have been long recognized. They also provide a mechanism linking impaired insulin peptides activity with metabolic disturbances in brain illnesses such as Alzheimer´s dementia. As it is usually the case, more questions than answers have been unveiled with these findings.
Ignacio Torres Aleman
Cajal Institute, Spanish Research Council, Madrid, Spain
Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I
Fernandez AM, Hernandez-Garzón E, Perez-Domper P, Perez-Alvarez A, Mederos S, Matsui T, Santi A, Trueba-Saiz A, García-Guerra L, Pose-Utrilla J, Fielitz J, Olson EN, Fernandez de la Rosa R, Garcia Garcia L, Pozo MA, Iglesias T, Araque A, Soya H, Perea G, Martin ED, Torres Aleman I
Diabetes. 2017 Jan
|Astroglial magnetic fields and cortical neuronal coupling In recent years, it has been demonstrated an increasing role of astrocytes in information processing and cognitive functions, which depends on the close relationship between neurons and astrocytes into the…|
|Astrocytic modulation of brain waves The human brain contains two major cell populations: neurons and glia. While neurons can propagate electrical signals, known as action potentials, glial cells remain electrically unexcitable. For this reason, for…|
|Dementia with Lewy bodies and Parkinson’s… Dementia with Lewy bodies (DLB) and Parkinson's disease-dementia (PDD) are two closely related major neurocognitive disorders with Lewy bodies of unknown etiology. Both disorders show notable overlap in their clinical…|
|Prolactin regulates neurovascular coupling in male… Recent studies indicated that increased prolactin levels have negative effects on cognitive function in non-psychiatric populations and impair processing speed in patients with psychosis. According to the basic research, prolactin…|
|Astrocytes, friend or foe in the brain Glia, the “support” cells of the nervous system, are vital to the production, maintenance, and repair of one of the greatest triumphs of vertebrate evolution: the myelin sheath. For nerves…|
|How cancer cells communicate with nervous and immune systems In the last decade, studies have shown that cancer cells can influence their environment and bi-directionally communicate with other systems including immune and nervous systems. The neuro-immune interaction is a…|