Impaired Skeletal Muscle Mitochondrial Efficiency in People with Type 1 Diabetes

Abstract

Mitochondrial dysfunction precedes diabetic complications in people with type 1 diabetes mellitus (T1D). Mitochondrial oxidative capacity, a product of energy production efficiency, oxygen consumption, and mitochondrial density, is critical for glycemic control and overall physical functioning. Compared to healthy people, oxidative capacity is reduced in people with T1D, despite similar mitochondrial density. The influence of mitochondrial energy production efficiency and oxygen consumption on mitochondrial oxidative capacity in vivo remains unknown.PURPOSETo test the hypothesis that muscle oxygen consumption is increased and mitochondrial efficiency is reduced in people with T1D.METHODS10 people with type 1 diabetes (T1D; Age: 24 ± 1yrs, BMI: 24.3 ± 0.9 kg/m2) and 10 demographically matched healthy controls (CON; Age: 27 ± 1yrs, BMI: 25.6 ± 1.7 kg/m2) participated in this study. A venous blood sample was collected to assess glycemic control (HbA1c) and hemoglobin values. Near infrared spectroscopy (NIRS) was used to assess changes in oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin/myoglobin of the gastrocnemius following 15s of electrical stimulation and multiple rapid arterial occlusions. To calculate the phosphocreatine (PCr) recovery rate constant (kPCr), an index of mitochondrial oxidative capacity, post‐stimulation measurements were fit to a monoexponential curve. Muscle oxygen consumption (mVO2 = abs[([ΔO2Hb – Δ HHb]/2] x 60)/(10 x 1.04) x4] x 22.4/1000) was calculated for each occlusion and the slopes of the total hemoglobin (tHb = O2Hb+HHb) signal following each occlusion were converted to muscle blood flow [mBF = 1/hemoglobin (mmol/L) x ΔtHb/Δtime]. To calculate mitochondrial efficiency (MEff), the mVO2 necessary to achieve the measured kPcr at 100% efficiency was estimated (mVO2estimated = kPcr/100) and divided by the measured mVO2 [Meff = (mVO2estimated/mVO2observed) x 100].RESULTSHbA1c was significantly different between groups (T1D: 9.0 ± 0.8 vs. CON: 5.2 ± 0.2%; p=0.001). HbA1c was associated with MEff (r= −0.542, p=0.017), mVO2 (r= 0.522, p=0.022), and kPCr (r= −0.458, p=0.049). MEff was significantly lower in T1D (27.7 ± 0.1%) compared to CON (CON: 65.1 ± 0.1%; p=0.002) and was associated with mVO2 (r= −0.631, p=0.003) and kPcr (r= 0.762, p<0.001). Average mVO2 was significantly greater in T1D compared to CON (T1D: 0.05 ± 0.012 vs. CON: 0.03 ± 0.005 mLO2/min/100g; p=0.044); however, average mBF was similar between groups (T1D: 0.05 ± 0.01 vs. CON: 0.08 ± 0.03 mL/min/100mL; p=0.224).CONCLUSIONMuscle oxygen consumption is elevated and mitochondrial efficiency is reduced in people with type 1 diabetes compared to controls. In addition, greater mitochondrial efficiency contributes to lower muscle oxygen demand and greater oxidative capacity, all of which are positively associated with tighter glycemic control. Taken together, these results suggest that impaired mitochondrial efficiency contributes to skeletal muscle mitochondrial dysfunction in people with type 1 diabetes.Support or Funding Information1R01HL137087‐01A1