Fasting Metabolic Flexibility in Prediabetes

Metabolic flexibility cannot be easily clinically assessed, but the respiratory exchange ratio (RER) measured via indirect calorimetry can indicate substrate utilization. When indirect calorimetry is performed to measure resting metabolic rate, a normal RER should reflect a lipolytic metabolism (close to 0.7). We aimed to describe fasting glucose metabolism in relation to RER in patients seeking a nutritional intervention. In 10175 patients (7,222 (71%) females, median (quartiles) age of 46 (36, 55) years, and BMI of 28.3 (25.0, 32.3) kg/m2) a greater RER was associated with higher fasting values of glucose, insulin and higher insulin resistance (HOMA-IR), controlling for sex, age, and BMI (differences going from a RER of 0.7 to 1 RER for glucose 1.7 (95% CI 0.66, 2.8; p=0.002), for insulin 1.9 (95% CI 1.3, 2.6; p=<0.001), and for HOMA-IR 0.49 (95% CI 0.32, 0.66; p=<0.001)). As an higher RER relates to an altered glucose metabolism, within the whole sample we selected patients with prediabetes with 1 year follow-up. We matched 86 patients having either a RER indicating a lipolytic metabolism (<0.775) or glycolytic metabolism (>0.925). Patients were matched for sex, age, BMI, waist circumference, and arm muscle area. The high RER group had a lower probability of normalizing fasting glucose level within 1 year (log(OR) -0.89 (95% CI -1.8,-0.03; p=0.046)), with higher fasting glucose levels at followup (5.4 (95% CI 0.98, 9.9; p=0.017)). Moreover, while losing similar weight than the low RER group (-0.55 (95% CI -3.7, 2.6; p=0.7)), they lost a lower amount of fat mass (1.2 (95% CI 0.02, 2.4; p=0.047)). Our results suggest than an higher RER relates to a dysfunctional glycolytic metabolism at rest. We also show that prediabetic patients with higher RER are more likely to not respond to a lifestyle intervention, warranting a more intensive treatment for this subgroup. This lower probability of success doesn’t seem related to a lower adherence to the proscription, as weight loss was similar across RER categories, but to a lower weight loss quality. Disclosure A.Foppiani: None. R.De amicis: None. A.Leone: None. S.Bertoli: None. A.Battezzati: None. Funding Italian National Recovery and Resilience Plan Mission 4 Component 2 Investment 1.3 Call for Proposals (341) of 15 March 2022 of Italian Ministry of University and Research funded by the European Union - NextGenerationEU (PE00000003) Concession Decree (1550) of 11 October 2022 adopted by the Italian Ministry of University and Research (CUP D93C22000890001)