TY - JOUR

T1 - Insulin-Stimulated Muscle Glucose Uptake and Insulin Signaling in Lean and Obese Humans

AU - Ramos, Paola A.

AU - Lytle, Kelli A.

AU - Delivanis, Danae

AU - Nielsen, Søren

AU - LeBrasseur, Nathan K.

AU - Jensen, Michael D.

N1 - Publisher Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2021/4

Y1 - 2021/4

N2 - PURPOSE: Skeletal muscle is the primary site for insulin-stimulated glucose disposal, and muscle insulin resistance is central to abnormal glucose metabolism in obesity. Whether muscle insulin signaling to the level of Akt/AS160 is intact in insulin-resistant obese humans is controversial. METHODS: We defined a linear range of insulin-stimulated systemic and leg glucose uptake in 14 obese and 14 nonobese volunteers using a 2-step insulin clamp (Protocol 1) and then examined the obesity-related defects in muscle insulin action in 16 nonobese and 25 obese male and female volunteers matched for fitness using a 1-step, hyperinsulinemic, euglycemic clamp coupled with muscle biopsies (Protocol 2). RESULTS: Insulin-stimulated glucose disposal (Si) was reduced by > 60% (P < 0.0001) in the obese group in Protocol 2; however, the phosphorylation of Akt and its downstream effector AS160 were not different between nonobese and obese groups. The increase in phosphorylation of Akt2 in response to insulin was positively correlated with Si for both the nonobese (r = 0.53, P = 0.03) and the obese (r = 0.55, P = 0.01) groups. Total muscle GLUT4 protein was 17% less (P < 0.05) in obese subjects. CONCLUSIONS: We suggest that reduced muscle glucose uptake in obesity is not due to defects in the insulin signaling pathway at the level of Akt/AS160, which suggests there remain significant gaps in our knowledge of muscle insulin resistance in obesity. Our data imply that models of acute lipotoxicity do not replicate the pathophysiology of obesity.

AB - PURPOSE: Skeletal muscle is the primary site for insulin-stimulated glucose disposal, and muscle insulin resistance is central to abnormal glucose metabolism in obesity. Whether muscle insulin signaling to the level of Akt/AS160 is intact in insulin-resistant obese humans is controversial. METHODS: We defined a linear range of insulin-stimulated systemic and leg glucose uptake in 14 obese and 14 nonobese volunteers using a 2-step insulin clamp (Protocol 1) and then examined the obesity-related defects in muscle insulin action in 16 nonobese and 25 obese male and female volunteers matched for fitness using a 1-step, hyperinsulinemic, euglycemic clamp coupled with muscle biopsies (Protocol 2). RESULTS: Insulin-stimulated glucose disposal (Si) was reduced by > 60% (P < 0.0001) in the obese group in Protocol 2; however, the phosphorylation of Akt and its downstream effector AS160 were not different between nonobese and obese groups. The increase in phosphorylation of Akt2 in response to insulin was positively correlated with Si for both the nonobese (r = 0.53, P = 0.03) and the obese (r = 0.55, P = 0.01) groups. Total muscle GLUT4 protein was 17% less (P < 0.05) in obese subjects. CONCLUSIONS: We suggest that reduced muscle glucose uptake in obesity is not due to defects in the insulin signaling pathway at the level of Akt/AS160, which suggests there remain significant gaps in our knowledge of muscle insulin resistance in obesity. Our data imply that models of acute lipotoxicity do not replicate the pathophysiology of obesity.

KW - Akt signaling

KW - glucose uptake

KW - insulin clamp

KW - insulin resistance

KW - obesity

KW - skeletal muscle

KW - PROTEIN-KINASE-C

KW - PHOSPHORYLATION

KW - GLUCOSE-TRANSPORTER-4 GLUT4

KW - FREE FATTY-ACID

KW - GLYCOGEN-SYNTHASE

KW - SKELETAL-MUSCLE

KW - SUBSTRATE-SPECIFICITY

KW - GLUT4 TRANSLOCATION

KW - IN-VIVO

KW - RESISTANCE

KW - Humans

KW - Male

KW - Obesity/metabolism

KW - Insulin/metabolism

KW - Adult

KW - Female

KW - Glucose/metabolism

KW - Signal Transduction

KW - Muscle, Skeletal/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85103606695&partnerID=8YFLogxK

U2 - 10.1210/clinem/dgaa919

DO - 10.1210/clinem/dgaa919

M3 - Journal article

C2 - 33382888

AN - SCOPUS:85103606695

VL - 106

SP - e1631-e1646

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 4

ER -