Copyright © 2009 John Wiley & Sons, Ltd. Phytother. Res. 23, 1316–1325 (2009) DOI: 10.1002/ptr 1316 K. B. CHRISTENSEN ET AL. Copyright © 2009 John Wiley & Sons, Ltd. PHYTOTHERAPY RESEARCH Phytother. Res. 23, 1316–1325 (2009) Published online 27 January 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/ptr.2782 Identification of Plant Extracts with Potential Antidiabetic Properties: Effect on Human Peroxisome Proliferator-activated Receptor (PPAR), Adipocyte Differentiation and Insulin- stimulated Glucose Uptake Kathrine B. Christensen 1 *, Ariane Minet 2 , Henrik Svenstrup 2 , Kai Grevsen 3 , Hongbin Zhang 2 , Eva Schrader 4 , Gerald Rimbach 4 , Silvia Wein 5 , Siegfried Wolffram 5 , Karsten Kristiansen 2,6 and Lars P. Christensen 7 1 Department of Food Science, University of Aarhus, Kirstinebjergvej 10, 5792 Aarslev, Denmark 2 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark 3 Department of Horticulture, University of Aarhus, Kirstinebjergvej 10, 5792 Aarslev, Denmark 4 Department of Human Nutrition and Food Science, Christian-Albrechts University, Hermann-Rodewald-Str. 6, 24098 Kiel, Germany 5 Department of Animal Nutrition and Physiology, Christian-Albrechts University, Hermann-Rodewald-Str. 9, 24098 Kiel, Germany 6 Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark 7 Institute of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Niels Bohrs Allé 1, 5230 Odense M, Denmark Thiazolidinediones (TZDs) are insulin sensitizing drugs used to treat type 2 diabetes. The primary target of the TZDs is the peroxisome proliferator-activated receptor (PPAR) γ γ γ, a key regulator of adipogenesis and glucose homeostasis. Currently prescribed TZDs are full PPAR γ γ γ agonists, and their use is associated with several side effects. Partial PPAR γ γ γ agonists appear to be associated with fewer side effects but may still confer the desired insulin sensitizing action. Extracts from common medicinal/food plants were tested in a screening platform comprising a series of bioassays, including tests for PPAR γ γ γ, α α α and δ δ δ transactivation, adipocyte differentiation and insulin-stimulated glucose uptake, allowing identification of plants containing potentially interesting PPAR agonists. Twenty-two plant extracts out of 133 were found to increase insulin-stimulated glucose uptake and 18 extracts were found to activate PPAR γ γ γ, 3 to activate PPAR α α α and γ γ γ, 6 to activate PPAR δ δ δ and γ γ γ, and 9 to activate PPAR γ γ γ, α α α and δ δ δ. Among the 24 different plant species tested in the platform, 50% were shown to contain compounds capable of activating PPAR γ γ γ and stimulating insulin-dependent glucose uptake with no or little effect on adipocyte differentiation warranting further studies and characteri- zation. Copyright © 2009 John Wiley & Sons, Ltd. Keywords: medicinal plants; food plants; type 2 diabetes; peroxisome proliferator-activated receptors (PPARs); adipocyte differentiation; glucose uptake. Received 21 August 2008 Revised 8 December 2008 Accepted 8 December 2008 * Correspondence to: Kathrine B. Christensen, University of Aarhus, Faculty of Agricultural Sciences, Department of Food Science, Kirstinebjergvej 10, 5792 Aarslev, Denmark. E-mail: kathrine.bisgaard@agrsci.dk Contract/grant sponsor: EU Interreg IIIA and the Danish Council for Strategic Research; contract/grant number: 2101-01-0065. INTRODUCTION Obesity is the major factor predisposing individuals to a complex of dyslipidaemic/metabolic disorders col- lectively named the metabolic syndrome characterized by a group of metabolic risk factors in one person. They include: abdominal obesity, atherogenic dyslipi- daemia, elevated blood pressure, insulin resistance or glucose intolerance, a prothrombotic state and a pro- inflammatory state. Eventually, this may lead to the development of overt type 2 diabetes (T2D) and fatal cardiovascular disorders (Mlinar et al., 2007). An important early event preceding overt symptoms of the metabolic syndrome is the unnoticed development of insulin resistance. Insulin resistance is a state in which the cells do not respond to normal levels of insulin and one key factor conferring insulin resistance is excess release of free fatty acids (FFAs) from visceral adipose tissue (Gimeno and Klaman, 2001). FFAs impair insulin signalling in insulin sensitive tissue such as the muscles. Insulin resistance is also affected by the release of certain hormones and cytokines from adipose tissue, e.g. tumour necrosis factor α that increases insulin re- sistance. By contrast, the adipocytokines adiponectin and leptin are crucial for maintaining a normal level of insulin sensitivity. Adiponectin increases the catabolism of FFAs and thereby reduces insulin resistance (Mlinar et al., 2007). Insulin resistance is initially counteracted by an increased release of insulin from the β-cells to maintain glucose homeostasis. Over time the β-cells become unable to secure a sufficient insulin release resulting in hyperglycaemia and eventually the patient develops overt T2D (Mlinar et al., 2007). According to