Comparing the effectiveness of calorie restriction with and without time-restricted eating on the circadian regulation of metabolism: rationale and protocol of a three-arm randomised controlled trial in adults at risk of type 2 diabetes

• Time-restricted eating (TRE) may extend the cardiometabolic health benefits of calorie restriction (CR). • Few studies have compared the effects of CR with and without TRE on health. • The optimal time of day to initiate TRE is unclear. • This will be the largest randomised controlled trial to delineate the effects of CR with and without TRE. Time-restricted eating (TRE) may extend the cardiometabolic health benefits of calorie restriction (CR). However, few studies have compared its effect on the circadian regulation of glucose metabolism and the optimal time of day to initiate TRE is also unclear. This study aims to compare the effectiveness of CR with and without TRE on glucose tolerance in response to 3 identical meals consumed over the day. A parallel, single-blinded, 3-arm randomised controlled trial will be conducted in 114 adults, aged 35 to 75 years with a BMI ≥25.1 but <45.0 kg/m 2 , elevated waist circumference and fasting blood glucose (≥5.6 mmol/L), and who score ≥12 on the Australian Type 2 Diabetes Risk Assessment tool. Participants will be stratified by sex and fasting blood glucose (≤6.0 mmol/L; >6.0 mmol/L) and then randomised (1:1:1) to CR (unrestricted meal timing), eCR (0800 to 1600) or dCR (1200-2000) for 8 weeks. The primary outcome is the change in the natural logarithm of the mean over 3 identical meals of the postprandial glucose area under the curve (AUC). The analysis will be performed using a covariate adjusted linear regression of the differences in postprandial glucose log AUC at 8 weeks from baseline. This randomised clinical trial will be the first to delineate the benefits of CR alone or in combination with time restricted eating on postprandial glucose metabolism over the day in adults at increased risk of type 2 diabetes. This protocol describes a parallel, single-blinded, 3-arm randomised controlled trial exploring the effects of 8 weeks of calorie restriction with and without time-restricted eating initiated early (8am to 4pm) or late (12pm to 8pm), on markers of glucose metabolism in 114 adults with overweight or obesity and at-risk of type 2 diabetes. The primary outcome is the change in the natural logarithm of the mean over 3 identical meals of the postprandial glucose area under the curve (AUC). Created in Canva.