Cerebrospinal Fluid Insulin Levels Increase During Intravenous Insulin Infusions in Man*

Abstract

We hypothesized that plasma insulin crosses the blood-cerebrospinal fluid (CSF) barrier and, as people gain weight, provides a physiological feedback signal to the central nervous system to inhibit food intake and further weight gain. However, it has not been demonstrated in man that insulin can enter the CSF from peripheral blood. To test whether increases in plasma insulin result in elevated CSF immunoreactive insulin (IRI) levels, we infused insulin iv in varying amounts approximating postprandial levels in eight normal subjects for 4.5 h. Euglycemia was maintained [88 +/- 3 (+/- SEM) mg/dl] by means of a variable glucose infusion. Samples were obtained every 30 min for measurements of insulin in peripheral plasma and insulin in lumbar CSF. Plasma IRI increased from a mean basal level of 12 +/- 1.2 microU/ml to a mean (during the 180- to 270-minute period) of 268 +/- 35 microU/ml. CSF IRI increased in all subjects during the infusion from a mean basal level of 0.9 +/- 0.1 microU/ml to a mean (during the 180- to 270-min period) of 2.8 +/- 0.4 microU/ml (P less than 0.006). By contrast, CSF IRI in two subjects who received an infusion of 0.9% saline did not increase. In summary, CSF insulin concentrations increased during peripheral infusions of insulin. This is the first demonstration in man that plasma insulin gains access to CSF and indicates a mechanism whereby peripheral insulin could provide a feedback signal to the central nervous system.

A high-fat-diet-induced cognitive deficit in rats that is not prevented by improving insulin sensitivity with metformin

“…Peripheral hyperinsulinaemia reduces insulin transport across the blood/ brain barrier, generating insulin deficiency in the brain (for a review, see Craft [36]), and thus reducing the protective actions of insulin on neurons. Conversely, hyperinsulinaemia in the periphery has been reported to promote hyperinsulinaemia in the central nervous system (CNS) [37]. In contrast with the protective effects of physiological insulin, hyperinsulinaemia can sensitise neurons to toxin and stress-induced insults in culture [38].…”

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

“…In several species including man, acute elevations of plasma insulin levels have been consistently found to induce corresponding increases in CSF insulin concentrations, indicating that the brain content of insulin is normally finely tuned to circulating insulin concentrations [28]. Obese humans, however, whose plasma insulin levels are elevated as a result of peripheral insulin resistance, do not display parallel increases in CSF insulin levels, but rather have a decreased CSF:plasma insulin ratio [29].…”

Low cerebrospinal fluid insulin levels in obese humans

“…In healthy men, insulin concentrations in cerebrospinal fluid (CSF) increase after acute elevations of plasma insulin levels, indicating that the brain content of insulin is normally finely tuned to circulating insulin [1]. Central nervous insulin promotes weight loss [2] and attenuates peripheral insulin resistance via inhibition of hepatic gluconeogenesis [3].…”