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Literati-Nagy B.,Drug Research Center Ltd | Tory K.,N Gene Research and Development Ltd | Peitl B.,Debrecen University | Bajza A.,N Gene Research and Development Ltd | And 5 more authors.
Metabolic Syndrome and Related Disorders | Year: 2014

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 secretagogues 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. © Mary Ann Liebert, Inc.


Literati-Nagy Z.,Semmelweis University | Tory K.,N Gene Research and Development Ltd. | Literati-Nagy B.,Drug Research Center Ltd. | Kolonics A.,N Gene Research and Development Ltd. | And 10 more authors.
Cell Stress and Chaperones | Year: 2012

Weight gain and dysfunction of glucose and lipid metabolism are well-known side effects of atypical antipsychotic drugs (AAPD). Here, we address the questionwhether a heat-shock protein (HSP) co-inducer, insulin sensitizer drug candidate, BGP-15, can prevent AAPD-induced glucose, lipid, and weight changes. We also examined how an AAPD alters HSP expression and whether BGP-15 alters that expression. Four different experiments are reported on the AAPD BGP-15 interventions in a human trial of healthy men, a rodent animal model, and an in vitro adipocyte cell culture system. Olanzapine caused rapid insulin resistance in healthy volunteers and was associated with decreased level of HSP72 in peripheral mononuclear blood cells. Both changes were restored by the administration of BGP-15. In Wistar rats, weight gain and insulin resistance induced by clozapine were abolished by BGP-15. In 3T3L1 adipocytes, clozapine increased intracellular fat accumulation, and BGP-15 inhibited this process. Taken together, our results indicate that BGP-15 inhibits multiple metabolic side effects of atypical antipsychotics, and this effect is likely to be related to its HSP co-inducing ability. © Cell Stress Society International 2012.


Literati-Nagy Z.,Semmelweis University | Tory K.,N Gene Research and Development Ltd | Literati-Nagy B.,Drug Research Center Ltd | Kolonics A.,N Gene Research and Development Ltd | And 4 more authors.
Pathology and Oncology Research | Year: 2012

Atypical antipsychotic drugs (AAPD) are widely used to treat severe psychiatric disorders, have well documented metabolic side effects such as disturbances in glucose metabolism, insulin resistance and weight gain. It has been shown that BGP-15, a hydroxylamine derivative with insulin sensitizing activity can prevent AAPD provoked fat accumulation in adipocyte cultures, and insulin resistance in animal experiments and in healthy volunteers. The aim of this study was to compare the preventive effect of BGP-15 with conventional oral antidiabetics on metabolic side effects of AAPDs. We found that BGP-15 that does not belong to either conventional insulin sensitizers or oral antidiabetics, is able to counteract insulin resistance and weight gain provoked by antipsychotic agents in rats while rosiglitazone and metformin were not effective in the applied doses. Our results confirm that BGP-15 is a promising new drug candidate to control the metabolic side effects of atypical antipsychotics. Data indicate that this rat model is suitable to analyze the metabolic side effects of AAPDs and the protective mechanism of BGP-15. © Arányi Lajos Foundation 2012.


Literati-Nagy Z.,Semmelweis University | Tory K.,N Gene Research and Development Ltd. | Literati-Nagy B.,Drug Research Center Ltd. | Bajza A.,N Gene Research and Development Ltd. | And 4 more authors.
Pathology and Oncology Research | Year: 2013

Abdominal obesity is referred for as a common pathogenic root of multiple risk factors, which include insulin resistance, dyslipidemia, hypertension, and a pro-atherogenic and pro-inflammatory state. Irrespective of its psychiatric side effects, rimonabant through blocking cannabinoid-1 receptor (CB1R) induces an increase in whole body insulin sensitivity. The aim of this work was to study the effect of selected doses of another insulin sensitizer compound BGP-15, and rimonabant on insulin resistance in Zucker obese rats with a promise of inducing insulin sensitization together at lower doses than would have been expected by rimonabant alone. We found that BGP-15 potentiates the insulin sensitizing effect of rimonabant. The combination at doses, which do not induce insulin sensitization by themselves, improved insulin signaling. Furthermore our results suggest that capsaicin-induced signal may play a role in insulin sensitizing effect of both molecules. Our data might indicate that a lower dose of rimonabant in the treatment of insulin resistance and type 2 diabetes is sufficient to administer, thus a lower incidence of the unfavorable psychiatric side effects of rimonabant are to be expected. © 2013 Arányi Lajos Foundation.

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