Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: a randomised crossover trial

Abstract

Aims/hypothesis: Time-restricted eating (TRE) is suggested to improve metabolic health by limiting food intake to a defined time window, thereby prolonging the overnight fast. This prolonged fast is expected to lead to a more pronounced depletion of hepatic glycogen stores overnight and might improve insulin sensitivity due to an increased need to replenish nutrient storage. Previous studies showed beneficial metabolic effects of 6-8 h TRE regimens in healthy, overweight adults under controlled conditions. However, the effects of TRE on glucose homeostasis in individuals with type 2 diabetes are unclear. Here, we extensively investigated the effects of TRE on hepatic glycogen levels and insulin sensitivity in individuals with type 2 diabetes.

Methods: Fourteen adults with type 2 diabetes (BMI 30.5±4.2 kg/m², HbA_1c 46.1±7.2 mmol/mol [6.4±0.7%]) participated in a 3 week TRE (daily food intake within 10 h) vs control (spreading food intake over ≥14 h) regimen in a randomised, crossover trial design. The study was performed at Maastricht University, the Netherlands. Eligibility criteria included diagnosis of type 2 diabetes, intermediate chronotype and absence of medical conditions that could interfere with the study execution and/or outcome. Randomisation was performed by a study-independent investigator, ensuring that an equal amount of participants started with TRE and CON. Due to the nature of the study, neither volunteers nor investigators were blinded to the study interventions. The quality of the data was checked without knowledge on intervention allocation. Hepatic glycogen levels were assessed with ¹³C-MRS and insulin sensitivity was assessed using a hyperinsulinaemic-euglycaemic two-step clamp. Furthermore, glucose homeostasis was assessed with 24 h continuous glucose monitoring devices. Secondary outcomes included 24 h energy expenditure and substrate oxidation, hepatic lipid content and skeletal muscle mitochondrial capacity.

Results: Results are depicted as mean ± SEM. Hepatic glycogen content was similar between TRE and control condition (0.15±0.01 vs 0.15±0.01 AU, p=0.88). M value was not significantly affected by TRE (19.6±1.8 vs 17.7±1.8 μmol kg^-1 min^-1 in TRE vs control, respectively, p=0.10). Hepatic and peripheral insulin sensitivity also remained unaffected by TRE (p=0.67 and p=0.25, respectively). Yet, insulin-induced non-oxidative glucose disposal was increased with TRE (non-oxidative glucose disposal 4.3±1.1 vs 1.5±1.7 μmol kg^-1 min^-1, p=0.04). TRE increased the time spent in the normoglycaemic range (15.1±0.8 vs 12.2±1.1 h per day, p=0.01), and decreased fasting glucose (7.6±0.4 vs 8.6±0.4 mmol/l, p=0.03) and 24 h glucose levels (6.8±0.2 vs 7.6±0.3 mmol/l, p<0.01). Energy expenditure over 24 h was unaffected; nevertheless, TRE decreased 24 h glucose oxidation (260.2±7.6 vs 277.8±10.7 g/day, p=0.04). No adverse events were reported that were related to the interventions.

Conclusions/interpretation: We show that a 10 h TRE regimen is a feasible, safe and effective means to improve 24 h glucose homeostasis in free-living adults with type 2 diabetes. However, these changes were not accompanied by changes in insulin sensitivity or hepatic glycogen.

Trial registration: ClinicalTrials.gov NCT03992248 FUNDING: ZonMW, 459001013.

Keywords: Circadian rhythm; Glucose homeostasis; Hepatic fat; Hepatic glycogen; Insulin sensitivity; Intermittent fasting; Lifestyle intervention; Mitochondrial oxidative capacity; TRE; Type 2 diabetes.

Fig. 1

Effect of TRE on EGP (a), plasma NEFA (b), R_d (c), NOGD (d) and fat oxidation (e) measured during a hyperinsulinaemic–euglycaemic two-step clamp (n=14). *p<0.05 (data were analysed with paired t tests). R_d, Rate of disappearance

Fig. 2

(a–d) Twenty-four-hour glucose levels on days 15 (a), 16 (b), 17 (c) and 18 (d) during TRE or CON (n=10). Mean 24 h glucose from day 15 to day 18 (n=10) analysed using a paired t test (e). Time spent in glucose range during days 15–18 (n=10) analysed using Wilcoxon tests with Bonferroni correction (f) *p<0.05. Hypo, hypoglycaemia defined as glucose levels <4.0 mmol/l; Low, low glucose levels defined as glucose levels 4.0–4.3 mmol/l; Normal range, glucose levels within the normal range defined as 4.4–7.2 mmol/l; High, high glucose levels defined as glucose levels 7.3–9.9 mmol/l; Hyper, hyperglycaemia defined as glucose levels >10 mmol/l

Fig. 3

Effect of TRE on 24 h energy expenditure (a), substrate oxidation (b–d), sleeping metabolic rate (e) and RER during sleep (f), (n=13). *p<0.05