Increased plasma fatty acid clearance, not fatty acid concentration, is associated with muscle insulin resistance in people with obesity

Abstract

Background: Although it is well-accepted that increased plasma free fatty acid (FFA) concentration causes lipid overload and muscle insulin resistance in people with obesity, plasma FFA concentration poorly predicts insulin-resistant glucose metabolism. It has been proposed that hyperinsulinemia in people with obesity sufficiently inhibits adipose tissue triglyceride lipolysis to prevent FFA-induced insulin resistance. However, we hypothesized enhanced FFA clearance in people with obesity, compared with lean people, prevents a marked increase in plasma FFA even when FFA appearance is high.

Methods: We assessed FFA kinetics during basal conditions and during a hyperinsulinemic-euglycemic clamp procedure in 14 lean people and 46 people with obesity by using [¹³C]palmitate tracer infusion. Insulin-stimulated muscle glucose uptake rate was evaluated by dynamic PET-imaging of skeletal muscles after [¹⁸F]fluorodeoxyglucose injection.

Results: Plasma FFA clearance was accelerated in participants with obesity and correlated negatively with muscle insulin sensitivity without a difference between lean and obese participants. Furthermore, insulin infusion increased FFA clearance and the increase was greater in obese than lean participants.

Conclusions: Our findings suggest plasma FFA extraction efficiency, not just plasma FFA concentration, is an important determinant of the cellular fatty acid load and the stimulatory effect of insulin on FFA clearance counteracts some of its antilipolytic effect.

Trial registration: ClinicalTrials.gov NCT02994459 NCT03408613.

Keywords: Adipose tissue; Fatty acids; Insulin resistance; Obesity.

Figure 1.

Palmitate concentration in plasma (A), appearance rate in plasma (B), plasma clearance rate (D), and mean residence time in the circulation (E) during basal conditions and during the hyperinsulinemic-euglycemic clamp procedure, and clamp-induced changes in palmitate appearance rate and plasma concentration (C). Values are median and interquartile range. For the outcomes in panels A, B, D, and E, there was a significant group (lean vs obese) × condition (basal vs clamp) interaction, P < 0.001. * Significantly different from the corresponding value in the lean group, P < 0.05. ^† Significantly different from the corresponding basal value, P < 0.05.

Figure 2.

Relationships between basal plasma palmitate concentration and plasma palmitate clearance rate (A), total palmitate disappearance rate (B), and palmitate disappearance rate in relation to fat-free mass (C). Abbreviations: FFM, fat-free mass.

Figure 3.

Relationships between muscle insulin sensitivity, assessed as muscle glucose uptake rate in relation to plasma insulin concentration during the hyperinsulinemic-euglycemic clamp procedure, and basal plasma palmitate concentration (A), plasma palmitate clearance rate (B), and palmitate disappearance rate from plasma (C). Abbreviations: MGU/I, muscle glucose uptake rate in relation to plasma insulin concentration; Rd, disappearance rate.