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Aims/hypothesis Mitochondrial cristae architecture is a key determinant of oxidative capacity in skeletal muscle. While mitochondrial dysfunction is common in type 2 diabetes, it remains unclear whether cristae density is reduced and whether it can be improved by exercise training. We therefore investigated the mitochondrial cristae density in skeletal muscle of individuals with type 2 diabetes compared with glucose-tolerant individuals with obesity and lean individuals, and examined the effect of high-intensity interval training (HIIT). Methods In a non-randomised intervention study, the effect of an 8 week supervised HIIT intervention combining rowing and cycling was examined in male participants (aged 40–65 years) with type 2 diabetes (n=15), glucose-tolerant individuals with obesity (n=15), and lean individuals (n=18). Muscle biopsies from the vastus lateralis muscle were analysed using transmission electron microscopy to quantify mitochondrial cristae density (cristae surface area per mitochondrial volume) and to derive cristae surface area per muscle volume, integrating mitochondrial abundance and ultrastructure. To ensure high stereological precision, a minimum of 49 mitochondrial profiles per sample were analysed. Results No differences in mitochondrial cristae density were observed between groups at baseline. HIIT induced a ~7% increase in cristae density across all groups, with the most pronounced adaptations in type 2 fibres and in the intermyofibrillar compartment. At baseline, participants with type 2 diabetes exhibited lower cristae surface area per muscle volume compared with lean individuals. Notably, HIIT increased cristae surface area per muscle volume by ~55%, exceeding the magnitude of previously reported increases in mitochondrial volume density. Conclusions/interpretation Skeletal muscle mitochondrial cristae density is not different between individuals with type 2 diabetes and glucose-tolerant individuals with obesity and lean individuals, and the capacity for cristae remodelling in response to exercise is not affected by type 2 diabetes. These findings highlight the plasticity of mitochondrial architecture and support HIIT as a potent stimulus for improving muscle oxidative and metabolic health in type 2 diabetes. Graphical Abstract

Aims/hypothesis At present, no disease-modifying therapies are available for individuals who have been newly diagnosed with type 1 diabetes, despite promising results from decades of clinical trials initiated at stage 3 disease onset. Historically, clinical trials have used changes in the C-peptide AUC (AUCCp) during a mixed meal tolerance test (MMTT) as the primary endpoint; however, this measure does not always correlate with clinical outcomes. Methods We analysed 4930 MMTT data points from 799 participants in nine Phase II stage 3 type 1 diabetes trials to determine whether a model-derived physiological measure of in vivo beta cell glucose sensitivity (βGS) could augment clinical trial strategies in type 1 diabetes. Results Older age and higher BMI were associated with maintenance of βGS (defined as loss <10% of the baseline value) and maintenance of HbA1c <53 mmol/mol (7.0%). Baseline βGS, age, HbA1c and insulin dose together predicted the magnitude of the effect on HbA1c following intervention. When positive and negative trials were compared, normalised βGS served as an earlier indicator of trial efficacy compared with AUCCp. Conclusions/interpretation Our results identified thresholds of change in βGS associated with a clinically significant impact on glycaemic management after intervention and suggest that baseline βGS in association with clinical and demographic parameters may be applied to identify individuals who are more likely to respond to an intervention. Graphical Abstract