Increased plasma lactate levels and insulin resistance in nondiabetic adults with obesity

Introduction: Obesity is a multifactorial condition associated with chronic diseases, including type 2 diabetes. In healthy individuals without diabetes, plasma lactate positively correlates with insulin levels, suggesting lactate may serve as a marker of insulin resistance preceding diabetes. The aim of this study was to examine the association between changes in plasma lactate levels during a two-step hyperinsulinemic-euglycemic clamp (HIEC) relative to insulin sensitivity (M-value from HIEC) in adults with obesity and without diabetes. Methods: This was a cross-sectional study. Seventy-five nondiabetic participants with obesity (age: 42.7 ± 10.8 years, BMI 34.0 kg/m 2 [32.4 –39.4 kg/m 2 ]) underwent a two-step HIEC [1s stage – 120 minutes, low dose insulin at 10 mU/m 2 /min and 2nd stage – 120 minutes – high dose insulin at (40 mU/m 2 /min). The glucose infusion rate (M-value, described as mg glucose/kg FFM/min) was calculated for the last 30 min of each step. Plasma lactate levels were measured from blood samples obtained during the HIEC (baseline, last 15 minutes of each step) using an enzymatic oxygen-rate biosensor based electrochemical analyzer (LM5 Lactate Analyzer, Analox Instruments USA, Atlanta, GA). We evaluated whether lactate levels increased during HIEC. Relationships between lactate levels and M-values were examined using Spearman’s correlation coefficient. All statistical analysis were completed using R Studio with a statistical significance of p< 0.05. Results: No significant difference was observed between baseline plasma lactate level and insulin sensitivity at Step 1. Lactate increased approximately 36% from Step 1 [0.772 (0.646 – 0.986)] to Step 2 [0.987 mmol/L (0.807 – 1.230), p< 0.001]; and 43% from baseline [0.722 (0.641 – 0.915)] to Step 2 [0.987 mmol/L (0.807 – 1.230), p< 0.001]. M-values significantly increased from Step 1 to Step 2 [2.0 (1.4 – 3.0) mg/kgFFM/min to 8.0 (5.1 – 11.8) mg/kgFFM/min; p=0.018)]. Lactate levels during Step 2 were strongly and positively correlated with M-values for the same step (ρ = 0.68, p< 0.001). The change in lactate levels between baseline and Step1 positively correlated with M-value for Step 1 (ρ = 0.30, p = 0.01), changes from Step 1 to Step 2 positively correlated with M-value for Step 2 (ρ = 0.66, p < 0.001); and the change between baseline and Step 2 also correlated with M-value for Step 2 (ρ = 0.72, p < 0.001). Fasting insulin positively correlated with baseline lactate (ρ = 0.29, p = 0.012). Conclusion: In patients with obesity and without diabetes, lactate levels increased during the course of a two-step HIEC. The strong positive association between lactate and M-value at the high insulin dose suggests enhanced glycolytic activity resulting in greater glucose uptake as well as lactate production. Additional studies are needed to determine whether alterations in lactate dynamics, specifically in response to insulin, precede declines in insulin sensitivity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.