Low and high carbohydrate isocaloric diets on performance, fat oxidation, glucose and cardiometabolic health in middle age males

Abstract

High carbohydrate, low fat (HCLF) diets have been the predominant nutrition strategy for athletic performance, but recent evidence following multi-week habituation has challenged the superiority of HCLF over low carbohydrate, high fat (LCHF) diets, along with growing interest in the potential health and disease implications of dietary choice. Highly trained competitive middle-aged athletes underwent two 31-day isocaloric diets (HCLF or LCHF) in a randomized, counterbalanced, and crossover design while controlling calories and training load. Performance, body composition, substrate oxidation, cardiometabolic, and 31-day minute-by-minute glucose (CGM) biomarkers were assessed. We demonstrated: (i) equivalent high-intensity performance (@∼85%VO2max), fasting insulin, hsCRP, and HbA1c without significant body composition changes across groups; (ii) record high peak fat oxidation rates (LCHF:1.58 ± 0.33g/min @ 86.40 ± 6.24%VO2max; 30% subjects > 1.85 g/min); (iii) higher total, LDL, and HDL cholesterol on LCHF; (iv) reduced glucose mean/median and variability on LCHF. We also found that the 31-day mean glucose on HCLF predicted 31-day glucose reductions on LCHF, and the 31-day glucose reduction on LCHF predicted LCHF peak fat oxidation rates. Interestingly, 30% of athletes had 31-day mean, median and fasting glucose > 100 mg/dL on HCLF (range: 111.68-115.19 mg/dL; consistent with pre-diabetes), also had the largest glycemic and fat oxidation response to carbohydrate restriction. These results: (i) challenge whether higher carbohydrate intake is superior for athletic performance, even during shorter-duration, higher-intensity exercise; (ii) demonstrate that lower carbohydrate intake may be a therapeutic strategy to independently improve glycemic control, particularly in those at risk for diabetes; (iii) demonstrate a unique relationship between continuous glycemic parameters and systemic metabolism.

Low carbohydrate high fat ketogenic diets on the exercise crossover point and glucose homeostasis

“…However, the LCHF/ketogenic diet reduced insulin load and insulin resistance, increased whole body fat oxidation, and demonstrated directional improvements in ex-vivo mitochondrial ATP production, ATP per Gram of O 2 consumed, and ATP per Gram of H 2 O 2 produced from carbohydrates, fat, and ketones when controlling per Gram of skeletal muscle, indicating increased mitochondrial capacity and efficiency in the LCHF/ketogenic diet group relative to the HCLF diet group. Taken together, this data suggests that the record levels of fat oxidation observed in our analyses of middle-aged competitive endurance athletes ( Prins et al, 2023a ), likely did not result from shifts mitochondrial volume over the 4 weeks LCHF/ketogenic dietary protocol, but instead resulted from mitochondrial function and efficiency changes in the low insulin environment in response to the LCHF/ketogenic diet. The low insulin environment appears to be a critical contributor to these observations as low blood insulin concentrations ( Bonadonna et al, 1990 ; Campbell et al, 1992 ; Horowitz et al, 1997 ; Weltan et al, 1998 ) favor increased adipose tissue lipolysis resulting in increased FFA availability, thereby providing increased substrate in the form of FFA for enhanced skeletal muscle fat metabolism.…”

“…Gribok et al, measured 24-h minute-to-minute substrate oxidation via whole-body indirect calorimetry and glycemia utilizing continuous glucose monitoring and found excellent agreement between measures of substrate oxidation (RER), glycemia and metabolic changes in response to high and low carbohydrate meals ( Gribok et al, 2016 ) supporting the link between diet, substate oxidation, insulin and glycemia. Thus, accumulated mitochondrial machinery in concert with diet-induced changes in mitochondrial function and insulin load may explain the record levels of fat oxidation observed in Prins et al middle-aged athletes ( Prins et al, 2023a ), as well as other observations in long-standing endurance athletes with exceptionally high fat oxidation rates while consuming LCHF diets ( Volek et al, 2016 ; Burke et al, 2021 ). These shifts in mitochondrial and insulin function may also help explain how fitness level/VO 2 max ( Lohmann et al, 1978 ; Wirth et al, 1981 ; King et al, 1990 ; Solomon et al, 2015 ), exercise intensity ( Lin et al, 2022 ), carbohydrate intake ( Collier and O’Dea, 1983 ), FFA availability and oxidation, and enzymatic changes ( Lohmann et al, 1978 ; Wirth et al, 1981 ; Puchalska and Crawford, 2017 ; Puchalska and Crawford, 2021 ) influence the crossover point, as all these factors influence, or are influenced by, mitochondrial and/or insulin biology, as noted above.…”

“…Exercise duration, dietary fat intake, age, VO 2 max, and percentage of type 1 muscle fiber all were associated with decreased RER, while dietary carbohydrate intake, exercise intensity, male sex, and carbohydrate intake before and during exercise increased RER. While these factors are important considerations on substrate oxidation and account for 36%–59% of RER variability in these models, it is important to denote that multiple studies have controlled for some, or all, of these variables and still demonstrate robust alteration of substrate oxidation with habituation to LCHF diets when directly assessing these effects in randomized controlled trials ( Prins et al, 2023a ). Additionally, insulin may also explain why many of these cited factors altered cross-over kinetics (i.e., fitness level/VO 2 max ( Lohmann et al, 1978 ; Wirth et al, 1981 ; King et al, 1990 ; Solomon et al, 2015 ), exercise intensity ( Lin et al, 2022 ), carbohydrate intake ( Collier and O’Dea, 1983 ), FFA availability and oxidation, and enzymatic changes ( Puchalska and Crawford, 2017 ; Puchalska and Crawford, 2021 ), as discussed below.…”

“…The most recent publication of Prins et al (2023a) provides more evidence of these paradoxical findings. They studied a group of highly trained recreationally competitive athletes who completed a 1609 m time trial (TT) and subsequently a high-intensity interval running session (6 × 800 m) on a laboratory treadmill following 4 weeks/31 days of adaptation to both the HCLF and LCHF diets.…”

“…It is known that endurance exercise training increases mitochondrial size, number, and oxidative activity in a dose-dependent manner (i.e., training volume) contributing to improved whole-body glucose metabolism ( Holloszy, 1967 ; Holloszy and Coyle, 1984 ; Constable et al, 1987 ; Kim et al, 2008 ; Bishop et al, 2019 ). Prins et al cohort was very fit competitive endurance athletes (VO 2 max: top 5% ( Rapp et al, 2018 )) with high endurance training volume (running: 50 km/week; 10 years) in their middle age, with considerable capacity to accumulate mitochondrial size and number for maximizing potential substrate oxidation ( Prins et al, 2023a ). Dietary strategies which dramatically lower insulin (i.e., LCHF/ketogenic diets) have been demonstrated to increase molecular markers of skeletal muscle mitochondrial biogenesis (i.e., PGC-1α; TFAM ( Kim et al, 2008 ; Bishop et al, 2019 )) in pre-clinical models over a short duration (3 weeks) independent of exercise ( Huang et al, 2021 ).…”