Anyiam, Oluwaseun
(2025)
An examination into the effects of very-low calorie diets and glucagon-like peptide-1 receptor agonists, individually or in combination, on skeletal muscle metabolism and glycaemic outcomes in individuals with type 2 diabetes living with obesity.
PhD thesis, University of Nottingham.
Abstract
Type 2 diabetes (T2D) and obesity are major issues of modern healthcare. Both are increasing in prevalence around the world and responsible for considerable expenditure in global health systems. On a patient level, individuals with both conditions suffer significantly from the consequences of associated complications, leading to increased levels of mortality and disability. Weight loss interventions are crucial for the management of both conditions, and two such interventions are very-low calorie diets (VLCD) and glucagon-like peptide-1 receptor agonists (GLP1RAs). They are both recommended for the treatment of T2D, and a role in weight management is also recognised.
However, the apparent loss of skeletal muscle mass (MM) associated with these, and other weight loss interventions is increasingly attracting interest. This is particularly relevant given that individuals with T2D and obesity exhibit increased rates of age-related loss of MM, predisposing them to greater risk of frailty and disability. Despite these concerns, there still remains inconsistency and uncertainty regarding the true impact of these interventions on MM, and methods of mitigating these effects remain elusive. Furthermore, some evidence suggests a potential muscle-preserving effect of GLP1RAs, which could be particularly attractive given its already well-recognised weight and glycaemic effects.
This body of work aimed to perform a detailed examination of the effects of these two weight loss interventions on muscle and clinical outcomes. In addition, a novel approach of combining the two interventions was explored, in order to determine whether this could elicit additive benefits on these outcomes.
Two meta-analyses were performed, providing a systematic review and quantitative synthesis of existing literature around the effects of these interventions on MM. The results of the initial meta-analysis suggested that GLP1RAs did not induce significant MM loss in individuals with T2D, but did in individuals without T2D. Notably, this differential effect is likely due to the doses used in the two populations. It was also found that less than 20% of total weight loss was attributable to MM. The second meta-analysis supported previous assertions that VLCD induce significant MM reductions, which comprise approximately 25% of total weight loss. However, this proportion was similar between individuals with and without T2D, providing reassurance that T2D does not aggravate MM loss during caloric restriction interventions.
The first empirical study outlined changes in MM in response to an 800 kilocalorie per day VLCD, the GLP1RA Semaglutide and a combination of the two, and related these to muscle protein synthesis (MPS) and breakdown (MPB). MPS significantly reduced in all groups, in a pattern consistent with the corresponding MM losses. Notably, Semaglutide reduced MPS to a lower extent than VLCD. Combination of the two interventions elicited numerically lower reductions in MM and MPS than VLCD alone, however these were non-significant. MPB was not significantly different between the groups, however the lack of a baseline measurement severely limited the conclusions that could be drawn from this.
The second empirical study assessed the impact of these three interventions on clinical outcomes relevant to individuals with T2D, in order to put the above findings into context. As expected, all interventions stimulated significant weight loss and improvement in overall glycaemic control. VLCD and the combination elicited greater weight and FM reductions than Semaglutide. Similar outcomes were observed between the VLCD and combination groups, except for beta-cell function (BCF) which improved to a significantly greater extent with the combination. This is particularly relevant as a larger magnitude of BCF amelioration is associated with more robust long-term diabetes remission.
Thus, the findings of the empirical studies suggest that combining VLCD and a GLP1RA may confer beneficial effects on both muscle-related and glycaemic outcomes, and as such requires further investigation. The findings of the meta-analyses were supported by the empirical mechanistic data. MM loss during weight loss interventions appears to be primarily mediated by changes in MPS, therefore approaches should be targeted at ameliorating this (such as exercise or increased protein intake). However, a synergistic role of MPB in this process cannot be ruled out and both of these topics present exciting avenues for ongoing research.
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