hana kahleova, md, phd - the physicians committee · hana kahleova, md, phd director of clinical...

Hana Kahleova, MD, PhD

Director of Clinical Research

PCRM

What is our body clock?

Central clock

Peripheral clock

Patterson RE et al. J Acad Nutr Diet. 2015 Aug; 115(8): 1203–1212.

Circadian rhythms

• 24-h period

• Disruption → metabolic disturbances

• Shift workers - ↑ risk of obesity and T2D

Knutsson A et al. Occup Med 2003;53:103-8

Glucose metabolism

during shift-work

Sharma A et al. Diabetologia 2017;60:1483-1490

Total β-cell function

Dynamic β-cell function Static β-cell function

Disposition index

Immunomodulation

Regulation of

circadian rhythms

Anti-cancer effects Regulation of

mitochondrial

functions

Antioxidant actions

Cardio-protective

effects

Anti-aging

properties

Stimulates

brown fat

Melatonin levels during the day

30

20

0

10

40

50

60

70

80

2:00 PM Darkness 2:00 AM

Time of Day

Melatonin ( pg/ml )

7:00 AM

Melatonin levels in diabetes

O’Brien IA et al. Clin Endocrinol (Oxf). 1986 Apr;24(4):359-64.

Healthy

Diabetes

Diabetes with

neuropathy

Forrestel AC et al. Diabetologia 2017;60:808-822

Ribas-Latre A et al. Mol Metab 2016 Jan 14;5(3):133-52.

Clock genes in diabetes

Hansen J et al. Sci Rep. 2016 Oct 19;6:35047.

Clock gene amplitude in obesity

and diabetes

Hansen J et al. Sci Rep. 2016 Oct 19;6:35047.

Clock gene rhythms and

delayed meals

Wehrens et al. Curr Biol 2017;27(12):1768-1775

Clock genes and

diet composition

Pivovarova O et al. J Clin Endocrinol Metab. 2015 Jun;100(6):2291-302.

Ribas-Latre A RD et al. Mol Metab 2016 Jan 14;5(3):133-52.

Fasting and clock genes

Ajabnoor GM et al. PLoS One. 2017 Apr 6;12(4):e0174342.

Caloric restriction

and clock genes

Patel SA et al. Sci Rep. 2016 May 12;6:25970.

Intermittent fasting and T2D

• Efficient for weight loss and ↓ risk of T2D Barnosky AR et al. Transl Res 2014;164:302-11

• Glycemic control – larger meals rich in fiber more beneficial Fernemark H et al. Plos One 2013;8:e79324

Patterson RE et al. J Acad Nutr Diet. 2015 Aug; 115(8): 1203–1212.

Resetting Your Clock While Traveling

+ 6 hrs

When to eat?

Meal Timing

• Dinner → ↑ fat deposition Ruge T et al. J Clin Endocrinol Metab,

May 2009, 94(5):1781–1788

• ↑ breakfast → ↓ BMI

Purslow LR et al. Am J Epidemiol 2008;167:188-92

Keim NL et al. J Nutr 1997;Jan 127(1):75-82

• Early eaters vs. late eaters – 420 people, 20 weeks

Garaulet M et al. Int J Obes 2013 Apr;37(4):604-11

Carbs in the morning!

Kessler K et al. Sci Rep. 2017; 7: 44170.

Breakfast and risk of T2D

Mekary RA et al. Am J Clin Nutr 2012;95:1182-9

Mekary RA et al. Am J Clin Nutr 2012;95:1182-9

Breakfast and meal frequency

Breakfast and glycemic control

Glucose: AUC 20% lower

Jakubowitz D et al. Diabetologia 2015 May;58(5):912-9

Breakfast and glycemic control Insulin: 20% higher

C-peptide: 20% higher

Jakubowitz D et al. Diabetologia 2015 May;58(5):912-9

Breakfast and incretins

t-GLP-1: 30% higher

i-GLP-1: 16% higher

Jakubowitz D et al. Diabetologia 2015 May;58(5):912-9

Skipping breakfast in T2D

Jakubowitz D et al. Diabetes Care 2015 Oct;38:1820-1826

PPG 37% PPG 27%

Skipping breakfast in T2D

Ins 17%

Ins 8%

Jakubowitz D et al. Diabetes Care 2015 Oct;38:1820-1826

iGLP-1 17%

Skipping breakfast in T2D

iGLP-1 19%

Jakubowitz D et al. Diabetes Care 2015 Oct;38:1820-1826

Skipping breakfast and

metabolic risk

Nas A et al. Am J Clin Nutr 2017 Jun;105(6):1351-1361.

ABSOLUTELY!

Breakfast every day?

But what’d you eat for dinner?

Volume 57 │ Number 8 │ August 2014

Methods

• Randomized cross-over study

• 54 patients with T2D treated by OHA

• Indirect calorimetry

• Caloric restriction -500 kcal/day

• 6 meals/day for 12 wks,

2 meals/day for 12 wks

Regimens 2 vs. 6 meals/day

Breakfast 6-10 a.m.

Lunch 12-4 p.m.

2 meals

6 meals

Breakfast 6-8 a.m.

Snack 8-10 a.m.

Lunch 12-1 p.m.

Snack 2-3 p.m.

Dinner 5-6 p.m.

2nd Dinner 8-9 p.m.

219 patients with T2D were screened

54 were randomized

165 were excluded • 112 did not meet inclusion criteria • 53 refused to participate

27 started with 6 meals/day 27 started with 2 meals/day

2 withdrew

25 started with 2 meals/day

23 completed 12 wks with 2 meals/day

2 withdrew

27 were included in the analysis

1 withdrew

26 started with 6 meals/day

24 completed 12 wks with 6 meals/day

2 withdrew

27 were included in the analysis

Enrollment of the participants and completion of the study

47/54 (87%) completed the whole study

Baseline characteristics Characteristics Study group (n=54)

Age (years) 59.4±7.0

Sex 29 (54%) men,

25 (46%) women

Diabetes duration

(years)

8.1±5.8

Smoking 10 (19%)

Weight (kg) 94.1±15.5

BMI (kg.m-2) 32.6±4.9

HbA1c (IFCC, mmol/L)

mmol/mol)

54.9±13.0

HbA1c (DCCT, %) 7.2±3.3

Diet

Energy -500 kcal/day

Carbohydrates 50-55%

Proteins 20-25%

Fats 25-30%

Cholesterol < 200 mg/day

Fibre 30-40 g/day

Methods - 1HMRS of the liver • 3T MR scanner (Magnetom – Trio Siemens)

• 3 volumes of interest (á 30 ml)

Longo R et al.; JMRI 1996; 5:281-285

Hajek M et al; MAGMA 2011 Oct; 24(5):297-304

Weight loss

6 meals/day: 5 lbs

2 meals/day: 8 lbs

Weight

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

A6 B2

***

∆ W

eig

ht

(kg

)

-0.045

-0.04

-0.035

-0.03

-0.025

-0.02

-0.015

-0.01

-0.005

0

A6 B2

**

Δ L

iver

fat

(%)

Liver fat

A6…6 meals a day

B2…2 meals a day

Mean±95%CI

Kahleova H et al. Diabetologia 2014;57:1552-60

HbA1c

ns

∆ H

bA

1c (

IFC

C, %

)

Insulin sensitivity (OGIS)

0

5

10

15

20

25

30

A6 B2

**

Δ O

GIS

(m

l.m

in−1

m−2

)

-0.35

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

A6 B2

Kahleova H et al. Diabetologia 2014;57:1552-60 A6…6 meals a day

B2…2 meals a day

Fasting plasma glucose

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

A6 B2

Δ G

luco

se (

mm

ol/

L)

**

C-peptide

-0.2

-0.18

-0.16

-0.14

-0.12

-0.1

-0.08

-0.06

-0.04

-0.02

0

A6 B2

*

Δ C

-pep

tid

e (

U/L

)

Kahleova H et al. Diabetologia 2014;57:1552-60 A6…6 meals a day

B2…2 meals a day

Beck Depression Inventory

∆ D

ep

ressio

n S

co

re

*

Hunger

***

∆ H

un

ger

-2.5

-2

-1.5

-1

-0.5

0

A6 B2

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

A6 B2

Kahleova H et al. Eur J Clin Nutr 2015;1-2 A6…6 meals a day

B2…2 meals a day

World‘s oldest man died at 114: Walter

Breuning

...Breuning attributed his longevity to

eating just two meals a day, working as long

as he could and always embracing

change… www.guardian.co.uk/world/2011/apr/15/world-oldest-man-dies-at-114

Clock genes and regulation

Pivovarova O et al. J Clin Endocrinol Metab. 2015 Jun;100(6):2291-302.

Clock genes in BAT

Moraes MN et al. Biochim Biophys Acta. 2017 Feb;1864(2):324-335.

Brown fat

May foods activate BAT?

• L-arginine – soy foods, beans, nuts and seeds Ma X et al. Amino Acids 2017 May;49(5):957-964

• Capsaicin in hot peppers Yoneshiro T et al. J Clin Invest 2013 Aug;123(8):3404-8

• Jalapeno peppers Saito M et al. Curr Opin Lipidol 2013 Feb;24(1):71-7

Ribas-Latre A RD et al. Mol Metab 2016 Jan 14;5(3):133-52.

AMPK

Day EA et al. Trends Endocrinol Metab 2017 Jun 21. S1043-2760(17)30068-1.

How to activate your AMPK

• Resveratrol Lan F et al. Nutrients 2017 Jul 14;9(7).

• Green tea Tan Y et al. World J Gastroenterol. 2017

Jun 7;23(21):3805-14.

• Curcumin Tong W et al. Oncol Lett 2016 Nov;

12(5):4139-46

How to activate your AMPK cont.

• Quercetin Dhanya R et al. Front Pharmacol 2017

Jun8;8:336.

How to activate your AMPK cont.

• Ginseng Kang OH et al. BMC Compl Altern Med. 2017

Jun 29;17(1):341.

• Mulberry Liu Y et al. Int J Mol Med. 2017 Jul 3.

Doi:10.3892/ijmm.2017.3050

• Fiber Hu GX et al. Med Hypotheses. 2010 Jan;74(1):123-6.

How to activate your AMPK cont.

• Exercise Thirupathi A et al. J Physiol Biochem. 2017Jul 14. doi: 10.1007/s13105-017- 0576-y.

• Caloric restriction Dong D et al.

Oncotarget. 2017 Mar 7;8(10):16109-16121.

• Fasting Lee D et al. Physiol Rep.

2017 Feb;5(4). pii: e13114.

doi: 10.14814/phy2.13114.

Snacking

• A common strategy to improve body weight and glycemic control

Snacking and energy balance

• More than 3 meals/day → ↑ energy intake → obesity → ↑ risk of T2D

Howarth NC et al. Int J Obes. Apr 2007;31(4):675–84 Mekary RA et al. Am J Clin Nutr 2013;98:436-43

• Snacking ↑ food stimuli, hunger and desire to eat

Duval K et al. Am. J. Clin. Nutr. Nov 2008;88(5):1200–5 Ohkawara K et al. Obesity 2013;21:336-43

How many meals?

Mekary RA et al. Am J Clin Nutr 2013;98:436-43

Aim • Meal frequency and timing

• Changes in BMI

Baseline characteristics

Variables Mean (SD)

Age (years) 57.72 (12.97)

BMI - Baseline (kg/m2) 26.61 (5.57)

BMI - HHF4 (kg/m2) 26.53 (6.04)

BMI difference (HHF4-Baseline) -0.08 (3.33)

Dietary fiber (g/day) 33.72 (15.82)

Exercise (min/week) 85.73 (96.08)

Follow-up time (Baseline-HHF4, years) 7.42 (1.23)

KCAL - Total 1945.17 (722.27)

N = 50,660

Methods • The primary outcome: change in BMI per year.

• Linear regression analyses adjusted for important

demographic and lifestyle factors.

1. Meal frequency • Number of meals and snacks

• Length of night fast

2. Meal timing • Breakfast (+/-)

• Time of the largest meal

Exposure variables

Covariates • Race

• Gender

• Smoking

• Education

• Socio-economic status

• Marital status

• Baseline BMI

• Kcal, fiber, alcohol intake

• Vegan/vegetarian

• Sleep hours

• Exercise

• Sedentary time

• Diabetes

• Statin use, high blood pressure medication

Number of meals and snacks per day R

ela

tive m

ean

Δ B

MI/

year

(kg

.m-2

)

Number of meals and snacks per day

-0.08

-0.06

-0.04

-0.02

0

0.02

0.04

0.06

0.08

1 2 3 4 5 ≥6

p<0.001

BMI

BMI

Kahleova H et al. J Nutr 2017 Jul 12 doi: 10.3945/jn.116.244749.

Consumption of breakfast

-0.045

-0.04

-0.035

-0.03

-0.025

-0.02

-0.015

-0.01

-0.005

0

0.005

No Yes

Rela

tiv

e m

ean

Δ B

MI/

year

(kg

.m-2

)

p<0.001

BMI Kahleova H et al. J Nutr 2017 Jul 12 doi: 10.3945/jn.116.244749.

-0.045

-0.04

-0.035

-0.03

-0.025

-0.02

-0.015

-0.01

-0.005

0

Breakfast Lunch Dinner

Timing of the largest meal R

ela

tiv

e m

ean

Δ B

MI/

year

(kg

.m-2

)

p<0.001

BMI in early eaters Kahleova H et al. J Nutr 2017 Jul 12 doi: 10.3945/jn.116.244749.

Length of night fast

(hours per day)

-0.03

-0.02

-0.01

0

0.01

0.02

0.03

0.04

7-11 12-17 18-24

Length of night fast R

ela

tiv

e m

ea

n Δ

BM

I/ye

ar

(kg

.m-2

)

p<0.001

BMI Kahleova H et al. J Nutr 2017 Jul 12 doi: 10.3945/jn.116.244749.

Do we need to eat snacks?

NO!!!

7.11 AM

Optimum time

to eat breakfast

6:00 – 10:00 pm

When most diets go wrong!

Conclusions

• Body clock:

–Central clock

–Peripheral clock

–Synchronization

Conclusions cont.

• Diet composition:

–Eat whole plant foods

–Carbs in the morning

Conclusions cont.

• Meal frequency:

–2-3 meals/day

–No snacks

Conclusions cont.

• Meal timing:

–Eat breakfast

–Breakfast as the largest meal

Eat breakfast like a king,

And dinner like a pauper.

Lunch like a prince,

Acknowledgements

Terezie Pelikanova

Lenka Belinova

Martin Hill

Dana Lapesova

Gary Fraser

Jan Irene Lloren

Andrew Mashchak

Neal Barnard

Melissa Busta

Rosendo Flores

Manuel Calcagno

Jill Eckart

Susan Levin

Karen Smith

Maggie Neola

Mallory Vial

Eat right when time is right!

Reset your body clock

with nutrition!