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Endocrine Care: Aiwei Yao-Borengasser, Vijayalakshmi Varma, Angela M. Bodles, Neda Rasouli, Bounleut Phanavanh, Mi-Jeong Lee, Tasha Starks, Leslie M. Kern, Horace J. Spencer, III, Amir Adel Rashidi, Robert E. McGehee, Jr., Susan K. Fried, and Philip A. Kern Retinol Binding Protein 4 Expression in Humans: Relationship to Insulin Resistance, Inflammation, and Response to Pioglitazone J Clin Endocrinol Metab 2007; 92: 2590-2597 [Abstract] [Full text] [PDF]

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Is Retinol-Binding Protein 4 (RBP-4) Really Unregulated By Inflammatory Processes?

Harpal S. Randeva, Krzysztof C. Lewandowski, Medical University of Lodz, Lodz, Poland   (26 September 2007)

Is Retinol-Binding Protein 4 (RBP-4) Really Unregulated By Inflammatory Processes? 26 September 2007
Harpal S. Randeva, Senior Lecturer & Consultant Endocrinologist Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK, Krzysztof C. Lewandowski, Medical University of Lodz, Lodz, Poland Send letter to journal: Re: Is Retinol-Binding Protein 4 (RBP-4) Really Unregulated By Inflammatory Processes? Harpal.Randeva{at}warwick.ac.uk Harpal S. Randeva, et al.	Yao-Borengasser et al. (1) in their recent paper report a positive correlation between RBP-4 mRNA in adipose tissue and adipose tissue inflammatory markers, adipose tissue monocyte chemoattractant protein (MCP-1) mRNA and CD68. The authors also report a lack of correlation between plasma RBP-4 levels and insulin sensitivity assessed by frequently sampled intravenous glucose tolerance test, a method previously reported to correlate well with the euglycaemic glucose clamp technique (r = 0.89; P < 0.001) (2). On these premises they suggest that RBP-4 is more likely to be related to inflammatory processes rather than insulin resistance. In our opinion, great caution is needed in interpretation of these data, as the observed correlations might reflect a local adipose tissue-related rather than a systemic effect. We have recently measured serum RBP-4 levels (Phoenix Pharmaceuticals Inc., intra-assay variation <5%, inter-assay variation <14%), serum IL-6 (Phoenix Pharmaceuticals, CV 4.2 % and 3.8% for intra- and inter-assay variation), as well as sVCAM-1 (R&D Systems, intra-assay variation: 3.5 % inter-assay variation 7.7%) in a cohort of 51 women at 28 weeks of gestation with various degrees of glucose intolerance (ranging from frank gestational diabetes, diagnosed according to the WHO criteria, to healthy controls). Detailed characteristics of these cohorts have been recently published (3). We have found raised serum levels of RBP-4 in women with GDM (53.9 ± 17.9 μg/ml vs. 29.7 ± 13.9 μg/ml in healthy controls, P ≤ 0.01, Mann-Whitney U test) and a lack of correlation between serum RBP-4 and IR assessed by HOMA and Insulin Resistance Index (4). Simultaneously, however, there was a negative correlation between serum RBP-4 levels and proinflammatory cytokine IL-6 (r = -0.36, P = 0007) and a negative correlation between serum RBP-4 and sVCAM-1 (r = -0.45, P = 0.001, Spearman rank correlation). There is evidence that acute inflammation in rats is associated with reduced plasma RBP levels (within 24 hours) as well as reduced RBP mRNA in liver as early as after 12 hours (5). Thus, the reported pro-inflammatory effects of RBP-4 would have to be related to chronic, as opposed to acute, inflammation. The authors also report an increase in both adipose and muscle RBP-4 expression after pioglitazone. Given the evidence that thiazolidinediones are associated with reduction of several pro-inflammatory markers and an increase in anti-inflammatory adiponectin, such an increase in RBP-4, is inconsistent with its putative proinflammatory effects and would be more consistent with our results (i.e., a negative association between serum RBP-4 and some inflammatory markers). We therefore, caution against over-interpretation of the evidence suggesting an association between RBP-4 and inflammatory processes. We would be also very interested to find our whether Yao-Borengasser et al. could find any relationship between plasma levels of RBP-4 and inflammatory markers? References 1. Yao-Borengasser A, Varma V, Bodles AM, Rasouli N, Phanavanh B, Lee M-J, Starks T, Kern LM, Spencer HJ, Rashidi AA, McGehee RE, Fried SK, Kern PA 2007 Retinol binding protein 4 expression in humans: Relationship to insulin resistance, inflammation, and response to pioglitazone. J Clin Endocrinol Metab 92:2590-2597 2. Bergman RN, Prager R, Volund A, Olefsky JM 1987 Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycaemic glucose clamp. J Clin Invest 79:790-800 3. Lewandowski KC, Stojanovic N, Press M, Tuck SM, Szosland K, Bienkiewicz M, Vatish M, Lewinski A, Prelevic GM, Randeva HS 2007 Elevated Serum Levels of Visfatin in Gestational Diabetes: A Comparative Study Across Various Degrees of Glucose Tolerance. Diabetologia 50:1033- 1037 4. Matsuda M, DeFronzo R 1999 Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care 9:1462-1470 5. Rosales FJ, Ritter SJ, Zolfaghari R, J.E. Smith JE, Ross AC 1996 Effects of acute inflammation on plasma retinol, retinol-binding protein, and its mRNA in the liver and kidneys of vitamin A-sufficient rats. J Lipid Res 37:962-971