Cerebrocortical Beta Activity in Overweight Humans
Responds to Insulin Detemir
Otto Tschritter1, Anita M. Hennige1, Hubert Preissl2,3, Katarina Porubska2,4, Silke A. Scha ¨fer1, Werner Lutzenberger2, Fausto Machicao1, Niels
Birbaumer2,5, Andreas Fritsche1, Hans-Ulrich Ha ¨ring1*
1Department of Internal Medicine IV, University of Tu ¨bingen, Tu ¨bingen, Germany, 2Institute of Medical Psychology and Behavioral Neurobiology,
University of Tu ¨bingen, Tu ¨bingen, Germany, 3Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical
Sciences, Little Rock, Arkansas, United States of America, 4Department of Neuro-Ophthalmology, University Eye Hospital, Tu ¨bingen, Germany,
5National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS), Human Cortical Physiology, Bethesda, Maryland,
United States of America
Background. 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. Methodology/Principal Findings. 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 5963 fT, 1ststep 6263 fT, 2ndstep 6665, 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). Conclusions/Significance. 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.
Citation: Tschritter O, Hennige AM, Preissl H, Porubska K, Scha ¨fer SA, et al (2007) Cerebrocortical Beta Activity in Overweight Humans Responds to
Insulin Detemir. PLoS ONE 2(11): e1196. doi:10.1371/journal.pone.0001196
The role of insulin signaling to the brain in normal physiology and
pathophysiology is so far only incompletely understood. The majority
of data on insulin action in the brain was obtained in animal models,
only few studies characterize insulin action in human brain.
Peripherally injected insulin crosses the blood-brain barrier [1,2]
and contributes to the regulation of food intake and energy
homeostasis . Insulin signaling in the brain serves as a feed-back
signal from the periphery to the brain to reduce appetite [4,5].
Furthermore, insulin receptors in the brain seem to be involved in
pathogenic mechanisms leading to a type 2 diabetes-like phenotype.
obese and insulin resistant phenotype . Activation of insulin
receptors in the central nervous system has been shown to be
essential for appropriate suppression of endogenous glucose pro-
duction during hyperinsulinemia in mouse models [7–9]. Further-
more, insulin has been found to be associated with cognitive function
in rodents . In humans, intranasal administration of insulin, an
application which raises insulin levels in the cerebrospinal fluid and
selectivelystimulatesthebrain,improves memoryfunction .
Moreover, reduced insulin signaling is a pathogenic factor of
Alzheimer’s disease [13,14] and might be associated with loss of
cognitive and memory function.
In a previous study we measured insulin effects on neuronal
activity of the human cerebral cortex using magnetoencephalogra-
In this study we observed that in obese individuals the brain appears
to be resistant to stimulation of beta- and theta-activity by insulin. In
subjects with a body-mass-index (BMI) of approximately 30 kg/m2,
and elevated body fat content, a physiologic dose of insulin did not
exert a detectable effect on this parameter of brain activity. These
results raised the question whether therapeutic tools exist to restore
the cerebral insulin response in overweight humans.
Modern insulin therapy regimens in type 1 and type 2 diabetes
aim to mimick the patterns of physiologic insulin secretion. For
this purpose, long- and short-acting insulin analogues have been
designed in recent years. Insulin detemir is a long-acting insulin
analogue and its delay of action is achieved by acylation of the B-
chain with myristic acid and reversible albumin binding [16,17].
The pharmacokinetics differ from human insulin and may
therefore cause tissue-specific effects.
Academic Editor: Kathrin Maedler, University of California at Los Angeles, United
States of America
Received July 4, 2007; Accepted October 29, 2007; Published November 21, 2007
Copyright: ? 2007 Tschritter et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Funding: This is an investigator initiated study. The study has been supported by
a grant of the Deutsche Forschungsgemeinschaft (DFG) as a part of the project
‘‘Klinische Forschergruppe 114’’ (KFO114) and by a research grant of NovoNordisk,
Copenhagen, Denmark. NovoNordisk provided information about pharmacoki-
netics of insulin detemir for intravenous application. The funders had no further
role in study design, collection and analysis of data, decision to publish, or
preparation of the manuscript.
Competing Interests: A.F. and H.-U.H. obtained the grant of the DFG and H.-U.H.
obtained the grant of NovoNordisk. A.F. and O.T. obtained travel cost
reimbursement by NovoNordisk for attending scientific meetings.
* To whom correspondence should be addressed. E-mail: hans-ulrich.haering@
PLoS ONE | www.plosone.org1 November 2007 | Issue 11 | e1196
It has been shown that the transport of insulin across the blood-
brain barrier is reduced in dogs with obesity induced by a high-fat
diet . Therefore, insulin resistance of the brain is at least in
part a consequence of reduced availability of insulin and may be
overcome by insulin analogues with altered pharmacokinetics and
tissue-selectivity for the brain. In a recentanimalstudywe found that
peripheral injection of insulin detemir results in higher brain tissue
concentrations of this insulin analogue compared to human insulin
in the presence of similar peripheral effects. Subsequently, insulin
receptor signaling in the hypothalamus and cerebral cortex was
enhanced when insulin detemir was injected i.v., and electroen-
cephalography recordings in these animals displayed a different
stimulation of the cortical activity compared to human insulin .
Based on these findings in mice, we hypothesized that insulin
detemir might restore the decreased cerebral insulin response in
overweight human subjects. Therefore, we designed a 2-step
hyperinsulinemic euglycemic clamp with i.v. infusion of insulin
detemir or human insulin and simultaneous MEG recording. To
ensure that potential cerebral effects are not a spill over from
peripheral insulin effects, we applied clamp conditions which
avoided overstimulation of peripheral tissues with insulin detemir.
Here we selected 10 overweight or slightly obese subjects who
were otherwise healthy and normal glucose tolerant according to
WHO criteria. As indicator of overweight, a percentage body fat
above the sex-specific normal range (male .19%, female .28%)
was taken. Body fat was measured by bioelectrical impedance
analysis using a BIA101A analyzer (RJL systems, Clinton Twp., MI
48035 USA). Differentiation of overweight from normal body
weight by percent body fat content resulted in inclusion of two
female subjects with a BMI slightly below 25 kg/m2but increased
body fat. Severe obesity (BMI .40 kg/m2) and/or psychiatric
disorders represented exclusion criteria. No subject took any
medication except for hormone substitution (like thyroid hor-
In these 10 subjects we studied the effect of insulin detemir and
human insulin on cerebrocortical activity. The effect of insulin
detemir on cerebrocortical function was then compared to the
human insulin effect measured in 12 lean and 34 obese non-
diabetic subjects. The subject characteristics of all three groups are
shown in table 1. Informed written consent was obtained from all
subjects prior to the study. The study protocol was approved by
the Ethics Committee of the Medical Faculty at the Eberhard-
Karls-University in Tu ¨bingen, Germany.
Oral glucose tolerance test
After a 10-hour overnight fast the subjects ingested a solution
containing 75 g of dextrose and venous blood samples were
obtained at 0, 30, 60, 90 and 120 minutes for determination of
plasma glucose and plasma insulin.
The human insulin experiment and the saline experiment with
simultaneous MEG recordings have already been established and
used in a previous study . In addition, we designed a 2-step
hyperinsulinemic euglycemic clamp with i.v. infusion of insulin
detemir. In this clamp a similar or even slightly lower effect on
peripheral glucose metabolism had to be achieved and the time-
profile of the plasma insulin concentrations had to be mimicked. We
first assessed the dose of insulin detemir in consideration of previous
studies on insulin detemir action during i.v. infusion in humans and
pharmacological data on insulin detemir kinetics. After a pilot study
to test the clamp protocol, 10 subjects participated in these three
experiments (insulin detemir [D], human insulin [HI] and saline[S])
on three different days approximately one week apart. The order of
the experiments was randomized and all participants were blinded
as to whether human insulin, insulin detemir or saline was infused.
An approximately 30-minute MEG block was performed in the
baseline period and at the end of each step of the clamp. Further
details of the clamp procedures and the bolus and infusion doses of
human insulin and insulin detemir are given in figure 1. To avoid
substantial adhesion of insulin detemir and human insulin to plastic
Table 1. Subjects characteristics.
LeanOverweight Overweight, insulin detemir**
Mean6SEM Mean6SEM Mean6SEM Range
N 12 34 10-
Sex (M/F)4/8 19/155/5-
Age (years)2962 3662 3062[23 … 42]
Weight (kg) 6263 8862 8866 [67 … 119]
BMI (kg/m2) 2261 2963 2961 [23 … 36]
Percent body fat (%) 1962 3161 3062 [21 … 42]
Percent body fat, females (%) 2461 3761 3564[30 … 42]
Percent body fat, males (%) 1061 2665 2564[21 … 29]
Waist-hip-ratio 0.8060.020.9160.010.8860.04[0.66 … 0.98]
Fasting plasma glucose (mmol/L) 4.760.15.060.1 5.260.1[4.6 … 5.7]
2 Hr plasma glucose (mmol/L)*
5.660.46.460.2 5.860.4[4.1 … 7.7]
Fasting plasma insulin (pmol/L) 3763 6166 52610[24 … 108]
2 Hr plasma insulin (pmol/L)*
195656 468665360699[69 … 989]
*Oral glucose tolerance test;
**subset of the overweight group
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materials like the infusion lines, the insulin solutions were prepared
using 48 mL NaCl 0.9% and 2 mL of the subjects’ own blood.
We chose MEG parameters that permitted sensitive assessment of
both spontaneous cortical activity and stimulated cortical activity
(discrimination between two sound qualities, auditory mismatch
negativity). Data were recorded in a continuous mode (sampling rate
312.5 Hertz [Hz]) starting with eyes open and closed (counter-
balanced over sessions and subjects)for 1.5 minutes each for analysis
of spontaneous cortical activity, followed by the auditory mismatch
experiment. Auditory mismatch negativity is independent of
alertness or attention and is considered to be a robust parameter
of preconscious cortical information processing [20,21]. While the
auditory mismatch experiment was different in some details, the
analysis of spontaneous cortical activity was performed as previously
described , including a correction for multiple comparisons in
the different frequency bands by a randomization approach .
Plasma glucose was determined using the glucose-oxidase method
glucose was determined by a HemoCue blood glucose photometer
using the glucose dehyrogenase method (HemoCue AB, Aengel-
holm, Sweden). Plasma insulin levels were determined by micro-
particle enzyme immunoassay (Abbott Laboratories, Tokyo, Japan).
MEGdatawasanalyzed bya repeatedmeasureANOVAcontaining
the condition factor (SUBSTANCE, e.g. human insulin and insulin
detemir) and the repeated measure factor level (baseline, 1ststep and
2ndstep of insulin infusion). To visualize the relative changes under
human insulin and insulin detemir MEG data of the insulin/detemir
experiment were divided by data of the saline experiment. MEG
parameters were calculated using SPSS 12.0 (SPSS, Chicago, IL)
incorporating Greenhouse-Geisser correction. For analysis of
metabolic data the software package JMP 4.0 (SAS Institute, Cary,
NC) was used. Non-normally distributed variables were logarithmi-
cally transformed, when necessary. Correlations were calculated
using least square regression analysis. A p-value of ,0.05 was
considered to indicate statistical significance.
Kinetics of human insulin and insulin detemir
concentrations in 10 overweight subjects
participating in the human insulin, insulin detemir
and saline experiment
Figure 1 shows the design of the clamp experiments. During the
saline experiment (S), plasma insulin levels slightly decreased from
basal 4967 pM to 1ststep 4866 pM and 2ndstep 4065 pM
(p=0.04) (Figure 2A).
In the human insulin experiment (HI) and the insulin detemir
experiment (D) basal plasma insulin concentration were not
different from S (HI 4866 pM, p=0.91; D 57610 pM,
p=0.16). During both clamps, plasma insulin and total serum
insulin detemir concentrations displayed similar time profiles
(Figure 2A). In each step the peak value after the priming bolus
was approximately 55% higher than the concentrations observed
during infusion of human insulin and insulin detemir, respectively.
However, due to the albumin binding  total serum concentra-
tions of insulin detemir were substantially higher (approximately
40-fold) at any time point than the corresponding plasma insulin
concentrations (Figure 2A).
Peripheral metabolic effects of human insulin and
insulin detemir in 10 subjects
Blood glucose concentrations were not different at baseline (S
4.860.4 mM, HI 5.060.3 mM, D 5.060.5 mM, all p.0.1) and
did not change significantly during the experiments (all p.0.2)
Though the total insulin detemir concentrations were higher
than the human insulin concentrations, the glucose infusion rate
required to maintain euglycemia was lower in the insulin detemir
experiment (Figure 2C). The lower glucose infusion rate indicates
that despite these high insulin detemir concentrations, no
overstimulation of peripheral glucose metabolism occurred.
Cerebrocortical measures of human insulin and
insulin detemir action in 10 overweight subjects
As we screened all frequency bands of spontaneous cerebrocortical
activity for differences between HI, S and D, we used
Figure 1. The 2-step hyperinsulinemic euglycemic clamp with human insulin or insulin detemir. Human insulin (HI) and insulin detemir (D) were
applied as a 2-step infusion. Each infusion step was primed with a bolus. Blood glucose was monitored every 5–10 min between minute 0 and
minute 180, and a variable glucose infusion was titrated to maintain euglycemia (blood glucose 5 mmol/l). Cerebrocortical activity was measured
with magnetoencephalography (MEG) during the baseline period and during the last 30 minutes of each insulin infusion step. In the control
experiment, a comparable volume of saline solution (S) was infused instead of HI, D and glucose. The MEG measurement, glucose monitoring and
blood sampling were performed analogously to the clamp experiments.
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a randomization approach to adjust for multiple testing as
previously described . As evoked responses we analyzed
auditory mismatch negativity. Between the saline and the human
insulin experiment spontaneous (Figure 2D) and evoked cerebro-
cortical activity (data not shown) were not different, confirming
our previous finding that in overweight and obese subjects the
insulin response of the brain is reduced . However, during the
insulin detemir experiment, beta activity increased from 5963 fT
at basal to 6263 fT in the 1ststep and 6665 fT in the 2ndstep
(p=0.001, detemir vs. human insulin) (Figure 2D).
Figure 2. Metabolic parameters and beta activity during infusion of human insulin, insulin detemir and saline in 10 overweight individuals. A:
Plasma human insulin and total serum insulin detemir concentrations. Similar profiles of plasma/serum levels (Mean6SE) of human insulin and
insulin detemir were achieved with both insulins. Approximately 98% of serum insulin detemir is bound to albumin. Therefore, total insulin detemir
concentrations are substantially higher than human insulin concentrations at corresponding time points. Human insulin was determined by
microparticle enzyme immunoassay (Abbott Laboratories, Tokyo, Japan) and insulin detemir by a modified radioimmunoassay (Capio Diagnostik,
Copenhagen, Denmark). B: Blood glucose concentrations. Blood glucose was measured twice at baseline and every 5–10 minutes during the
infusion of human insulin, insulin detemir or saline. Blood glucose concentrations were not different between the experiments at baseline (all p.0.1)
and did not change significantly during the experiments (all p.0.2). C: Glucose infusion rates. In the saline experiment no glucose was infused.
Despite much higher insulin detemir concentrations, the glucose infusion rate was lower in the detemir experiment, indicating a lower peripheral
effect (1ststep: insulin 1161 mmol kg21min21, insulin detemir 961 mmol kg21min21, p=0.01; 2ndstep: insulin 3663 mmol kg21min21, insulin
detemir 2663 mmol kg21min21, p=0.003), as intended by the experimental protocol. D: Changes in beta activity during the experiments. During
human insulin (HI) and saline (S) infusion, beta activity decreased slightly (p=0.70, HI vs. S). During insulin detemir (D) infusion beta activity increased
compared to HI (p=0.001, repeated measures ANOVA, adjusted for multiple testing in all frequency bands).
Cerebral Effect of Detemir
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Comparison of the insulin detemir effect on beta
activity with the human insulin effect in 12 lean and
34 obese subjects
To compare the effect of insulin detemir on beta activity with the
effect of human insulin, we subtracted the beta activity measured
during the saline experiment from beta activity measured during
the human insulin experiment or the insulin detemir experiment in
the same subject. At baseline, there was no difference between lean
and overweight subjects studied with human insulin or overweight
subjects studied with insulin detemir (all p.0.6). During the
second step of infusion beta activity was increased in the lean
group with human insulin compared to overweight individuals
(p=0.031) and with insulin detemir compared to human insulin in
the overweight group (p=0.040), while there was no difference
between the human insulin effect in lean and the insulin detemir
effect in obese subjects (p=0.78) (Figure 3A).
Inordertoreview the effectof insulin detemirinthe contextofthe
together in figure 3B. In this figure, the change of beta activity by
human insulin is shown as filled circles and open rhombs. The open
rhombs represent subjects who additionally participated in the
beta activity negatively correlates with BMI (r=20.38, p=0.0086)
as previously published . To further relate the impact of insulin
detemir on the change of beta activity to the data obtained with
human insulin, we added the data from the insulin detemir
experiments in figure 3 B (open squares) and connected the
corresponding data points of the human insulin and the insulin
detemir experiment of each subject with an arrow. The figure shows
that the effect of insulin detemir on beta activity is enhanced
compared to human insulin in all subjects, except for the most obese
one. In order to stress most specifically the difference of both insulins
in stimulating beta activity, we ‘‘corrected’’ the effect of insulin
detemir for the lower glucose infusion rates during insulin detemir
experiments. For this purpose, the detemir effect on beta activity was
multiplied with the ratio of glucose infusion rates (GIRhuman insulin/
GIRinsulin detemir) in each subject individually.
Figure 3. Insulin effects on beta activity in lean and overweight subjects. A: Comparison of the insulin detemir effect on beta activity with the
effects human insulin in lean and overweight subjects. The figure shows beta activity from human insulin experiments in 12 lean and 34
overweight subjects and from insulin detemir experiments in 10 overweight subjects. Data from corresponding saline experiments have been
subtracted. In the second step of the clamps beta activity was significantly higher in lean than in overweight subjects (p=0.031) and higher with
insulin detemir than with human insulin in overweight subjects (p=0.040). B: Relationship between body-mass-index (BMI) and cerebral effects of
insulin. The change in beta activity induced by human insulin (filled circles and open rhombs) was negatively correlated with BMI (r=20.38,
p=0.0086) under hyperinsulinemic euglycemic clamped conditions as previously published . The open rhombs represent the data obtained from
the insulin experiment of 10 overweight subjects who additionally participated in the insulin detemir experiment. The change in beta activity induced
by insulin detemir infusion is shown as open squares. An arrow indicates the corresponding values of each subject and illustrates the enhancement of
cerebrocortical action of insulin detemir compared to human insulin. To account for lower glucose disposal in the insulin detemir experiments, the
effect of insulin detemir on beta activity has been multiplied with the individual ratio of the glucose infusion rates (GIRhuman insulin/GIRinsulin detemir).
Cerebral Effect of Detemir
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Insulin receptors in the brain play an important role in a variety of
physiologic functions (memory, cognitive function, control of
appetite, energy homeostasis, and endogenous glucose produc-
tion). Cerebral insulin receptors seem to be involved in
neurodegenerative diseases such as Alzheimer’s disease and
metabolic diseases such as obesity and type 2 diabetes. The
prevalence of these diseases increases [23,24] and, especially for
obesity and diabetes, has reached epidemic proportions in western
populations. Cerebral insulin resistance (i.e. reduced availability
and/or effectiveness of insulin in the brain) might contribute to the
pathogenesis of these diseases and, therefore, strategies to improve
or overcome cerebral insulin resistance may become relevant for
the therapy and prevention of obesity, type 2 diabetes and
In a previous study, in which we established the detection of
insulin effects on cerebrocortical activity with MEG, we have
shown that human obesity is characterized by a reduced cerebral
insulin response . In the current study we designed
a hyperinsulinemic euglycemic clamp with i.v. application of
insulin detemir. As we hypothesized increased cerebrocortical
action of the insulin analogue, it was necessary to achieve a similar
or slightly lower effect on peripheral glucose metabolism than in
the experiment using human insulin. Furthermore the time-profile
of the plasma insulin concentrations had to be mimicked. First, 10
overweight subjects were investigated, and consistent with our
previous findings human insulin did not change cortical activity.
However, insulin detemir increased beta activity considerably, and
therefore seems to improve the cerebrocortical response in beta
activity. It is of note that the increase of the cerebrocortical effect
was achieved despite lower peripheral effects, which justifies the
conclusion of a brain-specific effect of insulin detemir in humans.
Furthermore, the effect of insulin detemir in these overweight
subjects was comparable to the effect of human insulin in the lean.
As proposed in the mouse study , an increased effect of
insulin detemir in the brain may be explained by differences in
albumin binding. In the brain, albumin concentrations are 200-
fold lower than in the circulation , while in skeletal muscle
they are only 5-fold lower . In contrast to the brain, in skeletal
muscle a considerable proportion of insulin detemir is bound to
interstitial albumin. While in the circulation the albumin-bound
insulin detemir appears to be metabolically inactive, it is unclear
whether the local albumin concentrations in the skeletal muscle
further reduces binding of insulin detemir to the receptor. In dogs,
human insulin and insulin detemir induced a similar glucose
uptake when interstitial concentrations of both insulins were
similar, while the serum concentrations of insulin detemir were
much higher than those of human insulin . This finding
indicates that in the circulation albumin-bound insulin detemir is
metabolically inactive because it does not contribute to the passive
transport to the interstitial fluid of the skeletal muscle while
albumin-bound insulin detemir in the interstitial fluid contributes
to receptor binding and is metabolically active. The main reason
for the increased effect of insulin detemir in the brain is probably
an increased transport across the blood-brain barrier. Insulin
crosses the blood-brain barrier via an insulin receptor mediated
active transport which is located on the vascular endothelium of
brain blood vessels . Like the insulin receptor in the skeletal
muscle cell, this receptor is exposed to free and albumin-bound
insulin detemir, however, in a much higher concentration (up to
40-fold higher). In contrast to the passive transport in peripheral
tissues, the albumin-bound insulin detemir contributes to the
active transport across the blood-brain barrier which leads to
higher brain tissue concentrations as observed in mice .
Beta activity and other frequency bands are very unspecific
measures of cerebrocortical activity. Changes in this parameter
may reflect multiple functions and at the current stage no specific
function can be assigned to the insulin effect. Therefore, it is
unclear whether the increase of beta activity by insulin in lean
subjects or by insulin detemir in overweight subjects is directly
involved in body weight regulation, glucose tolerance or
neuroprotection and whether it reflects a beneficial effect on
brain function. However, we have some circumstantial evidence of
a functional link as we recently found that a polymorphism in the
FTO gene, which is related to obesity, is associated with
a decreased insulin effect on cerebrocortical beta activity .
Though FTO is expressed in the brain, its function in humans is
unclear. However, a decreased insulin response of the brain beta
activity may contribute to the obesity effect of variation in this
gene locus. Another interesting aspect is that insulin detemir has
favorable effects on body weight development. Throughout all
phase III studies, patients receiving insulin detemir displayed no
weight gain or even weight loss, while patients receiving NPH
insulin displayed weight gain . This difference was observed
under comparable glycemic control, strengthening the assumption
of a specific weight-lowering effect of insulin detemir. Therefore,
one may speculate that the increased cerebrocortical effect of
insulin detemir in presence of comparable peripheral effects might
be involved in the beneficial effects of insulin detemir on body
weight development during insulin treatment.
In conclusion, we demonstrate that insulin detemir acts in the
human brain more efficiently than human insulin at comparable
or even lower peripheral metabolic effects. This tissue selectivity
has already been demonstrated in mice and might be explained by
the pharmacokinetic properties of insulin detemir. In the present
study we could stimulate cerebrocortical beta activity in subjects
who displayed no effect of human insulin in the brain. Therefore,
insulin detemir seems to be a tool to restore at least in part the
cerebrocortical insulin response in overweight humans. This
principle may become a new therapeutic paradigm in obesity,
type 2 diabetes and neurodegenerative diseases and might be
applicable to other peptides which act in peripheral tissues and the
We gratefully acknowledge the superb technical assistance of Anna Bury,
Heike Luz and Gabi Walker.
Conceived and designed the experiments: HH NB AF OT HP KP.
Performed the experiments: OT KP SS. Analyzed the data: AF OT HP.
Contributed reagents/materials/analysis tools: NB FM AH WL. Wrote the
paper: HH AF AH OT. Other: Study supervision: HH NB.
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Cerebral Effect of Detemir
PLoS ONE | www.plosone.org7 November 2007 | Issue 11 | e1196