Intermittent calorie restriction for diabetes remission Original paper

Type 2 diabetes (T2D) was long considered a progressive, irreversible condition, but recent evidence indicates that an intensive lifestyle intervention can lead to diabetes remission.^[1][2] Intermittent fasting diets that alternate days of ad libitum eating with modified fasting (i.e., very low calorie) days can significantly reduce body weight and improve cardiometabolic risk factors.^[3] Could a novel variant of this approach known as the Chinese Medical Nutrition Therapy diet (CMNT) be effective for achieving T2D remission?

In this 3-month randomized controlled trial, 72 participants (average age of 53, BMI range of 19 to 30) with T2D who were taking antidiabetic medications or insulin were assigned to consume a CMNT diet or an ad libitum control diet. The CMNT diet involved 5 days of very low energy intake (840 kcal/day; 46% of energy from carbohydrate, 46% fat, and 8% protein), during which all meals were provided, followed by 10 days of an ad libitum diet. This cycle was repeated 6 times during the intervention. Following the intervention, there was a 1-year follow-up period during which both groups consumed ad libitum diets. Both groups were recommended to follow the Dietary Guidelines for Diabetes in China during the ad libitum diet periods. Dietary intake was assessed at baseline, after the intervention, and after 12 months of follow-up using food frequency questionnaires. Dosages of antidiabetic medications were adjusted by physicians throughout the trial.

The primary outcome was diabetes remission, defined as an HbA1c of less than 6.5% after at least 3 months of ceasing antidiabetic medication, which was assessed after the intervention at 3 and 12 months of follow-up. The secondary outcomes were HbA1c, fasting glucose, blood pressure, anthropometrics, medication use, and quality of life assessed via the 5-level EuroQol 5 Dimensions questionnaire.

After the 3-month intervention, 18 of 36 (50%) participants in the CMNT group and 1 of 36 (3%) participants in the control group ceased antidiabetic medication use. Compared to the control group, the CMNT group experienced a decrease in fasting glucose (−33 vs. −3.8 mg/dL) and body weight (−5.93 vs. −0.27 kg). There was also an improvement in quality of life in the CMNT group compared to the control group.

After 3 months of follow-up, 17 of 36 (47%) participants in the CMNT group achieved diabetes remission, whereas only 1 of 36 (3%) participants achieved this in the control group. Additionally, HbA1c was lower in the CMNT group than the control group (5.66% vs. 7.87%).

After 12 months of follow-up, 16 of 36 (44%) participants in the CMNT group achieved diabetes remission, whereas 0 of 36 achieved remission in the control group. Additionally, HbA1c was lower (6.33% vs. 7.76%) and quality of life was higher in the CMNT group compared to the control group. Importantly, the initial change in body weight following the intervention remained stable in both groups after 12 months of follow-up.

Physical activity was not monitored during the study. The participants were instructed to maintain their usual physical activity habits.

When interpreting the results of this trial, it’s important to have a mechanistic understanding of the primary factors involved in the development of T2D and exactly how (physiologically) T2D remission is achieved. Mechanistic understanding makes it possible to discern why the CMNT diet was as effective as it was and provides the background for some ideas as to what diets in general can be used to achieve T2D remission.

T2D is a heterogeneous condition, with both genetic and environmental factors contributing to its manifestation. Nonetheless, its onset is primarily driven by excessive (i.e., beyond that which the individual can tolerate) weight gain, resulting in ectopic fat accumulation, most notably in the liver and pancreas.^[4] The presence of excess fat results in insulin resistance and increased glucose production in the liver and impaired beta-cell function and insulin secretion in the pancreas.^[5] In combination, these abnormalities give rise to chronic hyperglycemia (high blood sugar).

Because T2D is primarily driven by the consumption of too many calories, resulting in ectopic fat accumulation and an impaired function of organs involved in glycemic control, it’s plausible that the consumption of a hypocaloric diet that facilitates reductions in body weight and more importantly, intra-organ fat, would resolve the underlying dysfunctions.

Evidence suggests that a very low energy diet (VLED, about 600 kcal/day) can significantly reduce liver fat, liver insulin resistance, and normalize fasting glucose levels within 7 days.^[6] In this same study, it took about 8 weeks for significant reductions in pancreatic fat and improvements in beta-cell function to occur.

There has also been longer-term research that investigated the effects of a hypocaloric diet and weight loss on T2D remission. The DiRECT trial, the most notable trial of its kind, had participants consume a liquid meal replacement formula-based VLED (825–853 kcal/day) for 3 months followed by food reintroduction for 2–8 weeks as the participants transitioned to a weight-maintaining diet.^[7] At 12 months, T2D remission (defined as an HbA1c of no more than 6.5% after at least 2 months off all antidiabetic medications) was achieved by 46% of participants, and remission was closely related to the degree of weight loss maintained at 12 months. In participants who sustained a weight loss of 10–14.99 kg or at least 15 kg, T2D remission was achieved by 73% and 86% of participants, respectively.

Other trials have used a similar dietary intervention (i.e., a very low energy formula diet) with comparable reductions in body weight and HbA1c^[8] and T2D remission success.^[2][9]

In sum, the available evidence demonstrates that reductions in body weight are accompanied by reductions in HbA1c in a nearly dose-dependent manner in adults with overweight or obesity and T2D,^[10] which is driven by reductions in liver and pancreas fat and a recovery of beta-cell function.^[11]

Therefore, the effects of the CMNT diet can be primarily attributed to the significant weight loss it caused, which, importantly, was maintained after 12 months of follow-up. If weight regain is avoided after achieving significant weight loss and reversal of the mechanisms underlying T2D, the improvements in HbA1c will remain.^[12]

As demonstrated by the summarized study, among others,^[13][9][7] a continued hypocaloric diet is not necessary for the maintenance of T2D remission.^[5] Once T2D remission is achieved, a follow-up transition period can be used to maintain the lost weight. This process involves increasing caloric intake (and potentially reintroducing foods) in a stepwise fashion to establish a new steady state, along with the formation of other habits (e.g., increased physical activity, frequent monitoring of body weight^[14]) associated with improved weight loss maintenance success.

Essentially, the diet used to achieve T2D remission does not have to resemble the diet used to maintain T2D remission. In fact, there may be advantages to intentionally using an unsustainable diet, as evidenced by the effectiveness of the very low energy formula diet interventions in the aforementioned studies, among other research.

More rapid initial weight loss is associated with greater weight loss in the long term and improved weight loss maintenance.^[15][16][17] There are several potential reasons for this, such as greater initial weight loss resulting in perceived improvements in physical appearance, physical mobility, energy, and/or general health, which serve as reinforcers for dietary adherence.^[16]

Replacing one to three main meals per day with liquid meal replacements has been shown to produce significantly greater weight loss than other low energy diet interventions over 12–52 weeks.^[18] In addition, VLEDs (no more than 800 kcal/day) have been reported to produce significantly greater weight loss at 3 and 6 months compared to low energy diets (1,000–1,500 kcal/day),^[19] without greater rates of attrition.

Several studies that used a VLED intervention found that participants experienced improved well-being.^[19] This is in agreement with the findings of the summarized study, which reported significant improvements in quality of life after the intervention and after 12 months of follow-up in the CMNT group. The DiRECT trial also reported improved quality of life at 12 months in the intervention group.^[1] Collectively, these findings indicate that people find VLED to be just as acceptable as other less radical dietary interventions and perhaps even more acceptable due to greater weight loss and associated reductions in medication use and improvements in physical health.

It’s suggested that traditional prolonged dieting is made more difficult by the major drawbacks of associated hunger and daily decisions about what and how much to eat and that these issues can be avoided through a shorter dieting period involving more severe energy restriction and a liquid formula diet.^[5] Many people with T2D are willing to go to great lengths to alleviate their condition.^[5][20] These motivated individuals may be particularly well suited to take advantage of the potentially robust benefits of a very low energy formula diet.

While there isn’t a universal best diet for the achievement of T2D remission,^[21][22] there is a theoretical best diet for an individual person, and that’s whichever one they’re able to stick to long enough to achieve the significant weight loss required to reverse the underlying mechanisms of T2D. Some people may especially benefit from an intensive very low energy formula diet intervention.