This study is one of the first to show significant relationships between key cardiometabolic risk factors, such as gold-standard 1H-MRS quantified IHL%, and CRF in individuals with and without T2D. The findings of this study showed that the prevalence of MAFLD amongst participants with T2D was 65%, which coincide with previous reports . Further analyses showed that even relatively small variations in CRF were associated with increased IHL% and insulin resistance, which were significantly higher in individuals with the lowest CRF than those with highest CRF. Similarly, individuals with the highest CRF had lower cardiometabolic and inflammatory abnormalities than those with the lowest CRF. The findings of this study suggest that improving CRF should remain a key therapeutic target for the management of obesity-related disease such as comorbid T2D and MAFLD.
Low CRF is a well-accepted independent risk factor for morbidity and mortality , and improving CRF is being increasingly adopted as a therapeutic target for improving cardiometabolic health in individuals with or at risk of obesity-related disease [12, 13]. Currently, few studies have assessed the association between CRF and direct measures of IHL or MAFLD. For example, the results of the Young Finns study involving 463 participants showed that CRF was strongly, inversely, and independently associated with ultrasound-quantified fatty liver (p < 0.001) . However, that study measured IHL up to three years after initial CRF assessment and measured IHL using ultrasound, which is less accurate than 1H-MRS. Similarly, another study reported low CRF was inversely associated with increasing MAFLD activity and steatohepatitis severity measured via liver biopsy , however, liver biopsies were conducted up to four months after CRF assessment. The results of the study reported herein, which showed that individuals with the lowest CRF had significantly higher IHL% than those with the highest CRF, are in accordance with previous findings from an interventional study involving a mixed sample of adults with MAFLD and adults at risk of metabolic disease . The results of the current study add to existing evidence, highlighting that even relatively small variations in CRF are associated with increased IHL in inactive adults with or at risk of T2D. Importantly, the assessment of CRF and IHL was undertaken within a narrow timeframe (< 1 week) and IHL% was quantified using gold-standard 1H-MRS thus highlighting the novelty and methodological rigour of the present study.
There is strong evidence linking low CRF to insulin resistance. A recent meta-analysis of 8 cohort studies found that CRF was inversely associated with T2D prevalence independent of other risk factors such as BMI, TC, and family history of T2D . Similarly, the results of this study showed that CRF was inversely associated with insulin resistance and other cardiometabolic risk factors such as systolic hypertension and inflammation. While participants with T2D had lower CRF than those without T2D, the difference was not statistically significant. Furthermore, as physical activity is inversely associated with IHL independent of BMI , only inactive participants were included in this study in an attempt to control for higher levels of physical activity - which incur cardioprotective benefits. Because of this, the mean level of CRF of participants was quite low at 21.5 mL/kg/min. As reports show that CRF < 29.1 mL/kg/min increases the likelihood of developing metabolic syndrome six-fold , a greater number of participants with higher levels of CRF are required to provide more robust results.
While the mechanistic interplay between low CRF, MAFLD, and T2D remains unclear, it is purported that the incomplete oxidation of fatty acids in the mitochondria may contribute to the build-up of fatty acid by-products, such as ceramides and diacylglycerol
intracellularly, which impair insulin signalling pathways and mitochondrial function and may contribute to, or be the result of, low CRF [38, 39]. Importantly, T2D-related exercise intolerance appears to be reversed by structured exercise and is made evident by the amelioration of mitochondrial impairments, increased mitochondrial content, improved insulin sensitivity, decreased IHL and increased CRF [15, 16, 40, 41].
This study has limitations that should be considered when interpreting the results. Firstly, the results of this study, by nature, incorporated measures of CRF and IHL at a time-specific point and did not track the progression of any outcome to determine their relative importance in the development of MAFLD or T2D disease progression. Secondly, this study assessed the amount of IHL% per se and the methodology employed cannot determine the amount of fibrosis or classification of more severe liver diseases such as non-alcoholic steatohepatitis and/or their association with CRF. Additionally, whilst 1H-MRS is currently considered the gold-standard non-invasive measurement technique for IHL%, HOMA-IR is comparatively more limited and cannot provide inference into tissue-specific impairments in insulin sensitivity. Thirdly, although CRF was assessed using a validated graded exercise test model , the gold-standard of aerobic capacity testing is indirect calorimetry and where possible, this method should be utilised. Finally, while an attempt was made to control for high levels of physical activity by only recruiting individuals who reported to be inactive (exercising < 3 days/week), inter-participant variations in physical activity levels likely contributed to the associations between CRF and IHL.