Insulin in the brain: there and back again

Abstract

Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BECs), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BECs, protect the integrity of the BBB and its ability to transport insulin. Most of insulin's known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer's disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain.

Figure 1

Relative growth of the fields reviewed here as evidenced by publications per 5 year period. Publications on insulin greatly increased in the later half of the 1940’s and publications on insulin and the brain surged in the early 1960’s. Insulin and the BBB remains a little explored topic, but publications in all three fields are growing exponentially.

Figure 2

Schematic of relation among concepts of peripheral and central insulin receptors, forms of diabetes, and major actions of insulin. In the blood, insulin, the insulin receptor, and the GLUT-2 receptor are engaged in a negative feedback loop with glucose. At the BBB, the insulin receptor and the insulin transporter are both present with the receptor affecting several aspects of brain endothelial cell function and the transporter involved in the blood-to-brain translocation of insulin. Within the brain, the insulin receptor rarely induces glucose uptake by brain cells. Instead, it has effects on feeding that are largely opposite to those produced by insulin in the periphery. CNS insulin also has effects on cognition. Lack of insulin production by the pancreas induces diabetes mellitus (DM) type I. Resistance to peripheral insulin is well recognized in DM type II and resistance to CNS insulin is often referred to as DM type III. The relation between DM type II and type III requires further investigation.

Figure 3

Effect of Glucose on Insulin Transport Across Brain Endothelial Cells: Protective Effect of Pericytes. Primary monolayer cultures of mouse (CD-1 strain) brain endothelial cells were cultured alone (MBEC), in co-culture with astrocytes (MBEC + A) or with pericytes (MBEC + P), or in triculture with pericytes and astrocytes (MBEC + P + A). Cultures were incubated for 2 h at various concentrations of glucose ranging from 0 to 10 mg/ml. After the two hours, the glucose concentration was returned to 4.5 mg/ml, adioactive insulin with our without unlabeled insulin added to the luminal chamber, and abluminal contents sampled at 5, 10, 20, and 30 min. The permeability coefficient was calculated and expressed relative to the (0 mg/ml glucose radioactive insulin only group). A difference between the radioactive and the + unlabeled insulin group demonstrates the presence of saturable insulin transport. The results indicate that pericytes are important to the saturable transport of insulin across brain endothelial cells. *p<0.05 and **p<0.01 between indicated comparisons; + p<0.05 incomparison to the panel’s “0 mg/ml unlabeled insulin” group.