Insulin-mediated suppression of fatty acid release predicts whole-body insulin resistance of glucose uptake and skeletal muscle insulin receptor activation

To examine factors underlying why most, but not all adults with obesity exhibit impaired insulin-mediated glucose uptake, we compared: 1) rates of fatty acid (FA) release from adipose tissue, 2) skeletal muscle lipid droplet (LD) characteristics, and 3) insulin signaling events in skeletal muscle collected from cohorts of adults with obesity with "HIGH" versus "LOW" insulin sensitivity for glucose uptake. Seventeen adults with obesity (BMI: 36{+/-}3kg/m2) completed a 2h hyperinsulinemic-euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30min into the insulin infusion. Participants were stratified into HIGH (n=7) and LOW (n=10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW<400; HIGH>550 nmol/kgFFM/min/[{micro}U/mL]). Insulin-mediated suppression of FA Ra was lower in LOW compared with HIGH (p<0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibers was larger in LOW compared with HIGH (p=0.01). Additionally, insulin receptor (IR) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p<0.01), which aligned with attenuated insulin-mediated Tyr phosphorylation of IR{beta} and downstream insulin-signaling proteins in LOW. Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IR interaction with key regulatory proteins may be key contributors to impaired insulin-mediated glucose uptake commonly found in adults with obesity. KEY POINTSO_LIAlthough most adults with obesity exhibit impaired insulin-mediated glucose uptake (insulin resistance), some remain sensitive to insulin. Factors that "protect" adults with obesity from developing resistance to insulin-mediated glucose uptake are poorly understood. C_LIO_LIPotent suppression of fatty acid (FA) mobilization from adipose tissue by insulin is a strong predictor of whole-body insulin-mediated glucose uptake. C_LIO_LIParticipants with higher sensitivity for insulin-mediated glucose uptake had smaller intramyocellular lipid droplets (LDs) within the subsarcolemmal region of type II skeletal muscle fibers. C_LIO_LINovel findings revealed that insulin receptor (IR) interaction with the long-chain fatty acid transport protein, CD36, and the Src-family kinase, Fyn, directly associated with higher rates of glucose uptake under basal and hyperinsulinemic conditions. C_LIO_LITogether, the findings suggest impaired suppression of FA release from adipose tissue associates with reduced glucose uptake in skeletal muscle due in part to a defect in IR activation by CD36/Fyn and altered subcellular LD characteristics. C_LI