Improvement of Insulin Sensitivity by a Novel Drug Candidate, BGP-15, in Different Animal Studies Botond Litera ´ ti-Nagy, MD, 1 Ka ´ lma ´ n Tory, MD, PhD, 2 Barna Peitl, MD, PhD, 3 A ´ gnes Bajza, MSc, 2 La ´ szlo ´ Kora ´ nyi, MD, PhD, DSc, 1 Zsuzsanna Litera ´ ti-Nagy, MD, 4 Philip L. Hooper MD, 5 La ´ szlo ´ Vı ´gh, PhD, DSc, 6 and Zolta ´ n Szilva ´ ssy, MD, PhD, DSc 3 Abstract Background: Insulin resistance has been recognized as the most significant predictor of further development of type 2 diabetes mellitus (T2DM). Here we investigated the effect of a heat shock protein (HSP) co-inducer, BGP- 15, on insulin sensitivity in different insulin-resistant animal models and compared its effect with insulin se- cretagogues and insulin sensitizers. Methods: Insulin sensitivity was assessed by the hyperinsulinemic euglycemic glucose clamp technique in normal and cholesterol-fed rabbits and in healthy Wistar and Goto–Kakizaki (GK) rats in dose-ranging studies. We also examined the effect of BGP-15 on streptozotocin-induced changes in the vasorelaxation of the aorta in Sprague–Dawley rats. Results: BGP-15 doses of 10 and 30 mg/kg increased insulin sensitivity by 50% and 70%, respectively, in cholesterol- fed but not in normal rabbits. After 5 days of treatment with BGP-15, the glucose infusion rate was increased in a dose-dependent manner in genetically insulin-resistant GK rats. The most effective dose was 20 mg/kg, which showed a 71% increase in insulin sensitivity compared to control group. Administration of BGP-15 protected against streptozotocin-induced changes in vasorelaxation, which was similar to the effect of rosiglitazone. Conclusion: Our results indicate that the insulin-sensitizing effect of BGP-15 is comparable to conventional insulin sensitizers. This might be of clinical utility in the treatment of T2DM. Introduction I nsulin resistance plays a major role in the development of prediabetes and overt type 2 diabetes (T2DM). 1 Fur- thermore, clinical and experimental evidence suggests that both diabetes and insulin resistance cause endothelial dys- functions, which may diminish the antiatherogenic role of the vascular endothelium. 2–4 Diabetic endothelial dysfunc- tion is synonymous with decreased endothelium-dependent vasorelaxation to acetylcholine. 5 A recent large randomized clinical study of patients with stable coronary artery disease and T2DM observed that addition of an insulin-sensitizing drug, a thiazolidinedione or metformin, reduced peripheral artery disease, revascularization surgery, and leg amputa- tions—even when adjusting for improved glycemic control. 6 The peroxisome proliferator-activated receptor-g (PPAR-g) agonist the thiazolidinediones (TZDs), so-called insulin sen- sitizers, enhance insulin action in muscle and fat tissues. The major side effect, seen with troglitazone, the first TZD, is liver damage. Because of this dangerous side effect, the Food and Drug Administration (FDA) removed troglitazone from the market. Two other glitazones, pioglitazone and rosigli- tazone, cause weight gain and fluid retention 7 ; moreover, rosiglitazone is thought to increase the risk of cardiovascular events. 8 The side effects and the necessity for a safe and effective insulin sensitizer encourage development of com- pounds that improve insulin sensitivity through other mechanisms. BGP-15 [O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic acid], a hydroxylamine derivative, does not belong to the glitazone 1 Drug Research Center Ltd., Balatonfu ¨ red, Hungary. 2 N-Gene Research and Development Ltd., Budapest, Hungary. 3 Departments of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary. 4 Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Budapest, Hungary. 5 Division of Endocrinology, Metabolism, and Diabetes, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. 6 Biological Research Center, Hungarian Academy of Sciences, Institute of Biochemistry, Szeged, Hungary. METABOLIC SYNDROME AND RELATED DISORDERS Volume 12, Number 2, 2014 Ó Mary Ann Liebert, Inc. Pp. 125–131 DOI: 10.1089/met.2013.0098 125 125 125