DIABETES RESEARCH A N D CLINICAL PRACTICE 93S (2011) S47–S5 1

Insulin sensitivity of the human brain

Caroline Ketterer a , Otto Tschritter a , Hubert Preissl b,c , Martin Heni a , Hans-Ulrich Häring a ,
Andreas Fritsche a, *
a Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls
University Tübingen, Member of the German Centre for Diabetes Research (DZD), Tübingen, Germany
b MEG-Center, University of Tübingen, Tübingen, Germany
c Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

AR TI C L E I NF O A B S T R A C T

Keywords: The brain is an insulin sensitive organ and insulin signaling is important to regulate feeding
Brain behavior, body weight, and cognitive processes. Insulin resistance in peripheral tissues is a
Diabetes mellitus hallmark in the development of type 2 diabetes mellitus (T2DM), yet the finding of insulin
Insulin resistance resistance in the brain is relatively novel. Studies in humans revealed that environmen-
tal factors like obesity, age, and the genetic background have an impact on central insulin
sensitivity. According to the physiological effects of insulin in the brain, disturbances of
this signaling chain lead to an impairment of cognitive functions and a deterioration of
eating behavior with a potential role in the pathogenesis of obesity and T2DM. First at-
tempts to treat insulin resistance not only in peripheral tissues but also in the CNS have
therefore come on its way: Cerebral insulin resistance can at least partially be overcome
by intranasal treatment with insulin or by commercial insulins that exhibit specific ef-
fects in the brain due to their pharmacokinetic properties. Despite the advances towards
a better understanding of insulin function in the human brain in the last years, achieving
a more profound knowledge of mechanisms behind central insulin function and identi-
fying further strategies to overcome insulin resistance must be a main goal of future re-
search.
© 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
In contrast to earlier concepts, where the brain was thought
to be an insulin insensitive organ, it is now widely accepted
that insulin action plays an important role in the central
nervous system (CNS). Insulin receptors are expressed in
many areas of the brain with high concentrations in the
hypothalamus, the hippocampus and the cerebral cortex.
Circulating insulin crosses the blood–brain barrier via an ac-
tive receptor-mediated transport system. Interestingly, in the
* Correspondence to: Prof. Dr. med. Andreas Fritsche, Internal
Medicine IV, Medical Clinic Tübingen, Otfried-Müller-Str. 10, 72076
Tübingen, Germany. Tel.: +49 7071 2980590; fax: +49 7071 295974.
E-mail address: andreas.fritsche@med.uni-tuebingen.de
(A. Fritsche).
CNS, the hormone does not affect central glucose transport
and metabolism. However, in animal models central insulin
action seems to mediate glucose metabolism in the periph-
ery, e.g. by inhibition of hepatic gluconeogenesis [1]. While
this role of insulin could have only been shown in the ani-
mal model so far, other functions of insulin in the brain were
found in humans as well.
Insulin serves as a feed-back signal from the periphery
to reduce appetite and is therefore involved in body weight
regulation and eating behavior. Together with other pep-
tides like ghrelin or cholecystokinin, insulin is part of the
complex neuropeptidergic signaling network in the hypotha-
lamus that regulates anabolic and catabolic balance [2]. In
contrast to these other peptides, insulin action was addi-
tionally demonstrated in further brain regions besides the
hypothalamus [3].

0168-8227/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
S48 DIABETES RESEARCH A N D CLINICAL PRACTICE
Patients with Alzheimer’s disease exhibit impaired in-
sulin signaling within the brain. When administering insulin
selectively in the brains of these patients via a transnasal ap-
proach, memory function was found to improve significantly.
Improved memory function could also be shown in healthy
subjects, pointing towards effects of the hormone insulin in
cognitive functions under physiological circumstances [4,5].
During the last years, intensive research on the role of in-
sulin in the CNS has been performed. However, most of the
studies have been accomplished in animal models; the role
and mechanisms behind insulin action in the human CNS
still raises numerous questions and is far from being eluci-
dated.
2. What are the effects of insulin in the
human brain?
The assessment of insulin action in the human brain is chal-
lenging. Available methods include electroencepahlography
(EEG), magnetoencephalography (MEG), and functional mag-
netic resonance imaging (fMRI). Using positron emission to-
mography (PET), it was possible to determine insulin-evoked
glucose metabolism, thus making this technique also suit-
able for investigations of insulin action in the human brain
[6]. However, by assessing glucose uptake the PET technique
mainly measures metabolic processes, rather than neuronal
activity.
MEG allows detecting magnetic fields generated by the
electrical activity of cortical neurons. Thus, with its high
spatial and temporal resolution, it is suitable for nonin-
vasive measurements of neuronal activity in the human
cerebral cortex. Using this technique we could show that
stimulated as well as spontaneous cortical activity in-
creases with insulin infusion compared to saline during a
hyperinsulinemic-euglycemic clamp [7]. Beta and theta ac-
tivity were predominantly affected, showing an increase un-
der the hyperinsulinemic condition. Theta activity is mainly
related to activity in the hippocampus and associated with
memory performance and thus thought to be a signature
of memory consolidation. Moreover, reduced theta activity
has also been found to be associated with a loss of locomo-
tor activity and voluntary movements in rodents [8]. Hence,
our findings underline the role of cerebral insulin action in
regulation of memory processes and furthermore support
the presumption of an effect of insulin action on locomotor
activity also in humans.
The second frequency band affected by insulin, beta ac-
tivity, is associated with increased cortical processing activ-
ity. Combined with the fact that in patients with Alzheimer’s
disease insulin therapy improved memory performance, and
that in elderly individuals with T2DM cognitive function is
impaired, our findings support the view of insulin signaling
in the brain being of importance in cognitive function in
humans.
The technique of fMRI has a relatively higher spatial res-
olution compared to MEG and is able to measure metabolic
changes associated with neuronal activity with the blood
oxygen level dependent (BOLD) effect even in deep brain
structures. Using the fMRI technique combined with visual
93S (2011) S47–S5 1
stimulation (food and non food pictures) we could show, that
food pictures increase the BOLD response compared to non-
food pictures in brain regions which are involved in food
processing like the insular or the orbitofrontal cortex [9]. In
another fMRI study, measurements with a comparable stim-
ulation design were performed before and after treatment
with intranasal insulin. Since peripheral insulin levels and
glucose levels remain unaffected and stable when admin-
istering insulin intranasally, this approach allows assessing
selective insulin effects in the brain. When sniffing insulin,
the BOLD response was significantly reduced in the presence
of food pictures compared to placebo spray in the fusiform
gyrus, cortical frontal and temporal areas, and hippocampus;
this suppressing effect of insulin was not detected when
watching non food pictures [10]. The identified brain areas
are known to be involved in object recognition, appetite reg-
ulation, food craving and decision making.
Chronical effects of intranasal insulin were investigated
in a study, where insulin was administered over a period of
eight weeks. In normal-weight men, this intranasal adminis-
tration of the hormone lead to catabolic effects like reduced
body fat and waist circumference [3]. The underlying mecha-
nism was not investigated in this study. However, an altered
neuronal processing of food-related stimuli in the presence
of acute elevations of insulin, as shown in our fMRI study,
might be part of the mechanism that terminates food intake
and thus be involved in weight regulation.
3. Is there insulin resistance in the brain?
The intensively studied phenomenon of insulin resistance
in peripheral tissues is tightly linked with overweight and
a hallmark in the development of type 2 diabetes mellitus
(T2DM). With the compelling evidence of insulin action in
the CNS, the question arises if disturbances of insulin effects
in the brain – similar to those seen in peripheral tissues
– exist. Using MEG measurements, we compared the spon-
taneous cortical activity in normal weight vs. overweight
subjects during a hyperinsulinemic-euglycemic clamp [7].
We found that overweight subjects had no increase in the
beta and theta band of spontaneous cortical activity dur-
ing hyperinsulinemia. We furthermore found that the effects
of insulin on cortical activity are negatively related to the
amount of body fat and the degree of peripheral insulin re-
sistance. These findings strongly point towards a cerebral
insulin resistance in overweight humans. Cerebral insulin
resistance could be the result of various mechanisms at
different levels. Acute elevations of plasma insulin levels
have been found to correlate with cerebro-spinal-fluid (CSF)
insulin concentrations in healthy, normal weight humans.
However, in overweight humans, the ratio of CSF to plasma
insulin seems altered – elevated plasma insulin levels due to
peripheral insulin resistance are not accompanied by similar
elevations in cerebral insulin levels. An impaired blood–brain
barrier could, at least in part, be responsible for reduced in-
sulin effects in the brain. Accordingly, in overweight man,
eight weeks of intranasal insulin treatment (bypassing the
blood–brain barrier) lead to an improvement of declarative
and memory functions [3]. Yet, in contrast to the effects on
 DIABETES RESEARCH A N D CLINICAL PRACTICE 93S (2011) S47–S5 1 S49

body weight in normal-weight man, no reduction of body fat
occurred in overweight subjects. Therefore, disturbances of
insulin action, other than an altered blood–brain barrier only,
might exist.
4. Influences on insulin signaling in the brain
(see Fig. 1)
There are several known influences on peripheral insulin
sensitivity including a wide range of obesity related and/or
environmental, as well as genetic factors. Do these factors
that influence peripheral insulin sensitivity also possess an
impact on cerebral insulin effects?
Similar to peripheral tissues, we could establish that in-
sulin effects in the CNS negatively correlate with BMI. In
order to identify potential markers for cerebral insulin re-
sistance, we investigated metabolic factors that are pro-
duced by adipose tissue, dependent of the degree of obesity.
Adiponectin, leptin, and inflammation markers which are
known to mediate peripheral insulin resistance did not show
a correlation with insulin effects on cerebral theta activity
independent of BMI or body fat in our MEG measurements.
However, we found an association of saturated nonesterified
fatty acids (NEFAS) with cerebral insulin effects. These ef-
fects were independent of BMI, visceral fat mass and liver
fat, thus, pointing toward NEFAS being directly linked to
cerebral insulin resistance [11].
Insulin sensitivity in peripheral tissues decreases with
age. Yet, this correlation is likely to be due to body composi-
tion changes and weight gain rather than aging itself. Insulin
signaling in the brain has been shown to be involved in
cognitive processes. Since cognitive functions decrease with
age it is therefore plausible to investigate whether there are
insulin effects in the brain that correlate with age but are
independent of BMI. We found a correlation of aging and
beta activity independent of body weight. In contrast, the
effect of insulin on theta activity was negatively correlated
with BMI, but not with age. These findings strongly suggest
an age related decrease in beta activity, whereas peripheral
sensitivity and theta activity mainly depends on alterations
associated with obesity.
It is more and more accepted that not only environmental
factors but also genetics play an important role in the patho-
genesis of T2DM and Obesity. The downstream insulin sig-
naling molecule IRS-1 (insulin receptor substrate 1) is ubiq-
uitously expressed in the human brain and considered as
one of the genes associated with an increased risk of T2DM.
With MEG measurements we were able show that during
hyperinsulinemic–euglycemic clamp insulin effects on the

Fig. 1 – Insulin signalling in the brain and its effects on neuronal function can be assessed by fMRI and MEG. This helped to
identify several factors that influence insulin action in the brain (= “cerebral insulin sensitivity”) including body weight,
age, free fatty acids and genetic factors (see left). Insulin action in the brain is thought to result in regulation of food intake,
energy expenditure and physical activity. Disturbances of insulin effects in the brain (= “the insulin resistant brain”) may
contribute to the development of obesity and T2DM.
S50 DIABETES RESEARCH A N D CLINICAL PRACTICE
human brain differed between carriers of polymorphisms
in IRS-1 with insulin effects being absent in carriers of the
972Arg (risk) allele. It therefore seems that some of the in-
sulin effects in the brain are most likely due to disturbances
in the insulin signaling cascade rather than being explained
by an impairment of the blood–brain barrier only.
In genome-wide association studies, FTO has been iden-
tified as an obesity risk gene. Variants in the FTO gene are
suspected to cause a deterioration of body weight regulation
early in life, though the mechanisms behind this impact on
body weight are not clear. FTO is expressed in several human
tissues, including the brain, with high expression in the hy-
pothalamus. In our MEG studies, the response to insulin in
the brain was reduced in carriers of the risk allele of the FTO
gene, pointing towards a cerebral insulin resistance in these
subjects. We were able to show that increased body weight
in carriers of the risk allele of FTO gene is a consequence of
increased food intake, rather than impaired energy expen-
diture [12]. Thus, a cerebral insulin resistance in carriers of
the risk allele with a resulting potential impact on eating
behavior, might be involved in the effects of these variants
on body weight [13].
5. Can cerebral insulin resistance be
overcome?
Given the numerous effects of insulin in the CNS and the po-
tentially extensive impact on health if physiological insulin
signaling in the brain is disturbed, it is crucial to develop
strategies to overcome insulin resistance in the brain. Some
therapeutical approaches already exist. Insulin sensitizers
like the peroxisome proliferator activated receptor gamma
agonist rosiglitazone, for example, might exert its enhancing
effects on insulin sensitivity not only in the periphery but
also in the CNS. Accordingly, an improved memory function
in patients with Alzheimer’s disease was observed under
treatment with rosiglitazone [14]. In order to bypass the
blood–brain barrier, intranasal administration of insulin has
also been shown to influence at least some of the cerebral
functions affected by insulin signaling: it helped to improve
cognitive functions, but was ineffective in reducing body
weight in obese subjects. Insulin analogs have been designed
to mimic physiological insulin secretion patterns in the ther-
apy of diabetes mellitus. These insulins might be able to
achieve positive effects on insulin signaling in the brain, as
they can be designed not only to reach the brain in larger
amounts, but also to specifically target insulin receptors in
the brain. For example, intranasal administration of the
rapid acting analog insulin aspart, resulted in stronger ef-
fects on memory improvement than regular human insulin.
Insulin is commonly known to contribute to weight gain
during therapy. However, when treating patients with in-
sulin detemir, a long-acting insulin analog, they gain signifi-
cantly less, or even lose weight, compared to those that were
treated with NPH insulin [15]. Recently, Hallschmidt et al.
could show that intravenously infused detemir, while induc-
ing comparable peripheral effects, induced a negative direct
potential shift measured by EEG that was not observed dur-
ing human insulin infusion. This stronger detemir effect on
93S (2011) S47–S5 1
brain functions was accompanied by a relative decrease in
food consumption [16]. As mentioned above, we could show
in a previous study that the response to human insulin in the
brain is absent in overweight subjects [7]. Intriguingly, when
performing the clamp experiment with insulin detemir, the
insulin effect on cerebral beta activity during MEG was com-
parable to the effect of human insulin in lean subjects [17].
Since in the study peripheral effects were even lower, brain
specific effects of insulin detemir can be assumed. These
stronger effects of insulin detemir in the brain, overcoming
cerebral insulin resistance, might therefore account for its
positive effects on weight gain during insulin therapy.
6. Conclusion
After intensive research for the last couple of years, it is
now commonly accepted that there are insulin effects in
the brain. Since the possibilities to asses insulin function
in the human brain are limited, a lot of the data on cere-
bral insulin signaling derive from animal studies. By using
EEG, MEG, PET and fMRI, however, many of the findings of
studies in animal models could be confirmed in humans.
Cerebral insulin signaling is important for body weight reg-
ulation, eating behavior and involved in cognitive processes
and memory function. While it has no effect on cerebral
glucose fluxes, cerebral insulin action might have an impact
on peripheral glucose homeostasis. The finding of a cerebral
insulin resistance in humans, with its potential implications
for the pathogenesis of public health problems like obe-
sity and T2DM renders a special importance to understand
mechanisms behind insulin effects in the human brain, and
to identify strategies to overcome central insulin resistance.
Many more studies in humans will need to be accomplished
in order to answer these open questions; however, the ques-
tion whether insulin signaling in the human brain is of great
importance, has clearly found its answer.
Acknowledgement
This study was supported by the Deutsche Forschungsge-
meinschaft (KFO 114Fr1561/3-3), and by the “Competence
Network for Adiposity” (FKZ: 01G10837 and 01G10849) and
the German Center for Diabetes Research (DZD e.V.), both
funded by the German Federal Ministry of Education and
Research (BMBF).
Conflict of interest
The authors declare that they have no conflict of interest
concerning this paper.
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