Effects of exogenous lactate on lipid, protein, and glucose metabolism-a randomized crossover trial in healthy males

Abstract

Lactate may inhibit lipolysis and thus enhance insulin sensitivity, but there is a lack of metabolic human studies. This study aimed to determine how hyperlactatemia affects lipolysis, glucose- and protein metabolism, and insulin sensitivity in healthy men. In a single-blind, randomized, crossover design, eight healthy men were studied after an overnight fast on two occasions: 1) during a sodium-lactate infusion (LAC) and 2) during a sodium-matched NaCl infusion (CTR). Both days consisted of a 3-h postabsorptive period followed by a 3-h hyperinsulinemic-euglycemic clamp (HEC). Lipolysis rate, endogenous glucose production (EGP), and delta glucose rate of disappearance (ΔRd_glu) were evaluated using [9,10-³H]palmitate and [3-³H]glucose tracers. In addition, whole body- and forearm protein metabolism was assessed using [¹⁵N]phenylalanine, [²H₄]tyrosine, [¹⁵N]tyrosine, and [¹³C]urea tracers. In the postabsorptive period, plasma lactate increased to 2.7 ± 0.5 mmol/L during LAC vs. 0.6 ± 0.3 mmol/L during CTR (P < 0.001). In the postabsorptive period, palmitate flux was 30% lower during LAC compared with CTR (84 ± 32 µmol/min vs. 120 ± 35 µmol/min, P = 0.003). During the HEC, palmitate flux was suppressed similarly during both interventions (P = 0.7). EGP, ΔRd_glu, and M value were similar during LAC and CTR. During HEC, LAC increased whole body phenylalanine flux (P = 0.02) and protein synthesis (P = 0.03) compared with CTR; LAC did not affect forearm protein metabolism compared with CTR. Lactate infusion inhibited lipolysis by 30% under postabsorptive conditions but did not affect glucose metabolism or improve insulin sensitivity. In addition, whole body phenylalanine flux was increased. Clinical trial registrations: NCT04710875.NEW & NOTEWORTHY Lactate is a decisive intermediary metabolite, serving as an energy substrate and a signaling molecule. The present study examines the effects of lactate on substrate metabolism and insulin sensitivity in healthy males. Hyperlactatemia reduces lipolysis by 30% without affecting insulin sensitivity and glucose metabolism. In addition, hyperlactatemia increases whole body amino acid turnover rate.

Keywords: energy expenditure; insulin sensitivity; lactate; lipolysis; protein metabolism.

Graphical abstract

Figure 1.

Study day flowchart. CTR, control (sodium-matched NaCl infusion); LAC, lactate (sodium-lactate infusion). Created with BioRender.com

Figure 2.

Lactate concentration. Mean plasma l-lactate concentrations ±SD (n = 8). CTR, control (sodium-matched NaCl infusion); LAC, lactate (sodium-lactate infusion).

Figure 3.

Palmitate flux. Palmitate flux (μmol/min) in the postabsorptive state (A) (n = 7, due to technical issues with the palmitate infusion in one volunteer) and during the hyperinsulinemic-euglycemic clamp (HEC, B) (n = 8). CTR, control (sodium-matched NaCl infusion); LAC, lactate (sodium-lactate infusion).

Figure 4.

Glucose kinetics and insulin sensitivity. A: endogenous glucose production by the end of the postabsorptive period and the hyperinsulinemic-euglycemic clamp (HEC). Postabsorptive, n = 7; HEC, n = 6. B: glucose rate of disappearance (Rd_glu) by the end of the postabsorptive period and the hyperinsulinemic-euglycemic clamp (HEC). Postabsorptive, n = 7, HEC, n = 7. C: ΔRd_glu between the postabsorptive period and the HEC, n = 6. D: insulin sensitivity (M value), n = 8. All missing data were due to technical issues with the [3-³H]glucose infusion. In A and B, P values are based on the mixed model with time, intervention, and interaction between the two as fixed effects and participants as random effect. “Interaction, P” indicates the P value for the interaction between time and intervention, “intervention, P” indicates the P value for the effect of the intervention, “time, P” indicates the P value for the effect of time. P values between boxplots within a and b represent post hoc pairwise comparisons based on the model. In C and D, P values represent paired t tests as there was only one ΔRd_glu and M value from each study day. CTR, control (sodium-matched NaCl infusion); LAC, lactate (sodium-lactate infusion).

Figure 5.

Whole body amino acid and urea kinetics. Phenylalanine flux (A), phenylalanine hydroxylation to tyrosine (B), protein synthesis (C), phenylalanine net balance (D), urea flux (E). P values are based on the mixed model with time, intervention, and interaction between the two as fixed effects and participants as random effect. “Interaction, P” indicates the P value for the interaction between time and intervention, “intervention, P” indicates the P value for the effect of the intervention, and “time, P” indicates the P value for the effect of time. P values between boxplots within a and b represent post hoc pairwise comparisons based on the model. n = 8. CTR, control (sodium-matched NaCl infusion); HEC, hyperinsulinemic-euglycemic clamp; LAC, lactate (sodium-lactate infusion); Q_phe, phenylalanine flux; Q_pt, phenylalanine to tyrosine hydroxylation; Q_urea, urea flux; S_p, protein synthesis.

Figure 6.

Forearm phenylalanine kinetics. Phenylalanine rate of appearance (A), phenylalanine rate of disappearance (B), phenylalanine net balance (C). P values are based on the repeated-measures mixed model with time, intervention, and interaction between the two as fixed effects and participants as random effect. “Interaction, P” indicates the P value for the interaction between time and intervention, “intervention, P” indicates the P value for the effect of the intervention, and “time, P” indicates the P value for the effect of time. P values between boxplots within a and b represent post hoc pairwise comparisons based on the model. All measures in the postabsorptive period, n = 8; measures during hyperinsulinemic-euglycemic clamp (HEC) with control (CTR, sodium-matched NaCl infusion), n = 7, because of saline sample dilution at the time of sample drawing for n = 1. LAC, lactate (sodium-lactate infusion); Ra, rate of appearance; Rd, rate of disappearance.

Figure 7.

HCO₃⁻ concentration. Mean HCO₃⁻ concentrations ± SD [n = 7 for lactate (LAC, sodium-lactate infusion) and n = 8 for control (CTR, sodium-matched NaCl infusion)].

Figure A1.

Consort flow diagram.