Relationships between Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes Mellitus

• Published in: PloS one Vol. 8; no. 2; p. e51648
• Main Authors: van de Weijer, Tineke, Sparks, Lauren Marie, Phielix, Esther, Meex, Ruth Carla, van Herpen, Noud Antonius, Hesselink, Matthijs Karel C., Schrauwen, Patrick, Schrauwen-Hinderling, Vera Bettina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.02.2013; Public Library of Science (PLoS)
• Subjects: Aged; Automation; Biology; Biopsy; Blood Glucose - metabolism; Calorimetry; Control methods; Defects; Development and progression; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - metabolism; Diabetes therapy; Diabetics; Etiology; Exercise; Fatty acids; Fatty Acids, Nonesterified - metabolism; Flexibility; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Lipid Metabolism - physiology; Lipids; Male; Medicine; Metabolism; Middle Aged; Mitochondria; Mitochondria - metabolism; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Nutrition research; Obesity; Obesity - metabolism; Oxidation; Patients; Respiration; Skeletal muscle; Studies; Substrates; Toxicology; Type 2 diabetes; Weight control; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0051648

Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects. 49 non-insulin dependent male T2D patients and 54 male control subjects were enrolled, and a hyperinsulinemic-euglycemic clamp and indirect calorimetry were performed. A muscle biopsy was taken and intramyocellular lipid (IMCL) was measured. In vivo mitochondrial function was measured by PCr recovery in 30 T2D patients and 31 control subjects. Fasting NEFA levels were significantly elevated in T2D patients compared with controls, but IMCL was not different. Mitochondrial function in T2D patients was compromised by 12.5% (p<0.01). Whole body glucose disposal (WGD) was higher at baseline and lower after insulin stimulation. Metabolic flexibility (ΔRER) was lower in the type 2 diabetic patients (0.050±0.033 vs. 0.093±0.050, p<0.01). Mitochondrial function was the sole predictor of basal respiratory exchange ratio (RER) (R(2) = 0.18, p<0.05); whereas WGD predicted both insulin-stimulated RER (R(2) = 0.29, p<0.001) and metabolic flexibility (R(2) = 0.40, p<0.001). These results indicate that defects in skeletal muscle in vivo mitochondrial function in type 2 diabetic patients are only reflected in basal substrate oxidation and highlight the importance of glucose disposal rate as a determinant of substrate utilization in response to insulin.