Study evaluates simultaneous effects of exercise and diet-induced weight reduction in patients with type 2 diabetes

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In a recent article published in the Nature Metabolism Journal, researchers performed a four-armed, 16-week randomized clinical trial (RCT) between February 2019 and October 2021 in Copenhagen, Denmark, among 82 individuals with newly diagnosed type II diabetes (T2D).

Study: Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial. Image Credit: NokLekTravelLifestyle/Shutterstock.comStudy: Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial. Image Credit: NokLekTravelLifestyle/


The team recruited potential participants through the media, municipalities, and the Danish health data authorities.

The study population comprised men and women aged 18–80 years with body mass index (BMI) between 27 kg/m2 and <40 kg/m2, diagnosed with type II diabetes (T2D) in less than seven years but not receiving any insulin treatment.


Progressive deterioration of beta-cell function leads to the onset of T2D; thus, re-establishing normal beta-cell function could be pivotal to improving T2D pathogenesis. The disposition index (DI), the product of ‘insulin sensitivity’ and ‘insulin secretion’, is a widely accepted measure of beta-cell function.

It incorporates both these measures, i.e., insulin sensitivity and secretion, because the decrease in the former’s levels leads to an increase in the latter during normal physiological conditions.

Evidence suggests that exercise improves DI by improving insulin sensitivity and glucose disposal; however, how exercise affects insulin secretion amid prevailing insulin sensitivity remains to be clarified. In fact, the exact effects of exercise and diet-induced weight loss on beta-cell function in T2D are unclear.

Diet-triggered weight loss improves beta-cell function immensely. Thus, highly intensive weight management programs aim for weight loss alongside pharmacological therapy to treat hyperglycemia.

More importantly, there is an urgent need to understand the potential interactions between standardized dietary weight management therapies and pharmacological therapies when assessing the effects of exercise on DI among people living with T2D in a clinical setting.

About the study

In the present study, researchers randomly allocated all 82 participants to four intervention groups comprising 20, 21, 20, and 21 participants each. The first study group, CON, received standard care and maintained a habitual dietary and physical activity routine. The second group, DCON, received standard care and up to 25% reduced calories.

The third group, MED, also received standard care, dietary and exercise interventions, with two aerobic sessions per week and one aerobic plus resistance training session every week. Adding 150 to 165 minutes of exercise every week for 16 weeks. The fourth group, HED, received everything like MED, but their exercise training totaled 300 to 330 minutes per week.

Standard care encompassed the management of blood glucose, blood lipids, and blood pressure via pharmacological interventions, measured before initiation of interventions and at four, 12, and 16 weeks. In addition, the study nurse asked all participants about adverse events (if any) at each visit.

The team used the age-adjusted Oxford equation to estimate daily energy requirements. Based on self-reported, 3-day food records, a clinical dietician planned individualized recommendations and recipes (or a dietary plan) for each participant.

The dietary interventions aimed at curtailing ~25 to 30% energy/day with a macronutrient distribution ranging between 45–60, 15-20, and 20-35 energy percent (E%) for carbohydrates, protein, and fat, respectively.

The exercise intervention comprised aerobic and resistance training, as mentioned before. In all, the researchers conducted two experimental days at a gap of one week, first at baseline and then at a 16-week follow-up. They instructed all participants to discontinue glucose-lowering medication and refrain from any exercise 48 hours before the experimental days.

On experimental day one, participants with newly diagnosed T2D completed a three-hour mixed meal tolerance test (MMTT), whereas, on experimental day two, they performed a three-stage hyperglycemic clamp.

They calculated DI as the product of late-phase insulin secretion rate (ISR) and late-phase Insulin sensitivity index (ISI). The latter helped the researchers examine DI changes during the final 30 minutes of clamp-induced hyperglycemia (late-phase DI) after a 16-week intervention.

Additionally, the researchers explored the effects on some cardiometabolic risk factors, including maximal insulin secretory capacity via secretion indices derived from a liquid MMTT,  glucagon-like peptide 1 (GLP-1) sensitivity, glucose kinetics, etc.

Study findings

The mean age of all 82 study participants was 58.2 years (±9.8 years), and 35% were females. Not in the standard care CON group, but late-phase DI increased in all other intervention groups, which subsequently improved beta-cell function from baseline to 16-week follow-up. Moreover, the magnitude of increases across groups followed a linear dose–response relationship.

The late-phase glucose-stimulated insulin sensitivity index (ISI) also reflected this linear dose–response relationship. Conversely, the late-phase glucose-stimulated insulin secretion rate (ISR) increased more in all intervention groups than in CON.

Therefore, the authors speculated that a weight loss of ~7.5% body weight might be sufficient to re-establish late-phase ISR in this study population. It is also likely that exercise drives more changes in insulin sensitivity, while weight loss primarily drives changes in insulin secretion.

MMTT-derived oral DI increased more in all intervention groups than in CON. These increases were most pronounced in the MED and HED groups vs. the DCON group. Likewise, oral ISI increased in all groups compared with CON, with more pronounced increases in HED vs. DCON.

There were no inter-group differences for oral ISR. However, oral DI and oral ISI showed a curve-linear relationship when comparing three and six exercise sessions per week.

The authors noted three serious adverse events, one case each of ischemic attack and malignant melanoma in the CON group and prolactinoma in the DCON group.

Furthermore, the study data favored that the exercise component increased DI due to increases in insulin sensitivity rather than insulin secretion.


Among adults with T2D within seven years of diagnosis, exercise and diet-induced weight loss increased late-phase DI across a 16-week intervention with the most pronounced benefits due to exercising six times per week.

However, data from MMT experiments also suggested that increasing the exercise beyond three times per week when practicing diet-induced weight loss might be redundant to gain additional benefits, especially for the beta-cell function. Further work might confirm these findings.

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