Investigations of the Mechanisms of Diabetes Remission: A Focus on Adaptive Thermogenesis

Background The prevalence of diabetes and obesity have continued to rise over the last 30 years. In New Zealand one in three adults are have obesity and one in twenty have type 2 diabetes mellitus (T2DM). Thus, there is an urgent need to implement effective and scalable treatments for both diabetes and obesity. Bariatric surgery and low-calorie diets produce weight loss and reverse the disordered glucose metabolism associated with T2DM. Both treatments create a state of negative energy balance in which the individual’s dietary energy intake is lower than their energy expenditure. However, maintaining a negative energy balance with low-calorie diets is challenging. This is partly due to a compensatory reduction in resting energy expenditure (REE), adaptive thermogenesis, that occurs during weight loss. Adaptive thermogenesis diminishes the negative energy balance, undermining weight loss. A better understanding of what influences adaptive thermogenesis and ways to mitigate it may inform more effective dietary interventions for the treatment of diabetes and obesity. Objectives The overall aim of this thesis was to test the hypothesis that interrupting a low-calorie diet using an intermittent fast reduces adaptive thermogenesis during weight loss. To test this hypothesis, we first needed to develop an accurate and precise method for measuring REE using indirect calorimetry. Secondly, we needed to assess the relationship between REE and body composition in a local sample population. Thirdly, we needed to assess the safety of intermittent fasting in individuals with T2DM at risk of hypoglycaemia. Design In-silico validity and precision testing of indirect calorimetry was conducted using ethanol combustion and nitrogen dilution. Having determined the quality of in-silico calorimetry measurements, the test-retest reliability was assessed in two repeated measures studies of REE in human participants. To assess the relationship between body composition and REE, a cross-sectional study of body composition and REE using indirect calorimetry was conducted, the Predictions in Resting Energy Expenditure in Māori and Pacific (PREEMPt) study. Next, the safety of intermittent fasting in individuals with T2DM was assessed in a 12-week prospective randomised control trial. Having completed these studies, the Changes in Resting Energy Expenditure with Different Schedules of Calorie Restriction (CREEDS) study was conducted to address the primary hypothesis that intermittent fasting attenuates adaptive thermogenesis during weight loss. Results Following protocol refinement, high levels of precision and accuracy were observed during the nitrogen dilution studies and the second test-retest reliability study. The assessments of body composition and resting energy expenditure in the PREEMPt study were used to estimate the sample size required for the CREEDS study. We found that intermittent fasting increased the risk of hypoglycaemia on fasting days, this finding informed the design of the CREEDS study. In the CREEDS study, both intermittent fasting and continuous daily restriction resulted in adaptive thermogenesis, that was not mitigated by the intermittent fasting intervention. Of note, intermittent fasting was associated with a two-fold greater reduction in fat mass compared to continuous daily restriction. Conclusions Intermittent fasting does not mitigate adaptive thermogenesis seen during weight loss with a low-calorie diet.