Insulin resistance in type 2 diabetes youth relates to serum free fatty acids and muscle mitochondrial dysfunction

Abstract

Aims: Insulin resistance (IR) correlates with mitochondrial dysfunction, free fatty acids (FFAs), and intramyocellular lipid (IMCL) in adults with type 2 diabetes (T2D). We hypothesized that muscle IR would relate to similar factors in T2D youth.

Methods: Participants included 17 youth with T2D, 23 normal weight controls (LCs), and 26 obese controls (OBs) of similar pubertal stage and activity level.

Results: T2D and OB groups were of similar BMI. T2D youth were significantly more IR and had higher calf IMCL and serum FFA concentrations during hyperinsulinemia. ADP time constant (ADPTC), a blood-flow dependent mitochondrial function measure, was slowed and oxidative phosphorylation rates lower in T2D. In multiple linear regression of the entire cohort, lack of FFA suppression and longer ADPTC, but not IMCL or HbA1c, were independently associated with IR.

Conclusion: We found that elevated FFAs and mitochondrial dysfunction are early abnormalities in relatively well-controlled youth with T2D. Further, post-exercise oxidative metabolism appears affected by reduced blood flow, and is not solely an inherent mitochondrial defect. Thus, lowering FFAs and improving mitochondrial function and blood flow may be potential treatment targets in youth with T2D.

Keywords: Adolescents; Free fatty acids; Insulin resistance; Mitochondrial function; Type 2 diabetes.

Fig. 1

Average muscle metabolite concentrations before, during, and following exercise. Metabolite concentrations before, during and after 70% exercise are shown: A) shows inorganic phosphate, B) phosphocreatine concentrations, C) ADP D) intracellular pH. Metabolite concentrations before during and after 45% exercise are shown in: E) inorganic phosphate, F) phosphocreatine concentrations, G) ADP H) intracellular pH.

Fig. 2

Plantar flexion force before, during, and after 70% and 45% exercise. Plantar flexion force of the soleus and gastrocnemius muscles before, during, and after 70% and 45% exercise.