Guan et al. reply
We are pleased that our report of TZD induction of adipose glycerol kinase1 has prompted further investigation by other groups. Tordjman et al. recently confirmed our observation that rosiglitazone markedly induces glycerol kinase in mouse adipocytes11. In their correspondence, Tan et al. did not find increased glycerol kinase expression in rosiglitazone-treated human adipocytes or in adipose samples from rosiglitazone-treated type 2 diabetics. It is important to note that in the patients studied by Tan et al., rosiglitazone treatment did not lower plasma levels of NEFAs. This differs from nearly all rodent models, as well as several controlled human trials reporting significant lowering of NEFA levels by rosiglitazone and other TZDs5,12,13. Human responses are likely to be more heterogeneous than those of inbred rodent models. If, as we have hypothesized, adipose glycerol kinase induction is one factor contributing to NEFA lowering by TZDs, then lack of glycerol kinase induction may not be surprising in patient populations in which NEFA levels do not respond to TZDs. Larger studies will be needed to determine the extent to which TZD induction of adipose glycerol kinase is variable in humans, and whether this correlates with reduction in NEFA levels upon TZD treatment.
See A “futile cycle” induced by thiazolidinediones in human adipose tissue? by Tan et al.
References
Guan, H.P. et al. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat. Med. 8, 1122–1128 (2002).
Frayn, K.N. & Coppack, S.W. Assessment of white adipose tissue metabolism by measurement of arteriovenous differences. Meth. Mol. Biol. 155, 269–279 (2001).
Chakrabarty, K., Tauber, J.W., Sigel, B., Bombeck, C.T. & Jeffay, H. Glycerokinase activity in human adipose tissue as related to obesity. Int. J. Obes. 8, 609–622 (1984).
Maggs, D.G. et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 128, 176–185 (1998).
Miyazaki, Y. et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients. Diabetologia 44, 2210–2219 (2001).
Racette, S.B., Davis, A.O., McGill, J.B. & Klein, S. Thiazolidinediones enhance insulin-mediated suppression of fatty acid flux in type 2 diabetes mellitus. Metabolism 51, 169–174 (2002).
Fujiwara, T., Yoshioka, S., Yoshioka, T., Ushiyama, I. & Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 37, 1549–1558 (1988).
Finegood, D.T. et al. Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 50, 1021–1029 (2001).
Basu, A. et al. Systemic and regional free fatty acid metabolism in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 280, E1000–E1006 (2001).
Jensen, M.D. Adipose tissue and fatty acid metabolism in humans. J. R. Soc. Med. 95 (suppl. 42), 3–7 (2002).
Tordjman, J. et al. Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells. J. Biol. Chem. 278, 18785–18790 (2003).
Kumar, S. et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia 39, 701–709 (1996).
Chaiken, R.L. et al. Metabolic effects of darglitazone, an insulin sensitizer, in NIDDM subjects. Diabetologia 38, 1307–1312 (1995).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Guan, HP., Lazar, M. Reply to “A “futile cycle” induced by thiazolidinediones in human adipose tissue?”. Nat Med 9, 812 (2003). https://doi.org/10.1038/nm0703-812
Issue Date:
DOI: https://doi.org/10.1038/nm0703-812