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Effect of the Time of Day of Food Intake and Eating Occasions on Clock Gene mRNA Expression, Weight Loss, HbA1c, and Overall Glycaemia in Type 2 Diabetes Mellitus

Authors:
*Daniela Jakubowicz,1 Zohar Landau,1 Shani Tsameret,2 Julio Wainstein,1 Itamar Raz,3 Bo Ahren,4 Nava Chapnik,2 Maayan Barnea,5 Tali Ganz,1 Miriam Menaged,1 Naomi Mor,1 Yosefa Bar-Dayan,1 Froy Oren2
Disclosure:

The authors have declared no conflicts of interest.

Acknowledgements:

‘†’denotes that all authors contributed equally to the study.

Citation
EMJ Diabet.. ;7[1]:57-58. Abstract No AR06.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIM

Most of the metabolic processes involved in obesity, glycaemic control (i.e., β-cell function), muscular glucose uptake, and hepatic glucose production exhibit diurnal variations and are controlled by endogenous circadian clock genes (CCG).1 Consequently, human glucose metabolism is optimised for eating in the early hours of the day and fasting and sleeping in the evening and during the night. Meal timings that are not aligned with CCG, i.e., skipping breakfast, snacking all day, or high-carbohydrate (CHO) consumption in the evening, may lead to disrupted CCG, obesity, and hyperglycaemia.2,3 Traditional diet intervention (DI) aimed at weight loss and glucose control in Type 2 diabetes mellitus (T2DM) entails several small meals and snacks with calories and CHO uniformly distributed throughout the day, including a snack at night to avoid nocturnal hypoglycaemia.4 Although this DI is usually accompanied by antidiabetic drugs, many patients still require insulin treatment, which is gradually increased. This progressive increase in the total daily insulin dose (TDID), in turn, leads to weight gain and increased insulin resistance, and may result in a cycle of increased insulin, continued weight gain, decreased likelihood of achieving glycaemic targets, and insulin dose-depended cardiovascular risk and mortality.5 The authors recently showed that circadian misalignment by skipping breakfast versus eating breakfast led to downregulation of pivotal CCG, resulting in higher glucose, deficient insulin, and glucagon-like peptide-1 (GLP-1) secretion after  subsequent meals.6

The aim of this study was to explore whether, in insulin treated T2DM patients, a 3-month DI aligned with their CCG, consisting of three meals a day with most CHO consumed in the early hours of the day (Bdiet) and a smaller dinner would upregulate CCG, leading to more efficient weight loss and glycaemic control. Furthermore, if this was accompanied by less TDID compared to isocaloric traditional DI with CHO evenly distributed in three small meals and three snacks throughout the day (All-dayDiet).

METHODS

Twenty-eight T2DM patients (aged 69±7 years; BMI: 32.2±5 kg/m2; 19.9±8 years with T2DM; HbA1c 8.1±1.1 mmol/mol) were treated with insulin and randomly assigned to 12 weeks of either the BDiet with high-energy, CHO breakfast, and low CHO dinner (1,600±200 kcal; breakfast[B]:lunch[L]:dinner[D]; 50:33:17%), or the All-dayDiet with calories and CHO evenly distributed throughout the day (1,600±200 kcal, B:L:D 20:25:25% plus 3 snacks, 10% each). The study assessed body weight; daily 24-hour and nocturnal (00:00 to 06:00) glycaemia, using continuous glucose monitoring (CGM); appetite; craving scores; and CCG mRNA expression in white blood cells at 08:00, 12:00, 15:30, and 23:00, at baseline and after 2-week and 12-week DI, along with TDID.

RESULTS

Results showed that the BDiet led to greater weight loss (-5.4±0.9 versus +0.26±0.30% kg; p<0.05); reduced HbA1c (1.2±0.3% versus 0.2±0.4%; p<0.05); reduced fasting glucose (p=0.005), and reduced daily 24-hour mean glucose by 40±10 mg/dL versus 18±16 mg/dL (p<0.05). Mean nocturnal glucose decreased in the BDiet to 108.8±5.0 mg/dL versus 141.3±13.0 mg/dL in the All-dayDiet (p=0.03). CGM in the BDiet group showed a significant decrease in daily time spent in hyperglycaemia (>180 mg/dL) from 8 hours 59 minutes (37%) at baseline, to 3 hours 3 minutes (13%; p<0.01). Additionally, in the BDietthere was a reduction in the nocturnal time spent in hyperglycaemia from 1 hour 18 minutes (22%) at baseline, to 20 min (6%; p<0.05), compared to no change in the All-day diet (p=0.06). The craving scores (particularly for CHO or starches) assessed by the Food Craving Inventory questionnaire, were augmented by 4±5.1% with the All-dayDiet, while in participants in the BDiet group were significantly reduced by 36.0±7.7% (p<0.05).

The BDiet led to significant upregulation of the oscillation and amplitude of Brain and Muscle ARNT-Like 1, Period 2, Cryptochrome 1, and RAR-Related Orphan Receptor Alpha gene expression, as well as higher RAR-Related Orphan Receptor Alpha and Sirtuin 1 relative levels versus the All-dayDiet (p<0.01).

At the end of the intervention, TDID increased by 4.9±14 units/day (from 70.6±17 to 75.5±11 units/day) in the All-dayDiet; whereas, the TDID was significantly reduced by 27±16 units/day (from 73.5 ±16 to 33.8±15.2 units/day) in the  BDdiet (p<0.05).

CONCLUSION

The BDiet with high-energy and high CHO breakfast appears to be more effective than the All-dayDiet, in which calories and CHO are spread throughout the day. This leads to reduction in weight, HbA1c, appetite, and daily and nocturnal glycaemia, with significantly reduced TDID. The upregulation of CCG expression in the BDiet may be the underlying mechanism, enhancing β-cell secretion and muscle and hepatic insulin sensitivity, leading to improvement in daily and nocturnal glucose metabolism.

Shifting calorie and CHO consumption to the early hours of the day and eating for fewer occasions, is an effective strategy for the achievement of better diabetes control and outcomes with less total daily insulin dose.

References
Froy O, Garaulet M. The circadian clock in white and brown adipose tissue: Mechanistic, endocrine, and clinical aspects. Endocr Rev. 2018;39(3):261-73. Poggiogalle E et al. Circadian regulation of glucose, lipid, and energy metabolism in humans. Metabolism. 2018;84:11-27. Jakubowicz D et al. High-energy breakfast with low energy dinner decreases overall hyperglycemia in type 2 diabetic patients: A randomized clinical trial. Diabetologia. 2015;58(5):912-9. Hutchison AT, Heilbronn LK. Metabolic impacts of altering meal frequency and timing - Does when we eat matter? Biochimie. 2016;124:187-97. Herman ME et al. Insulin therapy increases cardiovascular risk in type 2 diabetes. Prog Cardiovasc Dis. 2017;60(3):422-34. Jakubowicz D et al. Influences of breakfast on clock gene expression and postprandial glycemia in healthy individuals and individuals with diabetic individuals:  A randomized clinical trial. Diabetes Care. 2017;40(11):1573-9.