Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance

Discussion

We found that insulin stimulates brain glucose metabolism, but this effect depends on the glucose tolerance of the subjects: insulin did not increase brain glucose metabolism in subjects with normal glucose tolerance but significantly increased glucose metabolism in patients with impaired glucose tolerance. That is, the effect of insulin on brain glucose metabolism was not maximal in the fasting state in patients with impaired glucose tolerance, although it was so in healthy subjects, suggesting that the groups are differentially placed on the insulin dose-response curve.

How are these seemingly unexpected results interpreted in the context of the concept of insulin resistance? With regard to healthy subjects, our results are consistent with previous studies that have shown no effects of physiological postprandial insulin levels on brain glucose metabolism.^[10,11] Thus, the effect of insulin on brain glucose metabolism is already maximal at physiological fasting insulin levels in healthy subjects, because decreasing insulin levels is able to decrease brain glucose metabolism.^[12,13] However, insulin-resistant patients are insensitive to decreasing insulin levels,^[12] whereas we found higher brain responses to insulin in these patients. These findings suggest that patients with peripheral insulin resistance need more insulin than healthy subjects to get the maximal effect of insulin on brain glucose metabolism. In the fasting condition, we did not find lower glucose metabolism in patients with impaired glucose tolerance, which argues against simple insulin resistance in the brain. However, similar glucose metabolism was maintained with higher plasma insulin levels (Table 1), although the implications of this observation are unclear, given that decreasing plasma insulin does not decrease brain glucose metabolism in these patients.^[12]

Disturbances in brain insulin signaling in patients with impaired glucose tolerance may occur at multiple levels, including delivery of insulin in the brain across the blood-brain barrier, actions of insulin at insulin receptors, and downstream effects via second-messenger systems.^[4] Obese patients have a lower cerebrospinal fluid–to–plasma insulin ratio,^[6] which would suggest deficient delivery of insulin into the brain. However, obese patients also show decreased catabolic, but not cognitive, responses to intranasal insulin, which bypasses the blood-brain barrier,^[7] suggesting that insulin resistance in the brain occurs at multiple levels. Based on the current results, it may be speculated that some components along the insulin pathway in the brain are actually sensitized because of long-term deprivation of insulin stimulation and show exaggerated responses to high insulin levels in these patients. For example, if decreased insulin delivery across the blood-brain barrier and decreased responsiveness of insulin receptors inhibit stimulation of the insulin pathway at physiological insulin levels, despite compensatory hyperinsulinemia, we might expect to see increased responses to insulin when insulin levels are sufficiently high to overcome these deficits upstream in the signaling pathway. Unfortunately, no evidence for sensitization of any of the components in this signaling pathway exists in humans, and this hypothesis remains speculative until further data emerge.

We measured brain glucose metabolism using the macroparameter CMRglu and cannot therefore distinguish between increased glucose transport across the blood-brain barrier and increased brain hexokinase activity in patients with impaired glucose tolerance. Similarly, we cannot distinguish whether the effects of insulin on brain glucose metabolism are direct by stimulation of glucose metabolism, or indirect by stimulation of neuronal activity via neurotransmitter activity. Because our PET measurements with [¹⁵O]H₂O showed no effects of insulin on cerebral blood flow, we conclude that insulin does not increase brain delivery of glucose simply by increased cerebral blood flow. Previous studies have found decreased baseline cerebral blood flow in patients with type 1^[22] and type 2^[23] diabetes, likely representing microvascular damage from chronic hyperglycemia. We did not find such alterations in patients with impaired glucose tolerance, suggesting that microvascular damage may be minimal in this prediabetic state, insofar as biologically meaningful deficits are detected by [¹⁵O]H₂O PET.

The highest insulin-stimulated increase in glucose metabolism was seen in the posterior insula, a region that monitors bodily states and is implicated in reward functions.^[24] A recent study^[25] found increased functional responses to gastric distention in obese subjects in the posterior insula. Thus, the posterior insula may be one of the regions where insulin reduces feeding behavior in humans.

In conclusion, we used [¹⁸F]FDG PET to show that insulin does not stimulate brain glucose metabolism at physiological postprandial levels in healthy subjects but does so in patients with impaired glucose tolerance. These results suggest that insulin regulation of brain glucose metabolism is disturbed in metabolic syndrome.

Diabetes. 2011;60(2):443-447. © 2011 American Diabetes Association, Inc.

Cite this: Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance - Medscape - Feb 02, 2011.