Insulin receptors are also expressed throughout the brain with particularly high concentrations in the hypothalamus, the hippocampus, and the cortex.

In humans, however, positron emission tomography (PET) studies repeatedly failed to reveal effects of hyperinsulinemia on brain glucose uptake.  Since glucose transport is probably not an important downstream effector of insulin in neurons because this is largely facilitated by GLUT3 and, to a minor extent, GLUT1 (an insulin-independent glucose transporter) the human brain has been traditionally regarded as an insulin-insensitive organ.

Nevertheless, an insulin effect on neuronal glucose oxidation or glial glycogen metabolism can not be excluded. The most relevant neuronal insulin effect at the cellular level seems to be the inhibition of norepinephrine reuptake.

The resulting increase in synaptic cleft norepinephrine can have a variety of secondary effects, not only on the postsynaptic neuron but also on adjacent astrocytes (glial cells) via beta-adrenoceptor activation. Thus, insulin clearly has every potential to modulate central nervous system (CNS) activity.

Early work in animals suggested that insulin inhibits appetite at the CNS level.

When given directly into the brain, insulin-induced suppression of food intake and brain selective deletion of the insulin receptor resulted in hyperphagia,  obesity,  and metabolic insulin resistance in mice. Thus, the understanding of insulin regulation of appetite and its potential dysregulation in obesity should be of great relevance.

Given that insulin negatively regulates appetite in the CNS, the impact of CNS insulin on body weight regulation still remains widely unclear. In normal weight male subjects, insulin given intranasally over 8 weeks resulted in a weight loss of 1.3 kg and in a loss of 1.4 kg of body fat as determined by standard body impedance technique. 

Waist circumference decreased by 1.6 cm and plasma leptin levels dropped by an average of 27%. However, in normal weight female subjects, the same intervention yielded an increase of body weight by 1 kg mainly due to increased extracellular water.

A recent magnetoencephalography study demonstrated differential insulin effects in lean and overweight subjects. In this study, the stimulatory insulin effect (expressed as difference to the placebo experiment) on theta activity was significantly smaller in obese than in lean subjects.

Moreover, the attenuation of insulin-induced changes in theta activity was inversely correlated with body mass index (BMI) in a multivariate analysis and positively with insulin-stimulated glucose disposal, i.e., metabolic insulin sensitivity in a univariate analysis.

These early findings suggest that obesity is associated with reduced cerebrocortical insulin sensitivity.

Michael Stumvoll
Department of Medicine, University of Leipzig, Leipzig, Germany

Barry J. Goldstein
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical
College of Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.

Timon W. van Haeften
Department of Internal Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands

REFERENCES