Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity

TY - JOUR

T1 - Direct effects of FGF21 on glucose uptake in human skeletal muscle

T2 - implications for type 2 diabetes and obesity

AU - Mashili, Fredirick L

AU - Austin, Reginald L

AU - Deshmukh, Atul S

AU - Fritz, Tomas

AU - Caidahl, Kenneth

AU - Bergdahl, Katrin

AU - Zierath, Juleen R

AU - Chibalin, Alexander V

AU - Moller, David E

AU - Kharitonenkov, Alexei

AU - Krook, Anna

N1 - Copyright © 2011 John Wiley & Sons, Ltd.

PY - 2011/3

Y1 - 2011/3

N2 - Background: Fibroblast growth factor (FGF) 21, a novel member of the FGF family, plays a role in a variety of endocrine functions, including regulation of glucose and lipid metabolism. The role of FGF21 in skeletal muscle is currently not known. +Methods: Serum levels and skeletal muscle mRNA of FGF21 were determined in normal glucose tolerant (n = 40) and type 2 diabetic (T2D; n = 40) subjects. We determined whether FGF21 has direct effects on glucose metabolism in cultured myotubes (n = 8) and extensor digitorum longus skeletal muscle. +Results: Serum FGF21 levels increased 20% in T2D versus normal glucose tolerant subjects (p < 0.05), whereas skeletal muscle mRNA expression was unaltered. Fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), waist circumference, and body mass index (BMI) significantly correlated with serum FGF21 levels in T2D (p < 0.01), but not in normal glucose tolerant subjects. Serum FGF21 concentrations were greater in T2D patients in the highest tertile of fasting insulin (p < 0.05) and BMI (p < 0.05). Stepwise regression analysis identified BMI as the strongest independent variable correlating with FGF21. FGF21 exposure increased basal and insulin-stimulated glucose uptake in human myotubes, coincident with increased glucose transporter 1 mRNA, and enhanced glucose transporter 1 abundance at the plasma membrane. In isolated extensor digitorum longus muscle, FGF21 potentiated insulin-stimulated glucose transport, without altering phosphorylation of Akt or AMP-activated protein kinase. +Conclusions: Plasma FGF21 is increased in T2D patients, and positively correlated with fasting insulin and BMI. However, FGF21 has direct effects in enhancing skeletal muscle glucose uptake, providing additional points of regulation that may contribute to the beneficial effects of FGF21 on glucose homeostasis. Whether increased plasma FGF21 in T2D is a compensatory mechanism to increase glucose metabolism remains to be determined.

AB - Background: Fibroblast growth factor (FGF) 21, a novel member of the FGF family, plays a role in a variety of endocrine functions, including regulation of glucose and lipid metabolism. The role of FGF21 in skeletal muscle is currently not known. +Methods: Serum levels and skeletal muscle mRNA of FGF21 were determined in normal glucose tolerant (n = 40) and type 2 diabetic (T2D; n = 40) subjects. We determined whether FGF21 has direct effects on glucose metabolism in cultured myotubes (n = 8) and extensor digitorum longus skeletal muscle. +Results: Serum FGF21 levels increased 20% in T2D versus normal glucose tolerant subjects (p < 0.05), whereas skeletal muscle mRNA expression was unaltered. Fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), waist circumference, and body mass index (BMI) significantly correlated with serum FGF21 levels in T2D (p < 0.01), but not in normal glucose tolerant subjects. Serum FGF21 concentrations were greater in T2D patients in the highest tertile of fasting insulin (p < 0.05) and BMI (p < 0.05). Stepwise regression analysis identified BMI as the strongest independent variable correlating with FGF21. FGF21 exposure increased basal and insulin-stimulated glucose uptake in human myotubes, coincident with increased glucose transporter 1 mRNA, and enhanced glucose transporter 1 abundance at the plasma membrane. In isolated extensor digitorum longus muscle, FGF21 potentiated insulin-stimulated glucose transport, without altering phosphorylation of Akt or AMP-activated protein kinase. +Conclusions: Plasma FGF21 is increased in T2D patients, and positively correlated with fasting insulin and BMI. However, FGF21 has direct effects in enhancing skeletal muscle glucose uptake, providing additional points of regulation that may contribute to the beneficial effects of FGF21 on glucose homeostasis. Whether increased plasma FGF21 in T2D is a compensatory mechanism to increase glucose metabolism remains to be determined.

KW - Animals

KW - Body Mass Index

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Fibroblast Growth Factors

KW - Glucose

KW - Glucose Transporter Type 1

KW - Humans

KW - Insulin

KW - Male

KW - Mice

KW - Middle Aged

KW - Muscle, Skeletal

KW - Obesity

KW - RNA, Messenger

KW - Signal Transduction

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/dmrr.1177

DO - 10.1002/dmrr.1177

M3 - Journal article

C2 - 21309058

SN - 1520-7552

VL - 27

SP - 286

EP - 297

JO - Diabetes - Metabolism: Research and Reviews (Print Edition)

JF - Diabetes - Metabolism: Research and Reviews (Print Edition)

IS - 3

ER -