Optimizing measures of insulin-regulated lipolysis in humans

The goals of these studies were to test for errors in measuring the insulin concentration resulting in 50% suppression from baseline free fatty acid palmitate rate of appearance (FFA_palmitate IC₅₀) when measured with a two-step, euglycemic, hyperinsulinemic clamp (EHC). We also determined the reproducibility of FFA_palmitate IC₅₀ in weight-stable adults and assessed the magnitude of the change in FFA_palmitate IC₅₀ in response to weight loss. To accomplish this, we analyzed data from 46 studies of 27 volunteers enrolled in two ongoing clinical research studies that included weight loss by lifestyle intervention or bariatric surgery. FFA palmitate kinetics were measured using an intravenous infusion of [U-¹³C]palmitate under basal (fasting) and a two-step EHC. For 40 of 46 studies, calculating FFA_palmitate IC₅₀ using data from both steps of a EHC overestimated FFA_palmitate IC₅₀ compared with the first (low) dose, which suppressed palmitate Ra by > 50%. FFA_palmitate IC₅₀ did not change and was reproducible after 4 mo (r = 0.70, P = 0.02) for 10 weight-stable volunteers. Weight loss by either intervention reduced FFA_palmitate IC₅₀, and the reduction was correlated with fat loss and change in adipocyte size. We conclude that, although a two-step EHC (with an initial low dose) allows accurate assessment of FFA_palmitate IC₅₀, careful scrutiny of each set of study data is needed. These data will improve the ability of investigators to design studies that can detect small but important differences or changes in adipose tissue insulin action. NCT clinical trial numbers NCT03866408 and NCT03868592.NEW & NOTEWORTHY Accurate measures of insulin regulation of adipose tissue lipolysis (free fatty acid release rates) in humans can be accomplished using a two-step, hyperinsulinemic clamp experimental design, but careful scrutiny of the data is needed. The FFA_palmitate IC₅₀ measure is reproducible in weight-stable adults and responds to treatment interventions in a quantitative manner.