Delayed Skeletal Muscle Mitochondrial ADP Recovery in Youth With Type 1 Diabetes Relates to Muscle Insulin Resistance

Abstract

Insulin resistance (IR) increases cardiovascular morbidity and is associated with mitochondrial dysfunction. IR is now recognized to be present in type 1 diabetes; however, its relationship with mitochondrial function is unknown. We determined the relationship between IR and muscle mitochondrial function in type 1 diabetes using the hyperinsulinemic-euglycemic clamp and 31P-MRS before, during, and after near-maximal isometric calf exercise. Volunteers included 21 nonobese adolescents with type 1 diabetes and 17 nondiabetic control subjects with similar age, sex, BMI, Tanner stage, and activity levels. We found that youths with type 1 diabetes were more insulin resistant (median glucose infusion rate 10.1 vs. 18.9 mg/kglean/min; P < 0.0001) and had a longer time constant of the curve of ADP conversion to ATP (23.4 ± 5.3 vs. 18.8 ± 3.9 s, P < 0.001) and a lower rate of oxidative phosphorylation (median 0.09 vs. 0.21 mmol/L/s, P < 0.001). The ADP time constant (β = −0.36, P = 0.026) and oxidative phosphorylation (β = 0.02, P < 0.038) were related to IR but not HbA1c. Normal-weight youths with type 1 diabetes demonstrated slowed postexercise ATP resynthesis and were more insulin resistant than control subjects. The correlation between skeletal muscle mitochondrial dysfunction in type 1 diabetes and IR suggests a relationship between mitochondrial dysfunction and IR in type 1 diabetes.

Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids

“…In addition, we and others have documented decreased mitochondrial function and alterations in lipid metabolism in nondiabetic populations with IR, including burn trauma, aging, and HIV medication-related lipodystrophy (11,12,46). Most recently we found that the IR seen in type 1 diabetes, and insulinopenic state, is also related to mitochondrial dysfunction following exercise (10). Finally, defects in mitochondrial function and insulin signaling are even found in those individuals with a genetic risk for T2D prior to development of clinical hyperglycemia, indicating that mitochondrial alterations can be seen before clinical hyperglycemia, as in our participants (39).…”

“…In keeping with these findings, mitochondrial function has been shown to vary by sex (28). Many mitochondrial studies account for this by selecting to study one sex or balancing sex distribution within groups (10,27,53). However, in adults with vascular disease, once protein and muscle weight were corrected for, there were no differences in mitochondrial function per se (56).…”

“…All testing was performed fasting, with no strenuous exercise for the 3 days prior and in the follicular phase of the menstrual cycle if possible. Body composition (Hologic, Waltham, MA) was assessed by standard DEXA methods (10).…”

“…A hyperinsulinemic euglycemic clamp (80 mU·m Ϫ2 ·min Ϫ1 insulin) was performed fasting in the morning to measure IR, similar to our previously described methods (10,40). Briefly, serum glucose concentrations were maintained at ϳ95 mg/dl, based on serial blood samples drawn every 5 min, and analyzed at the bedside with a YSI (Yellow Springs Instrument, OH).…”

“…All exercise spectra were corrected for saturation using the fully relaxed spectra for that day. The jMRUi data were used to calculate the following metabolic variables as previously described (10,43). Calculations included the rates of oxidative phosphorylation (OxPhos) following exercise, creatine kinase reaction, initial PCr synthesis (VPcr), maximal mitochondrial function (Q max), and anaerobic glycolysis (AnGly).…”