Free fatty acids, glicentin and glucose-dependent insulinotropic polypeptide as potential major determinants of fasting substrate oxidation

The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calorimetry as a read-out for substrate oxidation following an overnight fast. This cross-sectional analysis consisted of 192 (92 women, 100 men) either lean or obese participants. Following an overnight fast, the respiratory quotient (RQ) was assessed, after which a 5-point 75-g oral glucose tolerance test was performed. Unlike glucose and insulin, fasting free fatty acids (FFA) correlated negatively with fasting RQ (p < 0.0001). Participants with high levels of the ketone body β-hydroxybutyric acid had significantly lower RQ values. Fasting levels of glucose-dependent insulinotropic polypeptide (GIP) and glicentin were positively associated with fasting RQ (all p ≤ 0.03), whereas GLP-1 showed no significant association. Neither BMI, nor total body fat, nor body fat distribution correlated with fasting RQ. No relationship between the RQ and diabetes or the metabolic syndrome could be observed. In the fasting state, FFA concentrations were strongly linked to the preferentially oxidized substrate. Our data did not indicate any relationship between fasting substrate oxidation and metabolic diseases, including obesity, diabetes, and the metabolic syndrome. Since glicentin and GIP are linked to fuel selection in the fasting state, novel therapeutic approaches that target these hormones may have the potential to modulate substrate oxidation.