The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease To the Editor: Shulman (Sept. 18 issue)1 theorized that ectopic fat plays a major role in the development of insulin resistance. We speculate, however, that insulin resistance may be caused by another major pathway, in which glucose itself, at high levels, plays a critical role. Reasonable evidence has shown that when glucose levels are elevated, glucose molecules may randomly bind to proteins similar to the insulin receptor on the plasma membrane of the cell and in time become advanced glycation end products.2 Circulating insulin levels would easily fail to dock properly with the advanced glycation end product deposited on the insulin receptor and would therefore fail to initiate the glucose-transport process, effectively causing insulin resistance.3 This pathway for glycation-induced insulin resistance would explain why insulin resistance often develops in persons who are not obese and who probably do not have substantial ectopic fat. Sang W. Shin, M.D., Ph.D. Korea University Seoul, South Korea [email protected]
Universidad Autónoma de Madrid Madrid, Spain [email protected] No potential conflict of interest relevant to this letter was reported. 1. Jope RS, Johnson GVW. The glamour and gloom of glycogen
synthase kinase-3. Trends Biochem Sci 2004;29:95-102.
Song J. Lee, Ph.D.
2. MacAulay K, Doble BW, Patel S, et al. Glycogen synthase ki-
Chungnam National University Daejeon, South Korea No potential conflict of interest relevant to this letter was reported. 1. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia,
and cardiometabolic disease. N Engl J Med 2014;371:1131-41.
2. Schalkwijk CG, Brouwers O, Stehouwer CD. Modulation of
insulin action by advanced glycation endproducts: a new player in the field. Horm Metab Res 2008;40:614-9. 3. Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. Curr Pharm Des 2008;14:987-9. DOI: 10.1056/NEJMc1412427
To the Editor: Shulman indicates that diacylglycerol (DAG) interferes with insulin-induced activation of glycogen synthase in the liver by increasing the phosphorylation of glycogen synthase kinase 3 (GSK3) (see the legend for Fig. 2 of the article). At the same time, DAG-activated protein kinase C epsilon (PKCε) inhibits the insulin receptor tyrosine kinase (the illustration for Fig. 2 of the article also features this chain of events, indicating that an increased level of phosphorylated GSK3 decreases glycogen synthesis). 2236
However, GSK3 is inactive in its phosphorylated form (owing to the activation of protein kinase B/Akt through the insulin-signaling pathway).1,2 Consequently, glycogen synthesis is induced because glycogen synthase remains dephosphorylated (and is therefore active).2 When the insulinsignaling pathway is blocked by suppression of the receptor tyrosine kinase upon the binding of PKCε, the phosphorylation of GSK3 is also suppressed,2 leading not to an increase in its phosphorylated form (as indicated by Shulman) but a decrease, leaving GSK3 dephosphorylated (i.e., active), and glycogen synthase inactive, so that glycogen synthesis diminishes. We believe that this point should be addressed in a subsequent article. Juan J. Aragón, M.D., Ph.D. Oscar H. Martínez-Costa, M.D., Ph.D.
nase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab 2007;6:329-37. DOI: 10.1056/NEJMc1412427
To the Editor: Shulman provides important information about the mechanisms by which increased storage of ectopic fat induces insulin resistance in the liver and in skeletal muscle. However, there is still limited information available on how such mechanisms affect other organs and tissues and thereby induce the development of cardiometabolic diseases. We have shown that in humans, the ectopic storage of fat in the liver, more so than skeletal muscle, is associated with impaired metabolism.1 The mechanisms of action involve hepatokines, proteins released from the steatotic liver.2 The hepatokine fetuin-A is a likely actor; its production is increased in nonalcoholic fatty liver disease, and it induces insulin resistance and subclinical inflammation in mice and humans.2,3 In addition, we can show that the relationship between circulating levels of fetuin-A and insulin resistance is particularly
n engl j med 371;23 nejm.org december 4, 2014
The New England Journal of Medicine Downloaded from nejm.org at TULANE UNIV on January 2, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence No potential conflict of interest relevant to this letter was reported.
A Controls (N=189) 54.60
r=−0.15; P=0.04
Insulin Sensitivity
33.12 20.09 12.18 7.39 4.48 2.72 1.65 122
148
181
221
270
330
403
493
Fetuin-A (µg/ml, Ln)
54.60
r=−0.43; P
n e w e ng l a n d j o u r na l
of
m e dic i n e
Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease To the Editor: Shulman (Sept. 18 issue)1 theorized that ectopic fat plays a major role in the development of insulin resistance. We speculate, however, that insulin resistance may be caused by another major pathway, in which glucose itself, at high levels, plays a critical role. Reasonable evidence has shown that when glucose levels are elevated, glucose molecules may randomly bind to proteins similar to the insulin receptor on the plasma membrane of the cell and in time become advanced glycation end products.2 Circulating insulin levels would easily fail to dock properly with the advanced glycation end product deposited on the insulin receptor and would therefore fail to initiate the glucose-transport process, effectively causing insulin resistance.3 This pathway for glycation-induced insulin resistance would explain why insulin resistance often develops in persons who are not obese and who probably do not have substantial ectopic fat. Sang W. Shin, M.D., Ph.D. Korea University Seoul, South Korea [email protected]
Universidad Autónoma de Madrid Madrid, Spain [email protected] No potential conflict of interest relevant to this letter was reported. 1. Jope RS, Johnson GVW. The glamour and gloom of glycogen
synthase kinase-3. Trends Biochem Sci 2004;29:95-102.
Song J. Lee, Ph.D.
2. MacAulay K, Doble BW, Patel S, et al. Glycogen synthase ki-
Chungnam National University Daejeon, South Korea No potential conflict of interest relevant to this letter was reported. 1. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia,
and cardiometabolic disease. N Engl J Med 2014;371:1131-41.
2. Schalkwijk CG, Brouwers O, Stehouwer CD. Modulation of
insulin action by advanced glycation endproducts: a new player in the field. Horm Metab Res 2008;40:614-9. 3. Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. Curr Pharm Des 2008;14:987-9. DOI: 10.1056/NEJMc1412427
To the Editor: Shulman indicates that diacylglycerol (DAG) interferes with insulin-induced activation of glycogen synthase in the liver by increasing the phosphorylation of glycogen synthase kinase 3 (GSK3) (see the legend for Fig. 2 of the article). At the same time, DAG-activated protein kinase C epsilon (PKCε) inhibits the insulin receptor tyrosine kinase (the illustration for Fig. 2 of the article also features this chain of events, indicating that an increased level of phosphorylated GSK3 decreases glycogen synthesis). 2236
However, GSK3 is inactive in its phosphorylated form (owing to the activation of protein kinase B/Akt through the insulin-signaling pathway).1,2 Consequently, glycogen synthesis is induced because glycogen synthase remains dephosphorylated (and is therefore active).2 When the insulinsignaling pathway is blocked by suppression of the receptor tyrosine kinase upon the binding of PKCε, the phosphorylation of GSK3 is also suppressed,2 leading not to an increase in its phosphorylated form (as indicated by Shulman) but a decrease, leaving GSK3 dephosphorylated (i.e., active), and glycogen synthase inactive, so that glycogen synthesis diminishes. We believe that this point should be addressed in a subsequent article. Juan J. Aragón, M.D., Ph.D. Oscar H. Martínez-Costa, M.D., Ph.D.
nase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab 2007;6:329-37. DOI: 10.1056/NEJMc1412427
To the Editor: Shulman provides important information about the mechanisms by which increased storage of ectopic fat induces insulin resistance in the liver and in skeletal muscle. However, there is still limited information available on how such mechanisms affect other organs and tissues and thereby induce the development of cardiometabolic diseases. We have shown that in humans, the ectopic storage of fat in the liver, more so than skeletal muscle, is associated with impaired metabolism.1 The mechanisms of action involve hepatokines, proteins released from the steatotic liver.2 The hepatokine fetuin-A is a likely actor; its production is increased in nonalcoholic fatty liver disease, and it induces insulin resistance and subclinical inflammation in mice and humans.2,3 In addition, we can show that the relationship between circulating levels of fetuin-A and insulin resistance is particularly
n engl j med 371;23 nejm.org december 4, 2014
The New England Journal of Medicine Downloaded from nejm.org at TULANE UNIV on January 2, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence No potential conflict of interest relevant to this letter was reported.
A Controls (N=189) 54.60
r=−0.15; P=0.04
Insulin Sensitivity
33.12 20.09 12.18 7.39 4.48 2.72 1.65 122
148
181
221
270
330
403
493
Fetuin-A (µg/ml, Ln)
54.60
r=−0.43; P
