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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!