This document summarizes research on obesity, brain insulin resistance, and the risk of type 2 diabetes. Key points:
1. Studies with over 3,000 individuals at risk for type 2 diabetes examined the relationship between insulin secretion, insulin sensitivity, and glucose tolerance.
2. Neuroimaging and metabolic studies identified brain areas involved in insulin signaling and found these areas have reduced function in obese individuals, indicating brain insulin resistance.
3. Insulin resistance in the hypothalamus was associated with increased visceral fat and predicted less success in lifestyle interventions. Intranasal insulin improved hypothalamic function.
4. Studies of over 2,000 individuals found subtypes of obesity based on metabolic health
3. Neuroimaging
Hubert Preissl
Niels Birbaumer
Stephanie Kullmann
Department of Internal Medicine
Andreas Fritsche
Baptist Gallwitz
Martin Heni
Anita Hennige
Caroline Ketterer
Rainer Lehmann
Kasia Linder
Fausto Machicao
Anna-Maria Ordelheide
Andreas Peter
Tina Sartorius
Silke Herzberg-Schäfer
Erwin Schleicher
Harald Staiger
Norbert Stefan
Otto Tschritter
Susanne Ullrich
Robert Wagner
Cora Weigert
Peter Weyrich
Department of Radiology
Claus D. Claussen
Jürgen Machann
Fritz Schick
Department of Surgery
Alfred Königsrainer
IDM-HMGU Munich
Omics platform
Martin Hrabe de Angelis
13. Tschritter et al., JCEM 2009
Visceral fat mass is associated with
brain insulin resistance
p=0.021
14. Fat distribution patterns determined
by MRI and MR-Spectroscopy
Subphenotypes of Obesity
Stefan et al., Arch Intern Med. (2008)
Stefan et al., Lancet D&E (2013)N >2000
MHO
Metabolically healthy obesity
(insulin sensitive)
MUHO
Metabolically unhealthy obesity
(insulin resistant)
15. Positive Energy Balance
-
Lipotoxicity
+
Lipotoxicity
Genetic
predisposition
Metabolically
Benign Fatty Liver
Metabolically
Malign Fatty Liver
The role of hepatokines in metabolism
Norbert Stefan and Hans-Ulrich Häring, Nature Reviews Endocrinology 2013
PNPLA3
Peter et al., Diabetes 2010
Peter et al., JCEM 2011
Kantartzis et al., Diabetes 2009
Peter et al., Diabetologia 2014
Peter et al., JCEM 2015
Dysregulated
Hepatokines
Target TLR4
Stefan et al., Diabetologia 2008
Kantartzis et al., Clin. Sci.2009
Stefan et al., Lancet DE 2014
Stefan, Häring, Nat. Med. 2013
Stefan et al., NEJM 2013
Fetuin
Fatty acid pattern
17. Region of interest:
Human hypothalamus
Functional magnetic
resonance imaging
(fMRI)
Coordinates based on
WFU Pickatlas tool
http://www.fmri.wfubmc.
edu/download.htm
18. Insulin sensitive brain areas in humans
Hypothalamus
Fusiform gyrus
Frontal areas
Heni et al., Nature Endocrine reviews 2015
Kullmann et al., Diabetes Care 2015
Heni et al., Diabetes 2014
Kullmann et al., Hum Brain Mapp. 2014
Heni et al., Hum Brain Mapp. 2013
Heni et al., Diabetologia. 2012
Kullmann et al., Neuroendocrinology. 2012
Kullmann et al., Cereb Cortex. 2012
Sartorius et al., Diabetes. 2012
Stingl et al., Neuroimage. 2012
Tschritter et al., Diabetologia. 2012
Kullmann et al., Hum Brain Mapp. 2012
Grichisch et al., Hum Brain Mapp. 2012
Guthoff et al., J Clin Endocrinol Metab. 2010
Tschritter et al., J Clin Endocrinol Metab. 2009
Tschritter et al., Diabetologia. 2009
Tschritter et al., Proc Natl Acad Sci U S A. 2006
19. Insulin resistance in the prefrontal cortex
R
middle frontal gyrus
Lean Obese
Kullmann, Heni et al., Diabetes care 2015
Only lean participants show a reduction in cerebral blood flow 30 min
after intranasal administration of insulin (p<0.001).
20. -2.0
-1.0
0.0
1.0
2.0
20 30 40 50 60 70
Increase in GLP1 after oral glucose intake
(pmol/l)
Changeinfood-cueinducedbrainactivity
intheorbitofrontalcortex(AU)
N=22 (11 per group)
Heni et al., Molecular Metabolism, in press
P<0.0001
= Lean
= Obese
anterior
posterior
Prefrontal cortex
GLP-1 associates with brain activity
in lean and obese humans
21. Impaired insulin action in the human brain:
Causes and metabolic consequences
Heni, Kullmann, Preissl, Fritsche, Häring 2015
22. Kullmann, Heni, Hallschmid, Fritsche, Preißl, Häring; Physiological Reviews invited
Insulin sensitive brain regions in humans
31. Possible causes of brain insulin resistance in humans
Heni, Kullmann, Preissl, Fritsche, Häring 2015
32. Effects of gestation on fetal brain functions assessed by fMEG
Linder et al Diabetologia 2014
Fetus
Effect of OGTT in insulin sensitive or insulin resistant mothers
Mother
33. Effects of gestation on fetal brain functions assessed by fMEG
Linder et al Diabetologia 2014
Linder et al JCEM 2015
Fetus
Effect of OGTT in mothers with and without gestational diabetes
Mother
PlasmaInsulin(pmol/l)
0
500
1000
1500
2000
Time (minutes)
0 30 60 90 120
NGT
GDM
Latency(ms)
180
200
220
240
260
280
300
320
340
34. Gestational diabetes Controls
Placenta
Umbilical Cord Blood
Metabolic phenotyping
at 24-31 weeks of gestation
(5-point OGTT, insulin secretion / sensitivity, metabolomics, microRNA)
Fetal MEG
Fetal
programing
Follow-up visits 1, 2, 5, 10 years postpartum
Fetal
MEG
N=160
PREG - Study Design
(N>600, aim N=1000)
39. Orbitofrontal cortex
Hypothalamus
0 1 3 5
Main effect of condition:
Insulin < Placebo. Intranasal insulin
induced fALFF decrease in the
hypothalamus and orbitofrontal
cortex.
Insulin reduces resting state activity in the
orbitofrontal cortex and the hypothalamus
17 lean women
Kullmann, Heni et al. Neuroendocrinology 2012
40. PREG - Study Design
(N>600, aim N=1000)
N=115N=160
Gestational diabetes Controls
Placenta
Umbilical Cord Blood
Biobank
Pathway analysis
75 g oGTT at 24-32 weeks of gestation
5 point frequently sampled
Fetal MEG
Fetal
programing
Follow-up visits 1, 2, 5, 10 years postpartum
Fetal
MEG
42. r=0.41,
p=0.004
Insulin effect on beta activity is
reduced with age
(but not with obesity)
Insulin effect on theta activity is
reduced with obesity
(but not with age)
r=0.33,
p=0.022
Tschritter et al , Diabetologia 2009
43. Concentrations of insulin and albumin in human
paired CSF/serum samples in relation to age.
Sartorius Plos One 2015