Eating in Sync with Circadian Rhythms for Weight Loss and Metabolic Health

Tamara Duker Freuman, MS, RD, CDNDecember 3, 2015

We’ve all met Patient X

• Overweight or obese, and struggling to lose

• Has pre-diabetes or diabetes, hyperlipidemia or high triglycerides

• Skips or skimps on breakfast

• Able to start off “good” each day, but things start to fall apart ~3-4pm

• Overeats at dinner, and grazes immediately after, well into the evening

• Has been able to lose weight on “diets” in past, but always regains

Patient X diet historyTime Food Commentary

7am Coffee

7:30 Either skip breakfast OR has a Greek yogurt OR a banana OR a granola bar

“I’m not so hungry when I get up, so I usually skip. I’ve found when I eat breakfast, it just makes me hungrier in mid morning and then I have to eat again!”

12:00pm Salad with grilled chicken ORChicken noodle soup

“I try to make a good, low calorie choice at lunch.”

3:00pm Granola bar from office pantry, candy from vending machine or a cookie from Starbucks

“I get STARVING at around 3pm and crave something sweet.”

“I think I might be a binge eater. I’m so good all day up to this point, and then I can’t control myself!”

6:30/7pm Meat and vegetable with a lot of riceORBig bowl pasta with sauce, some salad too.

“I get to dinner starving—I definitely eat too much at night. If there’s a bread basket, I often can’t control myself.”

8pm-11pm Grazing on ice cream, cookies, crackers/cheese, chips, a bowl of cereal…

“I just feel like I need something sweet… I’m not satisfied..”

Breakfast skipping associated with obesity, metabolic disturbances

Numerous observational studies have noted correlation between breakfast skipping, obesity in children and adults, e.g.:

• Szajewska & Ruszczynski (2010): Review of 16 cross sectional studies (n= >60,000 subjects) of

children/adolescents in Europe • Eating breakfast associated with reduced risk of overweight and obesity and lower BMI compared to skipping

• Timlin et al (2015): Prospective 5 year study of 2,200 teens • Inverse relationship between breakfast frequency and BMI after controlling for age, socioeconomic status, race, physical activity,

baseline weight status and baseline breakfast status

• Almoosawi et al (2013): Prospective cohort of 1500 British men and women born in 1946• CHO intake at breakfast or mid morning at age 43 had protective effect against abdominal adiposity at age 53• Increased CHO intake in morning with reduced fat intake at age 43 associated with reduced risk of metabolic syndrome and

lower TGs at age 53

• Cho et al (2003): NHANES III 1988-1994 data • Eating CHO-rich breakfast associated with significantly reduced BMI among adults compared to breakfast skipping or low CHO

(meat/egg) breakfasts

The above studies’ designs preclude ability to assess causation; lack of randomized intervention trials existed

Does a high CHO breakfast protect against obesity due to improved satiety?

Link between breakfast skipping and obesity hypothesized to be over-compensation of kcals at subsequent meals due to excess hunger…

• de Castro J (2007): Review of food diaries from ~900 free living men and women • When total proportion of daily CHOs relatively high in morning, there was lower total CHO and kcal intake for remainder of the day

• Possibly due to increased satiety from CHO intake in the morning?

If breakfast skipping doesn’t necessarily lead to overeating later in the day, what might account for the widely observed relationship between breakfast skipping and obesity?

…But research does not consistently show differences in of total energy intake among breakfast skippers

• Kant & Graubard (2015): NHANES data from 2,100 adults

• No significant difference in total daily energy intake or dinner intake among the same individuals on days in which they consumed or skipped breakfast

• Levitsky & Pacanowski (2013): Randomized crossover trial of two dozen healthy undergrads, mostly female

• Skipping breakfast did not result in compensatory overeating at subsequent meals compared to consuming a ~350 kcal high CHO or high fiber breakfast, or a larger, moderate CHO breakfast

Circadian rhythms are a more likely causal link (I) Human/animal models suggest metabolic processes operate on a “biological clock”

Variations in hormone levels, enzyme levels, glucose transporters at different dayparts differentially effect how calories, carbohydrates and fat are metabolized

• Diurnal variation in expression of genes coding for the hormones and rate limiting enzymes involved in metabolic pathways within liver, muscle and adipose tissues (Green et al 2008, Panda et al 2002)

• These so-called “rhythmic genes” are 5-20% of all genes expressed in these tissues

• The proteins they code for play roles relating to cholesterol and lipid metabolism, glycolysis and gluconeogenesis and oxidative phosphorylation (basically, energy metabolism and storage)

Mammalian ‘master biological clock’ located in the hypothalamus, influenced by external stimuli—most strongly, light (Froy, 2010)

• Arble et al (2009): Study of nocturnal mice who are typically more active during the dark phase

• Mice fed a high fat diet during a 12 hour “lights-on” phase gained more weight and body fat than mice fed isocaloric high fat diet during at the “right time” (a 12 hour darkness phase)

• Circadian system has governing role in weight gain

Adapted from Froy, O. Metabolism and Circadian Rhythms—Implications for Obesity. 2010. Endocrine Reviews, 31: 1–24.

Circadian rhythms are a more likely causal link (II)Diurnal/nocturnal variation in glucose tolerance has been observed in both human and animal models

• VanCauter et al (1991): Decreased glucose tolerance/insulin sensitivity in afternoon and evening compared to morning, no matter whether healthy human subjects were awake or asleep. Higher insulin secretion in evening and overnight compared to morning.

• Morgan et al (2003): Plasma triglycerides also influenced by circadian rhythms, with higher levels at night

• TG response to a standard meal higher in evening compared to daytime, and the day/night difference larger in men than in women

• Versteeg et al (2015): Better glucose tolerance and insulin sensitivity in early morning vs later in the day

CHO consumption at breakfast may affect glycemic response to subsequent meals favorably (“second meal phenomenon”)

• Jakubowicz D et al (2015): Breakfast consumption attenuates post-prandial hyperglycemia at lunch and this effect persists throughout the day in overweight patients with diabetes.

• Lee et al (2011): Among small group of middle aged Asians with Type 2 DM, consuming a mixed meal with 58g CHO at breakfast resulted in improved glucose tolerance following the same meal at lunch compared to skipping breakfast.

• Chowdhury et al (2015): In small cohorts of both lean AND obese adults without DM, glucose levels and insulin levels measured 1 and 2 hours after a high carb pasta lunch were significantly higher among breakfast skippers compared to those who had consumed a high GI, high CHO breakfast.

• Farshchi H et al (2005): Randomized crossover trial of healthy lean women showed lower post-prandial insulin sensitivity to a test meal (milkshake) after a two week period of breakfast skipping compared to the same test meal following a two week period of regular consumption of a high carb/high glycemic breakfast. Cholesterol and LDL levels were also higher after the breakfast omission period compared to breakfast eating period.

So where did Patient X go wrong?

After fasting 7-8 hours overnight, patient has <100 calories in first 5 hours of

waking

• Skipping breakfast (or skimping on breakfast, especially carbs) Missed oppty to mitigate glycemic effect of next meal via “second meal phenomenon”

• Shifts greater proportion of daily intake to evening

Patient doubles down

with a low carb, low

calorie lunch

• Limited % of total daily calories/carbs consumed in first daypart when glucose tolerance is the highest

• Lower levels of satiety going into the evening

Prolonged low blood sugar finally provokes

intense cravings for simple carbs and

sugar 3-4pm

• Patient begins consuming majority of kcals and CHOs precisely when circadian-governed insulin sensitivity begins declining and lipogenesis increasing

Patient consumes >50% of day’s calories in short window

of time in the evening

• Lack of satiety from earlier in day results in strong cravings even when physiological hunger has been addressed

• Pt continues grazing well past the 12-hour diurnal window of optimal glucose tolerance

Does timing of macronutrient intake actually affect metabolic markers in overweight humans?

Jakubowicz et al (2013) Among the first randomized intervention trials to test effect of differential daypart meal patterns in

overweight humans

• 74 non-diabetic overweight/obese women with metabolic syndrome completed the 12 week study

(BMI 32.4 kg/m2 +/- 1.8)

• All placed on 1400 calorie/d diet for 12 weeks, with bi-weekly RD assessment for diet compliance

• Randomized into two groups:

• Big breakfast group: 700 kcal breakfast, 500 kcal lunch, 200 kcal low carb dinner 86% of kcals

before dinner

• Big dinner group: 200 kcal low carb breakfast, 500 kcal lunch, 700 kcal dinner 50% of kcals

before dinner

• Groups similar in terms of age, BMI, waist circumference, baseline triglycerides, total

cholesterol, blood pressure, fasting glucose, fasting ghrelin, OGTT

Jakubowicz test meals:

• 2 slices whole wheat bread

• 4oz light tuna in water

• ½ cup caprese salad (tomato/mozzarella/basil)

• Standard Hershey milk chocolate bar

• 2 cups skim milk

• Americano coffee

• 50% of daily kcals• 45% of kcals from CHO• 30% of kcals from protein

• 36% of daily kcals• ~25% of kcals from CHO• ~50% of kcals from protein

• 14% of daily kcals• Low carb• 65% protein, 35% fat

Sample 700 kcal mealSample 500 kcal meal

(Lunch)Sample 200 kcal meal

• 5oz grilled chicken breast

• 1 cup melon

• 1 TBSP lite mayo

• 1 can beef broth soup

• 1 cup green salad w/ balsamic vinaigrette

• Diet coke

• 2 scrambled eggwhites

• 5 slices turkey breast

• Americano coffee

Findings: Frontloading calories and carbs metabolically favorable (I)

Both groups lost statistically significant amount of weight

Big breakfast group lost 2.5x more weight than dinner group (p < 0.0001)• 19# vs. 8#, respectively (11#

difference)

Big breakfast group had significantly greater reduction in BMI (p < 0.0001)• 10% reduction vs 5% reduction • 32.2 kg/m2 29.2 kg/m2 and 30.9

kg/m2, respectively

Weight loss

• Big breakfast group lost 1.9” more off waist circumference than dinner group (p < 0.0001)

• OGTT showed lower glucose and insulin levels in big breakfast group compared to big dinner group (p < 0.0001)

• ISI index of insulin sensitivity improved in both groups, but moreso in the big breakfast group compared to big dinner group (p < 0.0001)

Waist circumference/

insulin sensitivity

• Fasting glucose reduced significantly more in big breakfast group compared to big dinner group (11.5% versus 4.5%) (p < 0.0001)

• Fasting insulin levels significantly lower in big breakfast group at 12 weeks, despite starting off significantly higher at baseline

• 51% reduction from baseline, versus 29% reduction

• At 12 weeks, 9.9IU/mL vs. 13.2 IU/mL

Glycemic control

Findings: Frontloading calories and carbs metabolically favorable (II)

Mean triglycerides reduced by 33% in big breakfast group and INCREASED by 14.6% in big dinner group (p<0.0001)

• 179.7 mg/dL 119.4 mg/dL and 178.1 mg/dL204.1 mg/dL, respectively

HDL was slightly but significantly increased in the big breakfast group

No statistically significant change in LDL levels within or among the groups

Lipids

• Ghrelin levels were high and steady throughout the day in big dinner group. In big breakfast group, they dropped during breakfast and increased throughout the day, but never reached levels of dinner group.

• No difference in fasting ghrelin levels

• Lower hunger and higher satiety scores in big breakfast group compared to big dinner group

Satiety

Both groups decreased significantly, but no difference between the two groups (p>0.05)

Blood pressure

These findings directionally consistent in my clinical practiceWomen; many cases also involved calorie targets and electronic food journaling

Caucasian 55 year old female

PMH: Prediabetes, hyperlipidemia

Pt did not exercise during period of dietary intervention

Marlene C

Caucasian 30 year old female

PMH: Binge eating disorder, PCOS, diabetes

Pt initiated exercise regimen and metformin during period of dietary intervention

Jill R

Caucasian 62 year old female

PMH: GERD, NAFLD, hyperlipidemia (does not tolerate statins)

Pt did not exercise during period of diet intervention and did not use statin medication

Joan H

Baseline 6 months

Weight (lbs)

146 132.5 (9.2% loss)

BMI(kg/m2)

27.6 25.0

HgbA1c (%)

5.9 5.7

Total Chol 206 165

HDL 72 66

LDL 120 86

TGs 71 67

Baseline 6 months

Weight (lbs)

279 241 (13.6% loss)

BMI (kg/m2)

42.5 36.6

HgbA1c (%)

6.6 6.1*(after 4 months)

Total Chol

162 145

HDL 39 45

LDL 101 84

TGs 108 78

Baseline 14 months

Weight (lbs) 176 160 (9.1% loss)

BMI (kg/m2) 31.1 28.4

HgbA1c (%) 5.2 5.1

Total Chol 274 225

HDL 80 79

LDL 180 134

TGs 72 64

These findings directionally consistent in my clinical practice Men

African American 57 year old male; shift worker

PMH: Poorly controlled DM2 (despite meds), HTN, NAFLD, GERD, osteoarthritis

Joseph F.

Caucasian 29 year old male

PMH: Hypertrophic cardiomyopathy

Pt did not take statins or exercise during period of dietary intervention

Alex M

Hispanic 44 year old male

PMH: Diabetes, hyperlipidemia (on statin)

Pt began metformin and exercise at baseline

David C

Baseline (shift work)

2 wks (unemployed;

normal schedule)

2 wks later (back on

shift work 7 days)

Weight (lbs)

305 294.8(3.3% loss)

298.5(1.2% gain)

BMI(kg/m2)

49.3 47.6 48.2

HgbA1c (%)

10.3

Glucose 188 119 138

Total Chol

200

HDL 50

LDL 125

TGs 126

Baseline 13 months

Weight (lbs)

296 213(28% loss)

BMI (kg/m2)

40.8 29.1

Total Chol

N/A 170

HDL N/A 42

LDL N/A 105

TGs N/A 113

Baseline 2 months

Weight (lbs) 247 238(3.6% loss)

BMI (kg/m2) 37.6 36.2

HgbA1c (%) 9.6 5.7

Glucose 255 112

Total Chol 119

HDL 22

LDL 42

VLDL 55 (H)

TGs 275

So… how do you actually implement this diet in real life?

Presenting the “Slow-Slow-Low Carb Diet”Adapted for how free-living people live and eat

1. ALWAYS HAVE BREAKFAST! Minimum 300 kcals Should always include a carbohydrate, preferably a high fiber/lower glycemic one (“slow carb”) Can be deferred a few hours after waking if not so hungry immediately, but not skipped Ideally, satiating enough to preclude need for mid-morning snack

2. Lunch is most balanced, “main meal” of the day Plate method of portion allocation: ¼ plate lean protein, ¼ plate “slow carb”, ½ plate non

starchy veggies

3. Afternoon snack may be necessary if large gap between lunch/dinner (>5 hours) No more than 200 kcals High protein and fiber; no starches/grains (carb taper begins after lunch) Defensive eating: Prevents patients from arriving at dinner feeling “starving” Excess snacking, however, often compromises diet quality unless very well planned

4.Dinner is a small, low carb meal Easier to control food choice and portions when not feeling excessively hungry!

BreakfastMin 300 kcals; Highest relative % of CHO of all meals

• 1 cup cooked oatmeal/steel cut oats + 1oz nuts• 2 slices Ezekiel bread + ½ mashed avocado + sliced tomato (+/-

eggwhites)• 2 egg omelet with veggies + fruit + 1 slice WW toast• 1 plain Greek yogurt + 1/3-1/2 cup KIND granola + 1/3 cup

pomegranate arils or 1 cup berries• 3 Applegate Farms chicken sausages + 1 whole grain waffle +

fruit• 4 Wasa whole grain crispbreads + tomato + cucumber + 3 oz

fish (tuna, lox, smoked mackerel) + lowfat cream cheese• Eggwhites +1 slice cheese + tomato on WW 100-calorie

sandwich flat (+/- fruit)

…plus coffee with milk, modest amount sugar (or non caloric sweetener ) or no sweetener

LunchMost balanced, “main meal” of the day (Plate method)

• Turkey/bean chili + side salad• Large turkey sandwich on WW bread with pile of baby carrots on the side

(+/- side of soup)• Baked salmon + ½ cup lentils + 2 cups cooked green veggies• Grilled chicken breast + ½ large sweet potato + steamed broccoli ad lib• Large butternut squash soup + ½ grilled chicken or turkey sandwich on

whole grain bread• Mushroom barley soup + tuna scoop on bed of greens• Mexican quinoa bowl: 1/2 cup quinoa + ½ cup black beans + 3 oz chicken +

1/3 avocado + salsa + pile of greens• Shrimp/chicken with green beans/broccoli + 2/3 cup brown rice

I aim for 2/3 of daily kcals to be consumed by end of lunchtime

Snacks100-200 kcals once/d if needed; protein + fiber

• Apple with 1 TBSP peanut butter• Grape tomatoes + 1 string cheese• Hard boiled egg +/- ½ avocado • Whole piece of fruit +/- plain Greek yogurt

or low sugar skyr (Siggi’s)• 100 calorie pack nuts + ½ oz semisweet

chocolate chips • 2oz hummus/raw vegetable crudite• ½ cup cottage cheese + fresh melon or

pineapple• ½ cup shelled edamame• 3oz deli sliced turkey wrapped around

mini cucumber or pickle spears + mustard• 1 cup lentil or split pea soup• Tall skim latte +/- piece fruit

DinnerLight, low calorie (< 300-400 kcals), low carb

• Salad with fish, HB egg, or poultry• Cooked veggies with lean meat, fish, poultry• Spaghetti squash & turkey meatballs, marinara sauce• Lettuce wrap tacos• Turkey burger and a salad, lite dressing• Omelet or Frittata with side of haricot verts• Shakshouka• Chinese:

•Shrimp or Chicken + veggie stir fry (no rice)•Mu Shu dish without pancakes/plum sauce

• Japanese:• 1-2 naruto-style sushi rolls with miso soup or hijiki salad

• Thai:• Thai papaya salad + chicken satay appetizer (sauce on side, use sparingly)

Quality of carbs matters, but none off limits entirely

• Beans, lentils, chickpeas, tofu, edamame

• Dairy (milk, unsweetened yogurt, Greek yogurt)

• Whole fruit

• Cooked whole high fiber grains (steel cut/rolled oats, quinoa, wheatberries, barley, wild rice, whole grain pasta…)

• Starchy fruits & vegetables (peas, winter squash, sweet potatoes); bananas

• Processed whole grain foods (Whole grain breads, instant oatmeal) & lower fiber cooked grains (brown rice)

Lowest glycemic CHOs:

Make these the staples

• White starchy carbs (White rice, white potatoes, white bread) & Candy

• Processed/refined carbs: Low fiber cereals (Corn flakes, Rice Krispies, Special K, etc.), crackers, pancakes, bagels, pretzels, chips

• Juice, soda, SSBs

• Sweet snacks: Cookies, cakes, donuts, dried fruit

Highest glycemic CHOs:

Consume these least frequently

Why it works• Frontloading kcals and CHOs is metabolically favorable in sync with circadian

rhythms

• It is a low glycemic diet dietary pattern associated with long-term weight control

• Improved satiety from meals

• Not starving at dinner Improved portion control and ability to control food choice in evening

• More meals, fewer snacks fewer empty calorie foods

• Patients less likely to overeat CHOs at lunch than dinner restaurant portions smaller, patients fear afternoon “food coma”, less decision fatigue earlier in day

• Completely adaptable to cultural food preferences

• Anecdotally, pts report it doesn’t feel like a restrictive “diet”: nothing is entirely off limits long term compliance is good

• Flexible enough to allow dining out at most types of restaurants

• 80/20 rule results generally achieved even if patients cheat 1-2 days/week

When it might not work

• Vegan/Paleo style diets (though these patients less likely to present as obese and diabetic..) carb restrictions unrealistic

• Patients who travel a lot for work chronic jet lag disrupts circadian rhythms, minimal control over food availability

• Shift workers disturbed circadian rhythms and lack of continuity in wake/sleep/eating schedule

• Though data suggest shift workers may be well advised to consume majority of kcals/CHOs during daylight hours and distort to smaller meals/protein when need to eat during nighttime hours..?

• Insomnia?

• Depression?

References (I)Almoosawi, S., Prynne, C. J., Hardy, R., & Stephen, A. M. (2012). Time-of-day and nutrient composition of eating occasions: Prospective association with the metabolic syndrome in the 1946 British birth cohort. International Journal of Obesity, 37(5), 725–731. http://doi.org/10.1038/ijo.2012.103

Arble, D. M., Bass, J., Laposky, A. D., Vitaterna, M. H., & Turek, F. W. (2009). Circadian timing of food intake contributes to weight gain. Obesity, 17(11), 2100–2102. http://doi.org/10.1038/oby.2009.264

Brynes, A. E., Edwards, C. M., Ghatei, M. A., Dornhorst, A., Morgan, L. M., Bloom, S. R., & Frost, G. S. (2003). A randomised four-intervention crossover study investigating the effect of carbohydrates on daytime profiles of insulin, glucose, non-esterified fatty acids and triacylglycerols in middle-aged men. British Journal of Nutrition, 89(02), 207. http://doi.org/10.1079/bjn2002769

Challet, E. (2015). Keeping circadian time with hormones. Diabetes, Obesity and Metabolism, 17, 76–83. http://doi.org/10.1111/dom.12516

Cho, S., Dietrich, M., Brown, C. J. P., Clark, C. A., & Block, G. (2003). The effect of breakfast type on total daily energy intake and body mass index: Results from the Third national health and nutrition examination survey (NHANES III). Journal of the American College of Nutrition, 22(4), 296–302. http://doi.org/10.1080/07315724.2003.10719307

Chowdhury, E. A., Richardson, J. D., Tsintzas, K., Thompson, D., & Betts, J. A. (2015). Effect of extended morning fasting upon ad libitum lunch intake and associated metabolic and hormonal responses in obese adults. International Journal of Obesity. http://doi.org/10.1038/ijo.2015.154

Chowdhury, E. A., Richardson, J. D., Tsintzas, K., Thompson, D., & Betts, J. A. (2015). Carbohydrate-rich breakfast attenuates glycaemic, insulinaemic and ghrelin response to ad libitum lunch relative to morning fasting in lean adults. British Journal of Nutrition, 114(01), 98–107. http://doi.org/10.1017/s0007114515001506

de Castro, J. M. (2007). The time of day and the proportions of macronutrients eaten are related to total daily food intake. British Journal of Nutrition, 98(05). http://doi.org/10.1017/s0007114507754296

Farshchi, H., Taylor, M., & Macdonald, I. (2005). Deleterious effects of omitting breakfast on insulin sensitivity and fasting lipid profiles in healthy lean women. The American Journal of Clinical Nutrition., 2(81). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15699226

Froy, O. (2010). Metabolism and Circadian Rhythms—Implications for obesity. Endocrine Reviews, 31(1), 1–24. http://doi.org/10.1210/er.2009-0014

References (II) Green, C. B., Takahashi, J. S., & Bass, J. (2008). The meter of metabolism. Cell, 134(5), 728–742. http://doi.org/10.1016/j.cell.2008.08.022

Jakubowicz, D., Wainstein, J., Ahrén, B., Bar-Dayan, Y., Landau, Z., Rabinovitz, H. R., & Froy, O. (2015). High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: A randomised clinical trial. Diabetologia, 58(5), 912–919. http://doi.org/10.1007/s00125-015-3524-9

Jakubowicz, D., Wainstein, J., Ahren, B., Landau, Z., Bar-Dayan, Y., & Froy, O. (2015). Fasting until noon triggers increased Postprandial Hyperglycemia and impaired insulin response after lunch and dinner in individuals with type 2 diabetes: A Randomized clinical trial.  Diabetes Care, 38(10), 1820–1826. http://doi.org/10.2337/dc15-0761

Jakubowicz, D., Barnea, M., Wainstein, J., & Froy, O. (2013). High caloric intake at breakfast vs. Dinner differentially influences weight loss of overweight and obese women. Obesity, 21(12), 2504–2512. http://doi.org/10.1002/oby.20460

Kant, A. K., & Graubard, B. I. (2015). Within-person comparison of eating behaviors, time of eating, and dietary intake on days with and without breakfast: NHANES 2005-2010. American Journal of Clinical Nutrition, 102(3), 661–670. http://doi.org/10.3945/ajcn.115.110262

Kumar Jha, P., Challet, E., & Kalsbeek, A. (2015). Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals. Molecular and Cellular Endocrinology. http://doi.org/10.1016/j.mce.2015.01.024

Lee, S. ., Tura, A., Mari, A., Ko, S. ., Kwon, H. ., Song, K. ., … Ahn, Y. . (2011). Potentiation of the early-phase insulin response by a prior meal contributes to the second-meal phenomenon in type 2 diabetes. AJP: Endocrinology and Metabolism, 301(5), E984–E990. http://doi.org/10.1152/ajpendo.00244.2011

Levitsky, D. A., & Pacanowski, C. R. (2013). Effect of skipping breakfast on subsequent energy intake. Physiology & Behavior, 119, 9–16. http://doi.org/10.1016/j.physbeh.2013.05.006

Morgan, L., Hampton, S., Gibbs, M., & Arendt, J. (2003). Circadian aspects of postprandial metabolism. Chronobiology International., 5(20). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14535354

Panda, S., Antoch, M. P., Miller, B. H., Su, A. I., Schook, A. B., Straume, M., … Hogenesch, J. B. (2002). Coordinated transcription of key pathways in the mouse by the Circadian clock. Cell, 109(3), 307–320. http://doi.org/10.1016/s0092-8674(02)00722-5

References (III)

Szajewska, H., & Ruszczyński, M. (2010). Systematic review demonstrating that breakfast consumption influences body weight outcomes in children and adolescents in Europe. Critical Reviews in Food Science and Nutrition, 50(2), 113–119. http://doi.org/10.1080/10408390903467514

Timlin, M. T., Pereira, M. A., Story, M., & Neumark-Sztainer, D. (2008). Breakfast eating and weight change in a 5-Year prospective analysis of adolescents: Project EAT (eating among teens). PEDIATRICS, 121(3), e638–e645. http://doi.org/10.1542/peds.2007-1035

Van Cauter, E., Blackman, J., Roland, D., Spire, J., Refetoff, S., & Polonsky, K. (1991). Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. The Journal of Clinical Investigation., 3(88). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1885778

Versteeg, R. I., Serlie, M. J., Kalsbeek, A., & la Fleur, S. E. (2015). Serotonin, a possible intermediate between disturbed circadian rhythms and metabolic disease. Neuroscience, 301, 155–167. http://doi.org/10.1016/j.neuroscience.2015.05.067