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Resistin and Type 2 Diabetes: Regulation of Resistin Expression by Insulin and Rosiglitazone and the Effects of Recombinant Resistin on Lipid and Glucose Metabolism in Human Differentiated Adipocytes

Department of Medicine, University of Birmingham and Heartlands Hospital (P.G.M., F.M.F., G.V., R.C., A.H., C.L.M., P.M.S.C., A.H.B., S.K.), Edgbaston Birmingham, United Kingdom B15 2TH; and Glaxo-SmithKline, New Frontiers Science Park (S.A.S.), Harlow, United Kingdom CM19 5AW

Address all correspondence and requests for reprints to: Prof. S. Kumar, Warwick Medical School, University of Warwick, Coventry, United Kingdom CV4 7AL. E-mail: sudhesh.kumar{at}warwick.ac.uk.

Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 ± 87 pg/ml (mean ± SEM); 1 nM insulin, 1414.0 ± 89 pg/ml; 1 µM insulin, 1797 ± 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 ± 35 pg/ml; insulin, 1 µM insulin plus RSG, 1019 ± 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.

This work was supported by a University of Birmingham Studentship and in part by a Glaxo-SmithKline Research grant.

Abbreviations: BMI, Body mass index; FIZZ, found in inflammatory zone; HbA_1c, hemoglobin A_1c; HOMA, homeostasis model assessment; LPS, lipopolysaccharide; RELM, resistin-like molecules; RSG, rosiglitazone; TZD, thiazolidinedione.

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