Intracellular lactate- and pyruvate-interconversion rates are increased in muscle tissue of non-insulin-dependent diabetic individuals

Abstract

The contribution of muscle tissues of non-insulin-dependent diabetes mellitus (NIDDM) patients to blood lactate appearance remains undefined. To gain insight on intracellular pyruvate/lactate metabolism, the postabsorptive forearm metabolism of glucose, lactate, FFA, and ketone bodies (KB) was assessed in seven obese non-insulin-dependent diabetic patients (BMI = 28.0±0.5 kg/m2) and seven control individuals (BMI = 24.8±0.5 kg/m2) by using arteriovenous balance across forearm tissues along with continuous infusion of [3-13C1]-lactate and indirect calorimetry. Fasting plasma concentrations of glucose (10.0±0.3 vs. 4.7±0.2 mmol/liter), insulin (68±5 vs. 43±6 pmol/liter), FFA (0.57±0.02 vs. 0.51±0.02 mmol/liter), and blood levels of lactate (1.05±0.04 vs. 0.60±0.06 mmol/liter), and KB (0.48±0.04 vs. 0.29±0.02 mmol/liter) were higher in NIDDM patients (P < 0.01). Forearm glucose uptake was similar in the two groups (10.3±1.4 vs. 9.6±1.1 μmol/min/liter of forearm tissue), while KB uptake was twice as much in NIDDM patients as compared to control subjects. Lactate balance was only slightly increased in NIDDM patients (5.6±1.4 vs. 3.3±1.0 μmol/min/liter; P = NS). A two-compartment model of lactate and pyruvate kinetics in the forearm tissue was used to dissect out the rates of lactate to pyruvate and pyruvate to lactate interconversions. In spite of minor differences in the lactate balance, a fourfold increase in both lactate- (44.8±9.0 vs. 12.6±4.6 μmol/min/liter) and pyruvate- (50.4±9.8 vs. 16.0±5.0 μmol/min/liter) interconversion rates (both P < 0.01) were found. Whole body lactate turnover, assessed by using the classic isotope dilution principle, was higher in NIDDM individuals (46±9 vs. 21±3 μmol/min/kg; P < 0.01). Insights into the physiological meaning of this parameter were obtained by using a whole body non-compartmental model of lactate/pyruvate kinetics which provides a lower and upper bound for total lactate and pyruvate turnover (NIDDM = 46±9 108±31; controls = 21±3 - 50±13 μmol/min/kg). In conclusion, in the postabsorptive state, despite a trivial lactate release by muscle, lactate- and pyruvate-interconversion rates are greatly enhanced in NIDDM patients, possibly due to concomitant impairment in the oxidative pathway of glucose metabolism. This finding strongly suggest a major disturbance in intracellular lactate/pyruvate metabolism in NIDDM.