ueda2012 clinical pmi and metabolic disorders-d.leo pruimboom

1. Clinical PNI and metabolic disorders
When the immune system overrides the selfish
brain
Prof. Leo Pruimboom
President of the International Association for Clinical PNI
Associate Professor University of Graz (Austria)
Director European Master in Clinical PNI, University of Graz (Austria)
Februari 2012

2. "If we could give every individual
the right amount of nourishment
and exercise, not too little and not
too much, we would have found
the safest way to health."
Hippocrates 400 BC

3. 3
“Nothing in biology makes sense without
evolution”
Theodosius Dobzhansky 1973
“Nothing in medicine makes sense without
biology”
Frits Muskiet 2005

5. If society would be the cause, why are
their still lean people??????????

6. The impact of the insulin resistance
syndrome in modern society
Conference Statements and outline
• Adaptive on the short term
• Protective while enough insulin
• Deleterious on the long term
• Based on false triggers
• A psychoneuroendocrinoimmunological
disease
• An evolutionary solution
• The study of origin

7. Not insulin resistance but
insulin resistance syndrome
1. Pima Indians Higher insulin sensibility >> Obese
2. Low insulin >> Obese
3. High Insulin >> BMR << Obese
4. City Africans >> IR >> Obese
5. Ice-landers << IR
6. Kashmir-Himalayas << IR << Obese
Zargar AH et al. Diab Res Clin Practice 2000, 47:135-146.
Swinburn BA, et al. J Clin Invest 1991, 88:168-173.
Unger RH Nature Medicine 2006, 12(1):56-57
Kahn BB, Flier JS: J Clin Invest 2000, 106(4):473-481.

8. People eat to much and do not exercise
But they do know that this behavior makes them ill.
So why do they eat too much and don´t engage in
exercise??
Engagement in
minimal estimated
amount of exercise
Medical Hypotheses
77 (2011) 708–713

9. If so many people react the same, it has to have been
“programmed” by evolution
9

10. - Concepts of health
and disease - Master
10
Molecular Systems Biology 3:137

11. Offspring of Ad Libidum versus undernourished mothers.
Note; the adult UN offspring is shorter but fatter
Bernhard H. Breier,* Stefan O. Krechowec and Mark H. Vickers. Early life programming of obesity and the lazy phenotype.
Early Life Origins of Health and Disease, edited by E. Marelyn Wintour and Julie A. Owens.
©2006

12. High Glycemic Load
Insulin and cortisol toxicity
Meal frequency and HGL-Food
Guilherme
et al. Nature
reviews.
2009 (9); 367
– 377
Saltiel 2007)

14. Obesity and insulin
resistance Syndrome
CVD
Diabetes type II
Mental disorders
Depression
Autoimmune diseases
Insulin resistance
Syndrome
Acne
PCOS
Alopecia
Skin tags
Pigmentación
Acanthosis nigricans
Myopia
Cancer
Gout and psuedogout
Secular increase of height
Paradontosis
Apnea

15. Atherosclerosis
Insulin resistance, hypercholesterol and gram-
negative bacterial infection; the bodies defense
Specific
Oral Cave
Koren 2010, PNAS

16. High cholesterol protects against
bacterial infection at the account of
atherosclerosis
Ravnskov U. High cholesterol may protect against infections and
atherosclerosis. QJM. 2003 12;96(12):927-34.
Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis.
Lancet. 2000 09/09;356(9233):930-3.
Kitchens RL, Thompson PA, Munford RS, O'Keefe GE. Acute inflammation
and infection maintain circulating phospholipid levels and enhance
lipopolysaccharide binding to plasma lipoproteins. J Lipid Res. 2003
12;44(12):2339-48.

19. Comparative Biochemistry and
Physiology Part A 136 (2003) 95–112

20. 1. Hunter DJ. Diet, Body size and breast
cancer. Epidem Rev 1993; 15:110-32.
2. Stoll BA. Western diet, early puberty,
and breast cancer risk. Breast Cancer
Res Treat 1998;49:187-93.
3. Hankinson SE et al. Circulating
concentrations of insulin-like growth
factor-1 and risk of breast cancer.
Lancet 1998;351:1393-6

22. Hypoxie-Stress Reaction, Hypoxie induced
Factor 1 and Insulin Resistance Syndrome
Heel Spur Frey C Foot Ankle Int. 2007 Sep;28(9):996-9.
Epicondylitis lateralis Shiri et al. Am J Epidemiol. 2006 Dec 1;164(11):1065-74.
Epicondylitis madialis Shiri et al. Am J Epidemiol. 2006 Dec 1;164(11):1065-74.
Tendinopathy Gaida et al. Arthritis Rheum. 2009 Jun 15;61(6):840-9.
Achilles Tendinopathy Gaida et al. Med Sci Sports Exerc. 2009 Jun;41(6):1194-7.
Bursopathies Werner et al. J Occup Rehabil. 2005 Mar;15(1):37-46.
Chronic pain Ray et al. Pain. 2011 Jan;152(1):53-9.
Fibrosis Spencer et Am. J. Physiol Endoc. Met. 2010 Dec;299(6):E1016-27.
Divoux et al. Diabetes. 2010 Nov;59(11):2817-25
Keloid buliding Verma. Am J Clin Dermatol. 2010 Dec 1;11(6):433-6
Carpal Tunnel Syndr. Gell et al. J Occup Rehabil. 2005 Mar;15(1):47-55.
Rotator Cuff Tendinitis Wendelboe J Bone Joint Surg Am. 2004 Apr;86-A(4):743-7.
Migraine Takashima Brain Nerve. 2009 Oct;61(10):1143-53.

23. High IL-1
High IL-6
High TNF alfa High Central Pro-
inflammatory Profile
High NFkappaB
Lower IL-1
Lower IL-6
Lower TNF alfa Low Peripheral Pro-
inflammatory Profile
Lower NFkappaB
Non or hardly immune cell infiltration

25. Krüger , K.: T cell homing and exercise Exerc Immunol Rev 13:37-54, 2007

26. The shift from peripheral to central immune
acivity
CURRENT SCIENCE, VOL. 95, NO. 2, 25 JULY
2008

27. Er

28. The phylogenetical oldest system
= The immune system
JOURNAL OF EXPERIMENTAL ZOOLOGY (MOL DEV EVOL) 306B:496–520
(2006)

29. Simultaneous appearance
(Big) Brain
High basal metabolic rate
Glucocorticoid Receptor
Complete pancreas (98% exocrine – 2%
endocrine)
Mechanisms of Ageing and
Development 130 (2009) 216–221

31. Adult chimpanzee
Human newborn
Homo Floresiensis
Curr Anthropol. 1995 Apr.;36(2):pp. 199-221

32. Homo sapiens
Comparative
Biochemistry and
Physiology - Part A:
Molecular &
Integrative
Physiology. 2003
9;136(1):5-15.

33. Humans

34. Diabetes 49:1341–1346, 2000

35. 0
200
400
600
800
Fecal Elastase
Vegetarians
Omivores
0
5
10
15
20
Chymotrypsin
Vegetarians
Omnivores
Journal of Pediatric
Gastroenterology and Nutrition
38:224–226 © February 2004
ug/g stool
p<0.05
U/g stool
p<0.05
Legumes-Fibres
Kunnitz factors
Lipase/protease-
inhibitors
Lectins
Saponins
Bowman-Birk factors

36. Hypoinsulinemia causes pancreatic atrophy with fat replacement of the
exocrine pancreas in different species. These results indirectly show the
significant role of insulin on pancreatic exocrine function. However,
direct evidence is also available to highlight the key role of insulin. Both
endogenous and exogenous insulin evoke increases in pancreatic
enzyme synthesis and growth. Insulin is not only important in healthy
conditions, but is also involved in the regenerative processes during
pancreatitis. Human studies have also proved the necessity of insulin in
pancreatic exocrine function. In conclusion, insulin has long term effects
on the regulation of the biosynthesis of pancreatic digestive enzymes
and short term effects on the stimulation of pancreatic secretion

37. Vena portaI Intermittent insulin
50% insulin
50% insulin
Intact
Gap junction
23% blood
12,2% basic
insulin
25-35% blood
12,5-17,5%
basic insulin
Intrinsic repair of
acinar cells

38. Vena porta Continuous insulin
90% insulin
10% insulin
Resistance
Absence of
gap junction
23% blood
21% basic
insulin
25-35% blood
22,5-31%basic
insulin
Exogenic insulin
Repair acinar cells
Accumulation of
adipose tissue
Fatty heart

39. Trends Cogn Sci (Regul Ed ). 2005 05;9(5):250-7.

42. The youngest system Big Brain
The oldest system Immune system
Phylogenesis
Straub. J InternMed2010;267: 543–560
Brascha. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30
(2006) 827–853
Physiology Danger

43. Energy distribution in Physiology
The immune system = not expensive in rest
L. Pruimboom / Medical Hypotheses 77
(2011) 708–713

44. Chrousos, G. P. Nat. Rev. Endocrinol. 5, 374–381 (2009)

45. - Concepts of health
and disease - Master
45
Muscle Brain
(13 kcal/kilo) (197 kcal/kilo)
Glucose
Fatty acids Heart
Proteins (570 kcal/kilo)
Creatine-P
Liver (216 kcal/kilo)
Kidney (420 kcal/kilo) Immune system
Gut (212 kcal/kilo) (27 kcal/kilo)

46. J InternMed2010;267: 543–560.
Very expensive

47. Protein turnover (%) during chronic and massive
acute immune activation
Loss of muscles and induction of NPBD
Adapted from Lochmiller,
OIKOS 88: 87–98. Copenhagen 2000

48. Wound healing and high costs
Immune activation = 380 – 1500 kcal
Deep tissue production = size dependent
Hurd TA. Wound Care 2004.
Ord H. Br J Nurs 2007.

49. J InternMed2010;267: 543–560
Brain Behav Immun. 2011 01;25(1):1-5.

50. Famine (poor countries), IRS, LGI,
Autoinflammatory and Autoimmune diseases
Brain
Stable
-20%
Liver
- 40%
Kidneys
- 40%
Muscles
-20/-40/-60%
AMERICAN
JOURNAL OF
HUMAN BIOLOGY
23:29–34 (2011)
Immune
system

51. Inflammation

53. Vitamin A, D, DHA, EPA

54. Long term inflammation
leads to a non-permissive
brain syndrome with IR and
LR.
L. Pruimboom / Medical Hypotheses 77
(2011) 708–713

55. The reptile phenotype/loss of thryroid
function/hibernation
• Brain function: depression; poor memory; inability to
concentrate; mood swings; sleep disturbances; anxiety
• Skin/hair quality; dry skinn; puffy eyes; hair loss; coarse or brittle
hair
• Reproductive functions; irregular menstruation; heavy
menstruation; infertility; birth defects; erectile dysfunction;
delayed ejeculation
• Circulation/respiratory functions: high cholesterol; high blood
pressure; congestive heart failure; Sleep apnea
• Muscle/joint function: muscle cramps; weakness; pain; deep
voice; horse voice; pins and needles in hands/feet
• Metabolic functions: heat/cold intolerance; weight gain;
constipation; general tiredness
Pruimboom L. Medical Hypotheses 2011

56. Pruimboom, L. Van Nature 2009

58. 58

59. Clinical Psychoneuroimmunology
The science based on the film and not on the photo
Proximate medicine
Present
Loss of husband
Sedentary life
Sugar addiction
Insulin Resistance syndrome
Central adiposity
Lack of immune migration

60. Clinical PNI – Metamodel 1
The symptom
Causes
(nutrition, inactivity, lack of
sunshine, tabaco)
Non-complete
systemic
resolution
Non-complete
local resolution
Central appeal
of stress axes
Energy allocation
disorders

61. Clinical PNI – Metamodel 1
The symptom
Causes
(nutrition, inactivity, lack of sunshine,
tabaco)
Insulin
resistance
Cortisol
Resistance
LGI
Proximate
medicine

62. The symptom
Nutrition, inactivity, lack of sunshine,
tabaco, shift work, ACE, CLS,
Insulin
resistance
SAM>HPA
Sterile Inflammation
Exocrine
pancreatic
insufficiency
Energy
distribuition
disorderCortisol resistance
A
C
U
T
E
C
H
R
O
N
I
C
Reptile
Phenotype

63. Symptom
Nutrition, inactivity, lack of sunshine,
tabaco, shift work, ACE, CLS,
Cortisol/Insulin
resistance
SAM>>HPA
(Sub)Sterile Low
Grade
Inflammation
Exocrine
pancreatic
insufficiency
Energie
DeficiencyNTIS
A
C
U
T
E
C
H
R
O
N
I
C
Sedentary
Lifestyle
Increased
Protein turn
over

64. Causes of low grade
inflammation, insulin
resistance syndrome and non
permissive brain disorder
Obesity Reviews. 2011;12(5):339-45

65. British Journal of
Nutrition (2010), 104,
724–728
Kangaroo meat versus
domesticated meat
The role of food in low
grade inflammationKangaroo
Hybridised
meat

66. The study of origin
August 2011
Background: Recovering self-sufficiency in an “original
environment” during a short period of time
should be able to normalize insulin sensibility and
therefore inflammatory and metabolic biomarkers.
Individuals with pathologies based on “modern
lifestyle” should benefit of this intervention

67. Methodology: 10 persons lived for a period of 10 days in the
pyrenees during the summer of 2011. Searching for
food, water, shelter and day/nighttime biorhythm
were all part of the self-sufficiency study.
Immunological and metabolic biomarkers (soft
endpoints) and SF36 questionnaire (hard endpoint)
were used as measurements (6, 3, 1 month
before start, day of study-start, end of study, 4 months
after study). Food and water intake was constantly
monitored
Results: Their was a significant improvement of all biomarkers.
hsCRP was raised (as expected) after the study and
normalized 4 months later. Individuals with chronic
fatigue were and are symptom-less (n=2). Two subjects
with metabolic syndrome are still in the normal range.
Quality of life was improved in all subjects after
4 months (SF36)

68. 84
85
86
87
88
89
90
91
92
93
Glucose
11/08/11
21/08/11
21/12/11
P < 0,05
*
The study of origin; Pruimboom prep.
Pyrenees 2011
n=10 Glucose

69. 0
1
2
3
4
5
6
Insulin
11/08/11
21/08/11
21/12/11
P < 0,05
*
The study of origin; Pruimboom prep.
Pyrenees 2011
n=10 Insulin

70. 0
10
20
30
40
50
60
70
Triglicerides
11/08/11
21/08/11
21/12/11
P < 0,05
*
The study of origin; Pruimboom prep.
Pyrenees 2011
n=10 Triglicerides

71. 0
0.5
1
1.5
2
2.5
3
3.5
hsCRP
11/08/11
21/08/11
21/12/11
*p < 0,05
**p<0,05
**
*
The study of origin; Pruimboom prep.
Pyrenees 2011
n=10 hsCRP

72. 0
50
100
150
200
250
Cholesterol
11/08/11
21/08/11
21/12/11
P < 0,05
*
The study of origin; Pruimboom prep.
Pyrenees 2011
n=10 Cholesterol

74. Thank you for your attention

76. Signed an
informed
consent FOR
public use

77. Thank you for your attention