In a recent study published in the Nature Medicine Journal, researchers performed a three-arm, open-label, randomized controlled trial (RCT) between 26 September 2018 and 30 November 2021 among adults at a higher risk of developing type 2 diabetes (T2D).
Study: Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial. Image Credit: LightFieldStudios/Shutterstock.com
The study involved a six-month dietary intervention of two dietary regimens, early time-restricted eating (iTRE) and calorie restriction (CR), followed by a one-year follow-up.
Since the researchers anticipated that weight loss for iTRE and CR groups would be comparable, they also included a standard care group to ensure that at least some weight loss occurred.
It also helped them quantify the parallel change in the two active study groups, i.e., iTRE and CR groups.
Research has well-established the role of dietary interventions with moderate CR as an established strategy for weight loss and managing T2D. However, the health benefits of meal time and prolonged or intermittent fasting (IF) are still under investigation.
Nevertheless, a quick review of meta-analyses showed that IF, fasting spread across days of ad libitum eating, could be a great CR alternative for weight loss and health outcomes.
Theories have also pointed out that IF might better stimulate alterations in nutrient signaling pathways, lipid metabolism, and insulin sensitivity.
However, only two clinical trials have documented greater improvements via IF compared to CR. Studies examining postprandial glycemia assessments followed by mixed meals are better indicators of T2D risk than fasting assessment studies. In addition, these test assessments have more physiological relevance than oral glucose tolerance tests.
Overall, there is a shortage of high-quality evidence that IF is more effective in improving glucose tolerance than CR. Furthermore, studies have not yet compared or tested the effects of IF and CR on β-hexosaminidase, an isozyme that degrades glycosaminoglycans, oligosaccharides, etc.
Several studies have shown increased β-hexosaminidase activity in patients with diabetes, hepatic diseases, and, more recently, Alzheimer's disease (AD).
About the study
In the present study, researchers recruited participants aged 35 to 75 who scored ≥12 on the Australian T2D risk (AUSDRISK) assessment tool and randomly allotted them to iTRE, CR, or standard care groups in a 2:2:1 ratio.
These people showed not more than 5% weight fluctuations six months before study initiation. Also, they consumed no medications affecting glucose metabolism or weight management and did not have diabetes.
Post-randomization, the team asked the members of the iTRE, CR, and standard care groups to consume their prescribed menu.
For instance, they allowed the iTRE group to consume 30% of their baseline calorie requirements on fasting days, followed by 20 hour fast on any three days every week.
Likewise, the CR group followed a dietary regimen that reduced 30% of their daily baseline calorie needs. This group followed a rotating menu plan for dinner and snacks but did not follow a specific meal timing.
The iTRE and CR groups received only one diet counseling during six months of dietary intervention, while the standard care group followed no meal plans and received no counseling.
The team asked all study groups to attend clinical visits every 15 days during the first six months and once a month during the one-year follow-up. Throughout the study duration, participants maintained their usual physical activity regimens.
After six months, the researchers modified iTRE meal plans and reduced their iTRE days to once or two times per week. Likewise, the CR group received new targets that increased their calorie intake by 10% to 15%.
As its primary outcome, this RCT examined the differences in glucose tolerance tests after a mixed meal in iTRE vis-à-vis CR groups at six months.
As secondary outcomes, they compared iTRE vs. CR vs. standard care groups for changes in body weight, composition, fasting and postprandial glycemia markers, and cardiovascular and liver health.
Finally, the researchers explored the combined effect of iTRE and CR vs. standard care in bringing about prolonged reductions in insulin area under the curve (AUC).
The current RCT demonstrated that iTRE was far superior to CR in improving postprandial glucose tolerance in adults at a higher risk of developing T2D.
At month 6, the iTRE group had much-improved glucose tolerance than the CR group regardless of weight loss, with values equal to −10.10 vs. −3.57 mg dl−1 min−1, 95% confidence interval; however, these differences vanished at month 18.
Similar to this large trial, three other pilot studies have compared the effects of IF vs. CR on the same parameters.
Strikingly, they showed that IF significantly reduced postprandial triglycerides but not postprandial glucose or insulin in obese or non-obese individuals after two to eight weeks.
Indeed, improvements in glucose tolerance could occur in multiple ways, including insulin sensitivity/secretion and slower gastric emptying, to name a few. In this study, the authors noted a highly reduced postprandial insulin area under the curve (AUC), likely indicating improved insulin sensitivity.
Further, they observed higher reductions in fasting nonesterified fatty acids (NEFA) by iTRE, suggesting adipose tissue insulin sensitivity improvements. These fatty acids are robustly associated with an increased cardiovascular diseases risk.
The prescription of iTRE vs. CR also elicited favorable lipid profile alterations. This parameter likely also reduced ectopic lipid and spiked peripheral glucose uptake.
However, the insulinogenic index calculations displayed no difference in insulin secretion. Though not fully assessed, gastric emptying could have partly improved glucose tolerance following early TRE after a week.
The dietary intervention triggered more improvements in glucose tolerance but only marginally shifted HbA1c levels in those without T2D.
Both postprandial and fasting glucose influence HbA1c; however, the former is most robustly predictive of HbA1c levels in healthy people.
Interestingly, dietary interventions that improved glycemic control also reduced β-hexosaminidase activity, though its clinical relevance is unclear. Perhaps it represents that iTRE restored lipid metabolism and liver health more than CR.
All reported adverse events were transient and usually mild. For instance, fatigue was higher in iTRE vs. CR and standard care, whereas constipation and headache were higher in iTRE and CR groups but not the standard care group.
Lastly, a post hoc analysis showed that changing the diet plan in the iTRE cohort vs. no change did not substantially alter health outcomes.
To summarize, iTRE had a modest effect on postprandial glycemia after six months in response to a mixed-meal tolerance test than CR in adults at higher risk of T2D.
Thus, the study adds to data showing meal timing and IF regimens could be successfully incorporated into clinical practice.
However, future studies should examine whether intermittent fasting during a longer daily eating timeframe (e.g., 0800 to 1600 hours) would retain these benefits in the long term.