Insulin Sensitivity and Metabolic Flexibility Parallel Plasma TCA Levels in Early Chronotype With Metabolic Syndrome

Abstract

Context: People characterized as late chronotype have elevated type 2 diabetes and cardiovascular disease risk compared to early chronotype. It is unclear how chronotype is associated with insulin sensitivity, metabolic flexibility, or plasma TCA cycle intermediates concentration, amino acids (AA), and/or beta-oxidation.

Objective: This study examined these metabolic associations with chronotype.

Methods: The Morningness-Eveningness Questionnaire (MEQ) was used to classify adults with metabolic syndrome (ATP III criteria) as either early (n = 15 [13F], MEQ = 64.7 ± 1.4) or late (n = 19 [16F], MEQ = 45.5 ± 1.3) chronotype. Fasting bloods determined hepatic (HOMA-IR) and adipose insulin resistance (Adipose-IR) while a 120-minute euglycemic clamp (40 mU/m2/min, 5 mmoL/L) was performed to test peripheral insulin sensitivity (glucose infusion rate). Carbohydrate (CHOOX) and fat oxidation (FOX), as well as nonoxidative glucose disposal (NOGD), were also estimated (indirect calorimetry). Plasma tricarboxylic acid cycle (TCA) intermediates, AA, and acyl-carnitines were measured along with VO2max and body composition (DXA).

Results: There were no statistical differences in age, BMI, fat-free mass, VO2max, or ATP III criteria between groups. Early chronotype, however, had higher peripheral insulin sensitivity (P = 0.009) and lower HOMA-IR (P = 0.02) and Adipose-IR (P = 0.05) compared with late chronotype. Further, early chronotype had higher NOGD (P = 0.008) and greater insulin-stimulated CHOOX (P = 0.02). While fasting lactate (P = 0.01), TCA intermediates (isocitrate, α-ketoglutarate, succinate, fumarate, malate; all P ≤ 0.04) and some AA (proline, isoleucine; P = 0.003-0.05) were lower in early chronotype, other AA (threonine, histidine, arginine; all P ≤ 0.05) and most acyl-carnitines were higher (P ≤ 0.05) compared with late chronotype.

Conclusion: Greater insulin sensitivity and metabolic flexibility relates to plasma TCA concentration in early chronotype.

Trial registration: ClinicalTrials.gov NCT03355469.

Keywords: acyl-carnitines; amino acids; fat metabolism; obesity; substrate oxidation; type 2 diabetes.