Cerebrocortical Beta Activity in Overweight Humans Responds to Insulin Detemir

Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany.
PLoS ONE (Impact Factor: 3.23). 02/2007; 2(11):e1196. DOI: 10.1371/journal.pone.0001196
Source: PubMed


Insulin stimulates cerebrocortical beta and theta activity in lean humans. This effect is reduced in obese individuals indicating cerebrocortical insulin resistance. In the present study we tested whether insulin detemir is a suitable tool to restore the cerebral insulin response in overweight humans. This approach is based on studies in mice where we could recently demonstrate increased brain tissue concentrations of insulin and increased insulin signaling in the hypothalamus and cerebral cortex following peripheral injection of insulin detemir.
We studied activity of the cerebral cortex using magnetoencephalography in 12 lean and 34 overweight non-diabetic humans during a 2-step hyperinsulinemic euglycemic clamp (each step 90 min) with human insulin (HI) and saline infusion (S). In 10 overweight subjects we additionally performed the euglycemic clamp with insulin detemir (D). While human insulin administration did not change cerebrocortical activity relative to saline (p = 0.90) in overweight subjects, beta activity increased during D administration (basal 59+/-3 fT, 1(st) step 62+/-3 fT, 2(nd) step 66+/-5, p = 0.001, D vs. HI). As under this condition glucose infusion rates were lower with D than with HI (p = 0.003), it can be excluded that the cerebral effect is the consequence of a systemic effect. The total effect of insulin detemir on beta activity was not different from the human insulin effect in lean subjects (p = 0.78).
Despite cerebrocortical resistance to human insulin, insulin detemir increased beta activity in overweight human subjects similarly as human insulin in lean subjects. These data suggest that the decreased cerebral beta activity response in overweight subjects can be restored by insulin detemir.

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Available from: Katarína Štingl
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    • "It has been hypothesized [9] that due to the fatty acid moiety, ID more easily enters the brain, thereby potentially promoting satiety in relevant CNS regions and reducing appetite, food intake and body weight. Accordingly, ID may have stronger effects in modulating brain functions than other long-acting insulin formulations: ID, administered intravenously, enhanced cortical activity compared to human insulin (as measured by electroencephalography, EEG and magnetoencephalography, MEG) and decreased food intake in both preclinical [10] and clinical studies [11], [12]. However, the effects of ID on appetite regulating brain regions during food stimuli have not been studied and no data are available regarding insulin concentrations in human cerebrospinal fluid (CSF) during insulin treatment and its relation to insulin's central actions. "
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    ABSTRACT: Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (p = 0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (p = 0.02 for right and p = 0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (p = 0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli. NCT00626080.
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    • "The insulin receptor is prominently expressed in the hippocampus suggesting that insulin regulates hippocampal function and thereby possibly modulates cognition [1]. Impaired insulin signaling increases risk of Alzheimer disease [2], cognitive disabilities in diabetes mellitus [3] and decreases cerebrocortical beta activity in overweight humans [4] whereas intranasal administration of insulin improves hippocampal-dependent memory function [5]. Nevertheless, the mechanism underlying the insulin effects on hippocampal function is not understood. "
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    • "Assessing the effect of hyperinsulinemic states on cerebrocortical activity, Tschitter et al [38], [39] were the first to use magnetoencephalography in the study of obesity. In accordance with our findings, they reported involvement of beta band activity. "
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    ABSTRACT: Obesity is not only associated with metabolic abnormalities, but also with cognitive dysfunction and changes in the central nervous system. The present pilot study was carried out to investigate functional connectivity in obese and non-obese adolescents using magnetoencephalography (MEG). Magnetoencephalographic recordings were performed in 11 obese (mean BMI 38.8+/-4.6 kg/m(2)) and 8 lean (mean BMI 21.0+/-1.5 kg/m(2)) female adolescents (age 12-19 years) during an eyes-closed resting-state condition. From these recordings, the synchronization likelihood (SL), a common method that estimates both linear and non-linear interdependencies between MEG signals, was calculated within and between brain regions, and within standard frequency bands (delta, theta, alpha1, alpha2, beta and gamma). The obese adolescents had increased synchronization in delta (0.5-4 Hz) and beta (13-30 Hz) frequency bands compared to lean controls (P(delta total) = 0.001; P(beta total) = 0.002). This study identified increased resting-state functional connectivity in severe obese adolescents. Considering the importance of functional coupling between brain areas for cognitive functioning, the present findings strengthen the hypothesis that obesity may have a major impact on human brain function. The cause of the observed excessive synchronization is unknown, but might be related to disturbed motivational pathways, the recently demonstrated increase in white matter volume in obese subjects or altered metabolic processes like hyperinsulinemia. The question arises whether the changes in brain structure and communication are a dynamic process due to weight gain and whether these effects are reversible or not.
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