Slides van de lezing van Dr. Ir. Ben van Ommen tijdens het eerste jaarlijkse leefstijlcongres georganiseerd door TNO en het Leids Universitair Medisch Centrum LUMC

1. The nutritional systems biology
solution in Type 2 Diabetes and
Cardiovascular Desease prevention
and therapy".
Ben van Ommen
Systems approaches needed
Ben van Ommen

2. $10.694

4. … and NONE of them aims
at CURING the disease …!

5. Currie, Lancet 2010

6. The 5-year efficacy of diabetes type 2
treatment
Kahn, NEJM 2006

7. DIABETES PREVENTION PROGRAM RESEARCH GROUP, N
Post-Load Glucose
Fasting Glucose
ParticipantswithNormanPlasmaGlucose(%)

8. time
Inflammatory
response
Oxidative
stress
metabolic
stress
Inflammatory
stress
Too high: damage.
Too long: disease
Health and disease are characterized by flexibility,
i.e. the capacity to regain homeostasis upon a challenge.
homeostasis
Universal mechanism:
- Inflammation
- Metabolism
- Oxidation
- Mental stress
Too low:
inadequate protection.
(example: inflammation)

9. Visceral
adiposity
LDL elevated
Glucose toxicity
Fatty liver
gut
inflammation
endothelial
inflammation
systemic
Insulin resistance
systemic
inflammation
Hepatic IR
Adipose IR
Muscle metabolic
inflexibility
adipose
inflammation
Microvascular
damage
Myocardial
infactions
Heart
failure
Cardiac
dysfunction
Brain
disorders
Nephropathy
Atherosclerosis
β-cell failure
Reversible process
β-cell Pathology
High cholesterol
High glucose
gluc Risk factor
Hypertension
dyslipidemia
ectopic
lipid overload
Ìrreversible process
Hepatic
inflammation
Stroke
IBD
fibrosis
Retinopathy
Metabolically
healthy
reversibleirreversible
Nakatsuji, Metabolism 2009
75 g Glucose
The flexible phenotype: the system is a shock absorber
(“phenotypic flexibility”)

10. Even precision medicine will not cure type 2 diabetes

11. Wopereis et al, Genes and Nutrition, Sept 2017

12. Wopereis et al, Genes and Nutrition, Sept 2017

13. Disposition index
Hepatic insulin
resistance index
Muscle insulin
resistance index
Adipose insulin
resistance index
Liver
Pancreas
Muscle
Adipose

14. procyanidins
Carnitine, Choline, … Low glycemic index
Stannols,fibre
Omega 3/6 FA
Quercetin,
Se, Zn, …
epicathechins
carotenoids
Antho cyanins
polyphenols
The processes that orchestrate phenotypic flexibility
depend on calories and nutrients…

15. Blanco-Rojo, Diabetologia, Oct 2015
Type 2 diabetes subgroups react differently on different diets
0 30 60 90 120
time(min)
[Glucose]
healthy
T2D
(diagnosed)
IFG (liver)
IGT (muscle)
T2D subgroup glucose respose to Oral Glucose Tolerance Test
T2D
(non-diagnosed)
IGT & IFG
Personalized?
Mediterranean
diet improves
muscle IS
Low-fat diet
improves
liver IS
Mediterranean
diet improves
systemic IS

16. Liver

17. Matsuda, Nutr Met Card Dis 2010
Hepatic insulin sensitivity and peripheral insulin sensitivity

18. Malaguernera, Am J Gastoent 2010
L-Carintine supplementation to diet:
a new tool in treatment of non-
alcoholic steatohepatitis

19. Rutlegde, Nutr Rev 2007
Why does fructose produce a fatty liver?
-

20. VLDL
TG CHOL
Lipid
transport
MTHFD1 1958 GA/AA
Metabolic pathway of Choline

21. Cassidy, Diabetologia 2016
Personalized?

23. 8 weeks 600 Kcal diet
Lim and Taylor, Diabetologia 2011
Reversal of type 2 diabetes: normalisation of beta cell function in
association with decrease pancreas and liver triacylglycerol
Nestlé Optifast
(46% carb, 33% protein and
20% fat, micronutrients)
3 portions of non starchy
vegetables

24. before “study” after “study”
Body weight (kg) 96.7 +/- 17.5 81.9 +/- 14.8
Fasting blood glucose (mM) 8.3 (5.9-33.0) 5.5 (4.0-10.0)
T2D occurrence 100% 39%
Conclusion:
These data demonstrate that intentional weight loss achieved at home by health-motivated
individuals can reverse Type 2 diabetes.
Diabetes reversal should be a goal in the management of Type 2 diabetes.
Steven, Lim, Tayor, Diabet. Med. 2013
Population response to information on reversibility of Type 2 diabetes
Information on the Counterpoint Study (reversibility of Type 2 diabetes using a very low
energy diet) triggered 77 subjects to report their “self-experimentation results” to the
authors:

26. Lean et al, Lancet, 2017

27. Lean et al, Lancet, 2017

28. Shai, NEJM 359 (2008)
Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet

29. Decision tree used to determine type 2 diabetes subgroups

30. A. Liver insulin resistance and moderately impaired β-cell function
Week 1: VLCD, intensifying exercise regime
Week 2-12: LCD, Exercise emphasizing aerobic training
B Muscle insulin resistance and moderately impaired β-cell function
Week 1-12: LCD. Exercise mixing aerobic training and resistance training
C. Liver and muscle insulin resistance and moderately impaired β-cell function
Week 1: VLCD, intensifying exercise regime
Week 2-12: LCD, Exercise emphasizing aerobic training
D. Insufficient β-cell function and liver insulin resistance
Week 1-12: LCD, emphasis on low glycemic index. Low intensity exercise
E. Insufficient β-cell function and muscle insulin resistance
Week 1-12: LCD, emphasis on low glycemic index. Low intensity exercise including
resistance training
F. Insufficient β-cell function and liver and muscle insulin resistance
Week 1-12: LCD, emphasis on low glycemic index. Low intensity exercise including
resistance training LCD: 500 kcal lower than isocaloric needs

31. Intensive lifestyle coaching with advanced type 2 diabetes
patients
11 type 2 diabetic patients in
advanced disease state entered into
an intensive program of lifestyle
coaching:
- Motivational coaching
- Physical activity
- Healthy diet
Insulin dosing was reduced with 80%
in 3 weeks.
After three months, 10 out of 11
patients did not use insulin anymore.
Average Insulin trend

32. Glucose control parameters improved during the 12 week
intervention and remained OK.

33. Quantification of adipose deposits

34. Change of MRI fat compartments during the 12 week intense life style phase and
50 week follow up

35. glucose
insulin
w0 w12 w50 w0 w12 w50
glucose
insulin
OGTT Glucose and Insulin curves of 2 of the 11 subjects
Major differences!
Subject A Subject B

36. 2 stages in cure:
1 – reversal : Proper glucose control (easy if I hardly consume glucose)
2 – cure: Organ flexibility (= insulin sensitivity restored)
But what if I do not produce insulin anymore (beta-cell failure)?

37. Muoio, Cell 159, 2014

38. Popa and Mot, doi 10.5772/56467
mitophagy

39. Cheng, Longo, Cell 168, 2017
Fasting Mimicking Diet and beta-cell regeneration

40. Now: suppress glucose:
Sometimes: retreat if lifestyle works
The role of medication

41. procyanidins
Carnitine, Choline, … Low glycemic index
Stannols,fibre
Omega 3/6 FA
Quercetin,
Se, Zn, …
epicathechins
carotenoids
Antho cyanins
polyphenols
Future: personalized medicine & nutrition

42. Complications …

43. T2 Diabetes is a ‘systems disease’
Multiple interacting
physiological processes
T2 Diabetes initiates when
one or more biological
processes lose flexibility
Diagnosis of all relevant processes
and predispositions
Goal: regain flexibility in all relevant
processes, exploiting diet, lifestyle,
medication and genetics where
relevant
Physiological system
Obesogenic environment
Limited engagement with
health status
Social interactions are
important for outcome
Optimal coaching, participation
and communication
Integration of medical, social,
economical and mental
solutions
Social system
T2 Diabetes needs a ‘systems solution’
Patient empowerment
Implement in regional setting
Acceptance by accreditation
Healthcare system
Conflicting stakeholder interests
No focus on prevention
Short term financial vision

44. A “360 degree
diagnosis”

45. Joint Innovation Center
Fundamental
research
Applied research
Implementation
(economy & society)
- mechanisms of action
- systems biology
- behavioral change theory
- mathematical models
- artificial intelligence
- Health Data Cooperative
- ICT infrastructure
- personal health portal
- intervention strategies
- behavioural applications
- tailored solutions
- connect healthcare and
research (n=1)
- local new economy
- New services and products
- community involvement
- healthcare party buy-in
- multi-stakeholder consortium
- accreditation
- reimbursement

47. As-is LaM As-is LaM As-is LaM
5. Life style costs € 0.2 € 10 € 0.1 € 5 € - € 3
4. Employability costs € 76 € - € 6 € - € - € -
3. Complications & comorbidities € 19 € - € 8 € - € 2 € -
2. Direct medical costs € 11 € - € 5 € - € 2 € -
1. Medication € 25 € - € 16 € - € 5 € -
Total costs of a patient
now, and when treated with Lifestyle as Medicine
The financial aspects …
cost are 13x lower than
current practice
for a patient who is treated with
success at the moment of
diagnosis.
Total potential of
LaM (Euro’s)
€ 131k
€ 10k
€ 121K saving!
€ 35k
€ 5k
€ 9k
€ 3k
(Age 57) (Age 67)
€ 30K saving

48. CostsinKeuro
Age of diabetes onset
Lifestyle as Medicine consistently cost effective,
regardless of age at start

49. Citizen (habit) phase
start 2 wks 12 wks 1 year
Aim: cure by lifestyle
Intense personalized lifestyle program
- Start motivational coaching
- Health literacy
- Optimal diet
- Physical activity
- Introduction e-health
Aim: maintain changed lifestyle
All aspects of new lifestyle have settled into new
habits
- All tools are personalized and connected to a
sustainable support system
- Connected to one personal health data system
(Health Data Cooperative)
- Social, economic and regulatory environment
cooperates in habituation
THE ‘LIFESTYLE AS MEDICINE’ TIMELINE
Intense (cure) phase

50. LDL elevated
Fatty liver
gut
inflammation
endothelial
inflammation
systemic
Insulin resistance
systemic
inflammation
Hepatic IR
Adipose IR
Muscle metabolic
inflexibility
adipose
inflammation
High cholesterol
High glucose
dyslipidemia
ectopic
lipid overload
Hepatic
inflammation
Metabolically
healthy
Visceral
adiposity
systems interventions need systems diagnosis

51. work health
Insurance comp.
Healthy
communities
Healthcare staff
education
Health data
ownership
Healthcare
economy
regulation
research
government
leadership
Healthcare
system
comorbidities
patient
obese
Food industry
Healthcare
bankruptcy
Metabolically
healthy
diet
systems interventions need systems diagnosis

54. Mozaffarian, Circulation 2016
Lifestyle related health can only be optimized in a systems approach where all
relevant factors are addressed.

55. systems
change
in health
care
systems
change
in health
economy
Lee, Nutrition Reviews 2017

56. Strategy : First implement a systems change in a regional
setting
Western
Netherlands
The Netherlands
Rotterdam
Leiden
The Hague
and the rest …

57. If Lifestyle as Medicine
works, why do we
not use it?

58. Thanks to
Suzan Wopereis
Iris de Hoogh
Koen Hogenelst
Hanneke Molema
Femke Hoevenaars
Wilrike Pasman
Jildau Bouwman
Tim van de Broek
Marjan van Erk
Robert Kleemann
Eugene van Someren
André Boorsma
Wilma Otten
Pepijn van Empelen
Hilde van Keulen
Hanno Pijl
Maurice Bizino
Hildo Lamb
Gerault Eggermont
Niels Chavannes
Marise Kasteleijn
Mattijs Numans
Andrea Evers (UL)
John Verhoef (HL)
Health Coach
Luuk Simons
Bas Gerritsen
Un Cordoba
José Lopez-Miranda
Pablo Pérez-Martinez
Javier Delgado-Lista
Tufts University
José Ordovas
Larry Parnell