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Obesity and brain insulin
resistance: cause or
consequence
H.U. Häring Madrid 2015
0
0
100
200
300
400
500
600
700
800
900
Insulinsecretion
10 20 30 40 50 60
Insulin sensitivity
IFG/IGT)
NGT
T2D
Phenotypes in the TÜbingen Family study
Individuals at risk for type 2 diabetes TÜF ~ N = 3000
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
0
0
100
200
300
400
500
600
700
800
900
Insulinsecretion
10 20 30 40 50 60
Insulin sensitivity
Phenotypes in the TÜbingen Family study
Tübingen lifestyle intervention program TULIP
N = 400
0 5 10 15 20 25 30 35 40
IGI2
0
50
100
150
200
250
300
350
400 NGT
IFG and/or NGT
Diabetes
8 year follow-up of TULIP:
effect of baseline insulin secretion on glucose tolerance
Insulin Sensitivity
InsulinSecretion
0 Baseline
1 1 year lifestyle intervention
8 8 year follow up
8
108
1
0
0
0
100
200
300
400
500
600
700
800
900
Insulinsecretion
10 20 30 40 50 60
Insulin sensitivity
Phenotypes in the TÜbingen Family study
MRI and MR-Spect phenotyping
N>2000
MEG > 100
fMRI > 100
MEG: Modulation by Insulin (n~100)
Tschritter, PNAS 2006
Tschritter, Diabetologia 2007
Tschritter, Diabetologia 2009
Guthoff, JCEM 2010
Genetic variation: IRS1, FTO
basal Insulin
basal Insulin
Lean
Overweight
Reduced insulin effect on neuronal activity –
association with body weight
r=-0.74, p<0.001
Tschritter et al. PNAS 2006
Brain insulin resistance – improved with insulin detemir?
-8
-4
0
4
8
12
16
Basal
1st step
0.25 mU/kg/min
2nd step
1 mU/kg/min
Changeinbetaactivityvs.saline(fT)
Lean human insulin n=12
Obese human insulin n=34
Obese insulin detemir n=10
0 90 180 min
Insulin /
Saline0.25 mU/kg/min
MEG
1.0 mU/kg/min
MEGMEG
O. Tschritter et al., PLoSone 2007
Tschritter et al., JCEM 2009
Elevated levels of saturated free fatty acids are
associated with brain insulin resistance
Hans Haring-Lo último en obesidad
Control TLR-KO
IL-6 AB
IRS2
Ptyr-IRS2
Ptyr-IR
IR
Tschritter et al., JCEM 2009
Visceral fat mass is associated with
brain insulin resistance
p=0.021
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)
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
Stefan N, Häring HU, Nature Medicine 2013
Nature Medicine 2012
Region of interest:
Human hypothalamus
Functional magnetic
resonance imaging
(fMRI)
Coordinates based on
WFU Pickatlas tool
http://www.fmri.wfubmc.
edu/download.htm
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
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).
-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
Impaired insulin action in the human brain:
Causes and metabolic consequences
Heni, Kullmann, Preissl, Fritsche, Häring 2015
Kullmann, Heni, Hallschmid, Fritsche, Preißl, Häring; Physiological Reviews invited
Insulin sensitive brain regions in humans
a
p
Hypothalamus
2.0
2.5
3.0
3.5
Visceralfat(kg)after9month
Adjustedforbaseline
r=-0.76, p=0.001
-150 -100 -50 0 50 100 150
Cerebral insulin sensitivity before lifestyle intervention
Insulin-stimulated theta activity (fT)
Tschritter, …, Heni et al., Diabetologia, 2011
Insulin sensitivity of the brain predicts
success in lifestyle intervention
MEG
T1-weighted
contrast
Visceral fat
highlighted
Insulin sensitivity of the human hypothalamus
associates with visceral fat
Hypothalamus
Kullmann, Heni et al., Diabetes Care 2015
2
3
4
5
6
7
8
9
10
-30 -20 -10 0 10 20
p=0.0088
Subcutaneous
adiposetissue(l)
Insulin effect on hypothalamic CBF
10
15
20
25
30
-30 -20 -10 0 10 20
p=0.0095
Insulin effect on hypothalamic CBF
Totaladipose
tissue(l)
0
1
2
3
4
5
6
7
8
-20 -10 0 10 20
p=0.0206
Visceraladipose
tissue(l)
Insulin effect on hypothalamic CBF
Heni, Kullmann et al
unpublished
Association of fat compartments with
hypothalamic insulin sensitivity
Subcut. adipose tissue
Visceral adipose tissue
Total adipose tissue
-30 0 15 30 45 60 75 90 105 120 135 150 165 180 195 210
Glucoseinfusionrate
(mgxkg-1xmin-1)
0
1
2
3
4
5
Spray
Insulin spray
Placebo spray
Time (minutes)
Steady state
before spray Steady state after spray
p=0.0005
Results – glucose infusion rate
Heni et al., Diabetes, 2014
Results – insulin sensitivity index
+ 41 ± 8 %
p=0.0077
-0.7 ± 18 %
p=0.9
p=0.0094
Changeininsulinsensitivityindex
frombeforetoaftersprayapplication(%)
0
100
120
140
160
Placebo
spray
Placebo
spray
Insulin
spray
Insulinspray
Lean Overweight
Heni et al., Diabetes, 2014
Region of interest:
Human hypothalamus
N=11
Heni et al.,
Diabetes 2014
p=0.0168
r²=0.64
100
125
150
175
200
25 30 35 40 45 50 55 60 65
Insulinsensitivityindexafter
insulinsprayapplication(%)
Hypothalamic blood flow after nasal insulin,
baseline adjusted (ml x 100g-1 x min-1)
Heni, Kullmann, Preissl, Fritsche, Häring 2015
Possible causes of brain insulin resistance in humans
Heni, Kullmann, Preissl, Fritsche, Häring 2015
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
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
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)
Brain insulin
resistance
Obesity
MHO MUHO
Compensatory
hypersecretion
or
ß-cell dysfunction
Concept of the pathogenesis of type 2 diabetes mellitus
fatty
pancreas
fatty
liver
Effects of insulin Detemir on spontaneous
cortical activity in obese humans
-40
-20
0
20
40
60
80
Insulin-inducedchangeinbetaactivity(fT)
20 30
BMI
Cerebrocortical
insulin resistance is
improved by insulin
Detemir
Tschritter et al. 2008
r=0.33, p=0.022
p=0.22
p=0.26
r=0.41, p=0.004
fMRI
anterior
posterior
6
4
2
0
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
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
Insulin sensitivity
(AU, OGTT-derived)
CSF/serumratioinsulin
worsebetter
Insulin transport across the
blood brain barrier
Heni et al., Acta Diabetologia 2013
0.00
0.05
0.10
0.15
0.20
-0.05 0.00 0.05 0.10
p=0.0005. r²=0.5
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
Concentrations of insulin and albumin in human
paired CSF/serum samples in relation to age.
Sartorius Plos One 2015
Heni, Kullmann, Preissl, Fritsche, Häring in press
Insulin responsive brain areas in humans

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Hans Haring-Lo último en obesidad

  • 1. Obesity and brain insulin resistance: cause or consequence H.U. Häring Madrid 2015
  • 2. 0 0 100 200 300 400 500 600 700 800 900 Insulinsecretion 10 20 30 40 50 60 Insulin sensitivity IFG/IGT) NGT T2D Phenotypes in the TÜbingen Family study Individuals at risk for type 2 diabetes TÜF ~ N = 3000
  • 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
  • 4. 0 0 100 200 300 400 500 600 700 800 900 Insulinsecretion 10 20 30 40 50 60 Insulin sensitivity Phenotypes in the TÜbingen Family study Tübingen lifestyle intervention program TULIP N = 400
  • 5. 0 5 10 15 20 25 30 35 40 IGI2 0 50 100 150 200 250 300 350 400 NGT IFG and/or NGT Diabetes 8 year follow-up of TULIP: effect of baseline insulin secretion on glucose tolerance Insulin Sensitivity InsulinSecretion 0 Baseline 1 1 year lifestyle intervention 8 8 year follow up 8 108 1 0
  • 6. 0 0 100 200 300 400 500 600 700 800 900 Insulinsecretion 10 20 30 40 50 60 Insulin sensitivity Phenotypes in the TÜbingen Family study MRI and MR-Spect phenotyping N>2000 MEG > 100 fMRI > 100
  • 7. MEG: Modulation by Insulin (n~100) Tschritter, PNAS 2006 Tschritter, Diabetologia 2007 Tschritter, Diabetologia 2009 Guthoff, JCEM 2010 Genetic variation: IRS1, FTO basal Insulin basal Insulin Lean Overweight
  • 8. Reduced insulin effect on neuronal activity – association with body weight r=-0.74, p<0.001 Tschritter et al. PNAS 2006
  • 9. Brain insulin resistance – improved with insulin detemir? -8 -4 0 4 8 12 16 Basal 1st step 0.25 mU/kg/min 2nd step 1 mU/kg/min Changeinbetaactivityvs.saline(fT) Lean human insulin n=12 Obese human insulin n=34 Obese insulin detemir n=10 0 90 180 min Insulin / Saline0.25 mU/kg/min MEG 1.0 mU/kg/min MEGMEG O. Tschritter et al., PLoSone 2007
  • 10. Tschritter et al., JCEM 2009 Elevated levels of saturated free fatty acids are associated with brain insulin resistance
  • 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
  • 16. Stefan N, Häring HU, Nature Medicine 2013 Nature Medicine 2012
  • 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
  • 24. 2.0 2.5 3.0 3.5 Visceralfat(kg)after9month Adjustedforbaseline r=-0.76, p=0.001 -150 -100 -50 0 50 100 150 Cerebral insulin sensitivity before lifestyle intervention Insulin-stimulated theta activity (fT) Tschritter, …, Heni et al., Diabetologia, 2011 Insulin sensitivity of the brain predicts success in lifestyle intervention MEG T1-weighted contrast Visceral fat highlighted
  • 25. Insulin sensitivity of the human hypothalamus associates with visceral fat Hypothalamus Kullmann, Heni et al., Diabetes Care 2015
  • 26. 2 3 4 5 6 7 8 9 10 -30 -20 -10 0 10 20 p=0.0088 Subcutaneous adiposetissue(l) Insulin effect on hypothalamic CBF 10 15 20 25 30 -30 -20 -10 0 10 20 p=0.0095 Insulin effect on hypothalamic CBF Totaladipose tissue(l) 0 1 2 3 4 5 6 7 8 -20 -10 0 10 20 p=0.0206 Visceraladipose tissue(l) Insulin effect on hypothalamic CBF Heni, Kullmann et al unpublished Association of fat compartments with hypothalamic insulin sensitivity Subcut. adipose tissue Visceral adipose tissue Total adipose tissue
  • 27. -30 0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 Glucoseinfusionrate (mgxkg-1xmin-1) 0 1 2 3 4 5 Spray Insulin spray Placebo spray Time (minutes) Steady state before spray Steady state after spray p=0.0005 Results – glucose infusion rate Heni et al., Diabetes, 2014
  • 28. Results – insulin sensitivity index + 41 ± 8 % p=0.0077 -0.7 ± 18 % p=0.9 p=0.0094 Changeininsulinsensitivityindex frombeforetoaftersprayapplication(%) 0 100 120 140 160 Placebo spray Placebo spray Insulin spray Insulinspray Lean Overweight Heni et al., Diabetes, 2014
  • 29. Region of interest: Human hypothalamus N=11 Heni et al., Diabetes 2014 p=0.0168 r²=0.64 100 125 150 175 200 25 30 35 40 45 50 55 60 65 Insulinsensitivityindexafter insulinsprayapplication(%) Hypothalamic blood flow after nasal insulin, baseline adjusted (ml x 100g-1 x min-1)
  • 30. Heni, Kullmann, Preissl, Fritsche, Häring 2015
  • 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)
  • 35. Brain insulin resistance Obesity MHO MUHO Compensatory hypersecretion or ß-cell dysfunction Concept of the pathogenesis of type 2 diabetes mellitus fatty pancreas fatty liver
  • 36. Effects of insulin Detemir on spontaneous cortical activity in obese humans -40 -20 0 20 40 60 80 Insulin-inducedchangeinbetaactivity(fT) 20 30 BMI Cerebrocortical insulin resistance is improved by insulin Detemir Tschritter et al. 2008
  • 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
  • 41. Insulin sensitivity (AU, OGTT-derived) CSF/serumratioinsulin worsebetter Insulin transport across the blood brain barrier Heni et al., Acta Diabetologia 2013 0.00 0.05 0.10 0.15 0.20 -0.05 0.00 0.05 0.10 p=0.0005. r²=0.5
  • 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
  • 44. Heni, Kullmann, Preissl, Fritsche, Häring in press Insulin responsive brain areas in humans