The nutritional systems biology solution in Type 2 Diabetes and

Cardiovascular Desease prevention and therapy".

Ben van Ommen

System modifiers of glucose metabolism and metabolic health

Ben van Ommen

Hexokinase

ATP ADPglucose Glucose-6-phosphate

Gene

Metabolism

enzyme

hexokinase

ATP ADPGlucoseGlucose-6-phosphate

What about the effect of a spaghetti al tonno, apple pie with doublewhipped cream, espresso & sugar?

What about the difference between you and me?

Ànd …. Is glucose toxic …?

healthy

diabeticMy breakfast

0

1

2

3

4

5

6

7

8

9

10

-10 40 90 140 190 240

Glucose(mM)

My reaction

Time(min)

healthy

diabetic75 g glucose (OGTT)

Glucose(mM)

Time(min)

0

2

4

6

8

10

0 50 100 150

So for me, 75 grams of glucoseIs OK !

Glucose(mM)

Time(min)

0

2

4

6

8

10

0 50 100 150

Coca Cola

content Amount (g)Carbohydrate 78

glucoseLipids 0

SFAMUFAPUFA

Protein 0Energy 280 * 90 mg caffeine

T(max) 45 minC(max) 6.5 mM

Glucose(mM)

Time(min)

Jelly beans

0

2

4

6

8

10

0 50 100 150content Amount (g)Carbohydrate 88

glucoseLipids

SFAMUFAPUFA

ProteinEnergy 365

T(max) 60 minC(max) 8.2 mM

Glucose(mM)

Time(min)

Dextro energy

0

2

4

6

8

10

0 50 100 150content Amount (g)Carbohydrate 86

glucose 76Lipids 0

SFAMUFAPUFA

Protein 0Energy 325

T(max) 45 minC(max) 8.1 mM

Glucose(mM)

Time(min)

AA energy drink

0

2

4

6

8

10

0 50 100 150content Amount (g)Carbohydrate 83

glucoseLipids 0

SFAMUFAPUFA

Protein 0Energy 335

T(max) 45 minC(max) 10.2 mM

Visceral adiposity

LDL elevated

Glucose toxicity

Fatty liver

gutinflammation

endothelialinflammation

systemicInsulin resistance

systemic inflammation

Hepatic IR

Adipose IR

Muscle metabolicinflexibility

adiposeinflammation

Microvascular damage

Myocardialinfactions

Heartfailure

Cardiacdysfunction

Braindisorders

Nephropathy

Atherosclerosis

β-cell failure

Reversible processβ-cell Pathology

High cholesterolHigh glucose

gluc Risk factor

Hypertension

dyslipidemia

ectopic lipid overload

Ìrreversible process

Hepaticinflammation

Stroke

IBD

fibrosis

Retinopathy

Metabolicallyhealthy

reversibleirreversible

Nakatsuji, Metabolism 2009

75 g Glucose

The flexible phenotype: the system is a shock absorber(“phenotypic flexibility”)

Reduced phenotypic flexibility

challengeBlood samplingcomparisons

n=10

MetS

n=9

dyslipidemia

High cholesterol

Hypertension

High glucose

after hypercaloric intervention

0

0.5

1

1.5

2

2.5

3

3.5

4

Day 8 Day 15 Day 22 Day 29

chan

ge in

bod

y w

eigh

t (kg

)

Change in body weight and fat mass

0

0.5

1

1.5

2

2.5

3

Day 8 Day 15 Day 22 Day 29ch

ange

in fa

t mas

s I (

kg)

Change in fat massChange in body weight

Systemic stress response

inflammation Cortisol nmol/L 491.20 ± 109.63 463.55 ± 72.04 435.58 ± 138.97CRP ng/mL 1299.5 ± 1164 1566.2 ± 2504 4070.4 ± 4823IL-1β pg/mL 0.7 ± 1.0 0.9 ± 1.6 1.5 ± 2.6IL-6 pg/mL 1.3 ± 0.9 1.1 ± 0.9 2.5 ± 3.8IL-8 pg/mL 3.3 ± 1.7 3.5 ± 2.2 3.3 ± 1.2IL-10 pg/mL 17.7 ± 46.9 17.9 ± 48.1 422.2 ± 1247.9IL-12p70 pg/mL 22.7 ± 66.3 24.5 ± 72.1 440.4 ± 1242.6IL-18 pg/mL 303.8 ± 81.8 305.9 ± 97.7 342.8 ± 100.9TNFα pg/mL 4.5 ± 1 4.7 ± 1.2 7.5 ± 5.2IFNγ pg/mL 4.5 ± 1 4.7 ± 1.2 7.5 ± 5.2

Eicosanoids 9(S)-HODE ng/mL 3.87 ± 2.07 3.61 ± 1.27 3.53 ± 1.4913(S)-HODE ng/mL 4.03 ± 2.44 3.87 ± 1.42 3.53 ± 1.3211(S)-HETE ng/mL 0.0101 ± 0.0101 0.0114 ± 0.0128 0.0086 ± 0.007012(S)-HETE ng/mL 0.16 ± 0.13 0.13 ± 0.11 0.20 ± 0.219,10-DiHOME ng/mL 1.62 ± 1.62 1.74 ± 1.40 0.82 ± 0.24$

12,13-DiHOME ng/mL 2.34 ± 1.39 2.57 ± 1.10 1.52 ± 0.56$

19,20-DiHoPE ng/mL 0.74 ± 0.29 0.53 ± 0.30* 0.54 ± 0.288,9-DiHETrE ng/mL 0.036 ± 0.056 0.034 ± 0.041 0.038 ± 0.03811,12-DiHETrE ng/mL 0.088 ± 0.073 0.076 ± 0.071 0.077 ± 0.06914,15-DiHETrE ng/mL 0.109 ± 0.043 0.117 ± 0.034 0.106 ± 0.026

Immune response Leukocytes giga/L 5.8 ± 1.3 6.3 ± 1.6 6.6 ± 1.0Lymphocytes % 33.2 ± 6.0 34.7 ± 6.6 33.2 ± 6.5Neutrophils % 57.0 ± 6.0 55.1 ± 6.6 56.9 ± 6.9Monocytes % 5.3 ± 1.2 5.4 ± 0.9 5.2 ± 0.8

Lipid metabolismParameter Day 1 Day 29 MxSTriacylglycerides mmol/L 1.51 ± 0.64 1.98 ± 0.78 2.61 ± 0.7#

Cholesterol (total) mmol/L 5.04 ± 0.63 5.66 ± 0.86* 6.52 ± 0.93#

HDL cholesterol mmol/L 1.28 ± 0.33 1.4 ± 0.34* 1.24 ± 0.17LDL cholesterol mmol/L 3.07 ± 0.6 3.36 ± 0.76 4.09 ± 0.89#

Ratio cholesterol/HDL - 4.2 ± 1.1 4.2 ± 0.9 5.3 ± 0.8#,$

Adipose tissue mass and functionParameter Day 1 Day 29 MxS

Body composition Body weight kg 78.4 ± 8 81.2 ± 7.9* 96.0 ± 8.3#

BMI kg/m2 24.1 ± 1.8 25 ± 1.9* 29.1 ± 2.1#

Waist circumference cm 86.5 ± 6.5 91.6 ± 6.1* 105 ± 8.0

Expandability Fat mass kg 11.3 ± 3.3 12.7 ± 2.7* 26.9 ± 5.6#

Fat mass % 14.2 ± 2.9 15.5 ± 2.3 28.0 ± 4.8#

Fat free mass kg 67.1 ± 5.3 68.5 ± 6* 69.0 ± 6.9#

Lipolysis NEFA mmol/L 0.45 ± 0.12 0.37 ± 0.1 0.55 ± 0.2$

AA ng/mL 1213 ± 683 1022 ± 564 1217 ± 411DHA ng/mL 2971 ± 1858 3119 ± 2138 3124 ± 2154EPA ng/mL 189.1 ± 145.5 184.5 ± 158.9 182.5 ± 96.8

Adipokine excretion Adiponectin µg/mL 5.6 ± 2.0 8.6 ± 3.3* 5.6 ± 2.7$

Leptin ng/mL 3.3 ± 1.0 5.0 ± 1.9* 13.9 ± 7.4#,$

Resistin ng/mL 9.1 ± 1.9 8.6 ± 1.8* 10 ± 2.9

Glucose metabolismParameter Day 1 Day 29 Mx

insulin sensitivity Glucose mmol/L 5.20 ± 0.42 5.34 ± 0.33 5.97 ±Pancreas function Glucagon pg/mL 45.7 ± 16.3 61.3 ± 15.3 62.9 ±

Insulin mU/L 5.0 ± 3.0 7.1 ± 3.2* 13.7 ±C-peptide ng/mL 1.4 ± 0.4 1.7 ± 0.6* 3.0 ±Pancreatic polypeptide pmol/L 45.4 ± 19.9 40.4 ± 18.5 61.9 ±

Incretin production GLP-1 pM 9.5 ± 2.9 7.8 ± 3.7 5.2 ±GIP ng/mL 35.5 ± 11.1 35.5 ± 12.6 46.6 ±

Metabolic flexibilityDay 0 Day 29

Respiratory Quotient - 0.82 ± 0.05 0.86 ± 0.05 Resting Metabolic Rate MJ/day 6.59 ± 0.85 7.15 ± 0.74* 7 Endothelial adhesion

Parameter Day 1 Day 29SAA ng/mL 4296 ± 4577 3743 ± 3235sICAM-1 ng/mL 245.5 ± 73.6 268.0 ± 69.2sVCAM-1 ng/mL 392.8 ± 94.3 397.0 ± 83.7

The energy pulse and the control mechanisms

time

energy

Nutrition and phenotypic flexibility

A complex molecular machinery is activated upon a caloric stress, aiming to regain homeostasis.

…and homeostasis is maintained

The energy pulse and the control mechanisms

time

energy

Nutrition and phenotypic flexibility

Upon prolonged metabolic stress, the machinery to regain / maintain homeostasis increases its efforts.

and homeostasis is still maintained for the essential proccesses(glucose, triglycerides, inflammation)

0

0.5

1

1.5

2

2.5

3

3.5

4

Day 8 Day 15 Day 22 Day 29

chan

ge in

body

weig

ht (kg

)

Yet, the post prandial stress response may come at a cost… (lipid storage)

0

0.5

1

1.5

2

2.5

3

Day 8 Day 15 Day 22 Day 29

chan

ge in

fat m

ass I

(kg)

Change in fat massChange in body weight

Kardinaal, FASEB 2015

time

energy

homeostasis is lost

For a number of non-essential biomarkers, homeostatic control is lost already early on.

Insulin, C-peptide, adiponectin, leptin, resistin, …

time

energy

Oxidativestress

metabolicstress

Inflammatorystress Decreased flexibility

resulting in metabolic syndrome.

…and homeostasis is lost

eventually resulting in loss of homeostatic control of essential processes

glucose, Triglyceridesinflammation

Different adaption phases in the switch from healthy toward MetS

Based on hundreds of parameters ….

Kardinaal, FASEB 2015

What if we do it the other way: weight loss (the NutriTech study)

Insulin and glucose at OGTT - Weight maintenance group

Weight loss group

Parameter Fasting OGTT MMTT MMTT + PAGlucose 0.013 0.44 0.314 0.032Insulin 0.010 0.14 0,007 0,015TG 0.062 0 0.295 0.158Isoleucine 0.500 0 0.190 0.815Leucine 0.280 0 0.020 0.094Valine - 0 0.007 0.368Gamma-GT 0.003 0.021IL1-RA 0.275 0.003 0.004 0.021Matsuda index 0.037 0,085 0.028HOMA-IR 0,074 0.014 0,988Hepatic IR index 0,074 0.014 0,987Disposition index 0,880 0,908 0.033

Significantly changed biomarkers after 13 weeks weight loss diet

OGTTMixed Meal TT

MMTT &Physicalexcercise

Fasting

time

Hypothesis: the “control machinery” remains active in order to make sure that essential homeostatic) values profit first.

The concept of flexibility

Do we understand the challenge?

Do we understand the response?

James Cahill, Annu. Rev. Nutr. 2006. 26:1–22

Do we need glucose in our diet?

Do we need glucose in our diet?

James Cahill, Annu. Rev. Nutr. 2006. 26:1–22

Intensive lifestyle coaching with advanced type 2 diabetes patients11 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

Is insulin resistance reversible?

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

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

Liver

Pancreas

Muscle

Adipose

Disposition index

Hepatic insulin resistance index

Muscle insulin resistance index

Adipose insulin resistance index

OGTT glucose & insulin curvefasting free fatty acids

Phenotypic Flexibility as biomarker of health 134 biomarkers report on challenge responses in organs

Brain• Secondary messengers• Trp, Tyr, Phe, Met

Gut• Fructose, ribulose / xylulose• GIP, GLP-1• Indole-3-proprionic acid

Adipose tissue• Glycerol, NEFA & specific FFA• MG, DG• Leptin, adiponectin• Estimated SCD activity• C16:1 FFA• Adipose IR index

Kidney• Creatinin• Asp, Glu, Orn, Urea • Albumin

Vasculature• Cholesterol, HDL, LDL• SAA, sICAM, sVCAMMuscle

• Lactate, beta-alanine• Muscle IR index• Branched chain amino acids & derivatives• 1-methylhistidine, 3-methylhistidine• 4-hydroxyproline, 4-oxoproline

Liver• Ketone bodies• Central metabolism• ALAT, ASAT, ALP, GGT• CRP• TG• Liver IR index• Liver IS index

Pancreas• Disposition index• C-peptide• Insulin• Glucagon• HOMA-B

Metabolic challenge• Matsuda index, HbA1C, HOMA-IR• glucose, 1,5-anhydroglucitol• Glutathione ratio, uric acid, vit E• mannose, ribose, glycine, pseudo uridine• RQ measures

Blue = respondingGreen = not respondingBack = could not be determined

PhenFlex challenge:- 75 g glucose- 60 g palmoic oil- 20 g protein

Disposition index

Hepatic insulin resistance index

Muscle insulin resistance index

Adipose insulin resistance index

Liver

Pancreas

Muscle

Adipose

Gut

Kidney

Brain

Vasculature

PhenFlex biomarker panel

AMPK signaling

Jose Ordovas Larry Parnell Keith Grimaldi Henk v KranenInclusion of phenotypic flexibility process based risk factors

Jim Kaput

genetics

Disposition index

Hepatic insulin resistance index

Muscle insulin resistance index

Adipose insulin resistance index

Liver

Pancreas

Muscle

Adipose

Gut

Kidney

Brain

Vasculature

Visceral adiposity

LDL elevated

Glucose toxicity

Fatty liver

gutinflammation

endothelialinflammation

systemicInsulin resistance

systemic inflammation

Hepatic IR

Adipose IR

Muscle metabolicinflexibility

adiposeinflammation

Microvasculardamage

Myocardialinfactions

Heartfailure

Cardiacdysfunction

Braindisorders

Nephropathy

Atherosclerosis

β-cell failure

High cholesterolHigh glucose

Hypertension

dyslipidemia

ectopic lipid overload

Hepaticinflammation

Stroke

IBD

fibrosis

Retinopathy

Physical inactivity Caloric excess

Hurrying

Sweet & fat foods

β-cell Pathologygluc Risk factor

Lipids, alcohol, fructose

Carnitine, cholineOmega3-fatty acids

Stannols, fibre

Low glycemic index

epicathechins

anthocyanins

Soy

Quercetin, Se, Zn, …

Inflammatory response

Cognition Mobilizing

Heart ratevariability

Endorphins

Chronic StressDisruption circadian rhythm

parasympathetic tone

Sympatheticarousal

Worrying

Gutactivity

Sleep disturbance

Adrenalin

Fear

Challengestress

Heart rate

High cortisol

α-amylase

Reflexes

Excercise: four bouts of walking at 3–4 miles/h for 15 min with rest periods of 5 min between each walking bout: total duration 75 min.

Schiavon et al, Am J Physiol Endocrinol Metab 305: E557–E566, 2013

Individual values of resting sensitivity index (SIrest) and the effect size of acute exercise on insulin sensitivity (SIexercise)

Physical activity and glucose metabolismIn

sulin

sens

itivi

tyin

dex

Insu

linse

nsiti

vity

inde

x

Jingyi Qian and Frank A.J.L. Scheer - Trends in Endocrinology & Metabolism, May 2016, Vol. 27, No. 5

Circadian System and Glucose Metabolism: Implications for Physiology and Disease

procyanidins

Carnitine, Choline, … Low glycemic index

Stannols,fibre

Omega 3/6 FA

Quercetin, Se, Zn, …

epicathechins

carotenoids

Antho cyaninspolyphenols

Finally, the processes that orchestrate phenotypic flexibility all depend on nutrients…

Bottomline:

- it`s not about glucose, it`s about maintaining flexibility- It`s not about glucose, it`s about food and lifestyle- It`s not about glucose, it`s about calories