Clinical and Experimental Pharmacology and Physiology (2008) 35, 256– 261 doi: 10.1111/j.1440-1681.2007.04809.x Blackwell Publishing Asia Original Articles Effect of acarbose on obese diabetic rats C Pérez et al. EFFECTS OF CHRONIC ACARBOSE TREATMENT ON ADIPOCYTE INSULIN RESPONSIVENESS, SERUM LEVELS OF LEPTIN AND ADIPONECTIN AND HYPOTHALAMIC NPY EXPRESSION IN OBESE DIABETIC WISTAR RATS Coralia Pérez,* Teresa Fernández-Agulló, † Alain J De Solís,* Manuel Ros, † Antonio Andrés ‡ and José M Carrascosa* *Centre of Molecular Biology ‘Severo Ochoa’, Faculty of Sciences, Autonomous University, † Health Sciences Faculty, University Rey Juan Carlos, Alcorcón, Madrid and ‡ Biochemistry Section, Faculty of Chemistry, Regional Centre of Biomedical Research, University of Castilla La Mancha, Ciudad Real, Spain SUMMARY 1. Inhibitors of intestinal glucosidases have been shown to improve glycaemic control in diabetic and obese humans and animals. In the present study, we have investigated the effect of 3 months treatment with acarbose on adiposity, food intake and the modulation of hypothalamic neuropeptide Y (NPY) in obese diabetic Wistar (WDF) rats and the possible correlation between changes in overall insulin sensitivity and the level of circulating adipokines, leptin and adiponectin. In addition, we investigated the effect of acarbose on adipocyte insulin signalling. 2. Mature male WDF rats were randomly distributed to one of three treatment groups (no acarbose or 20 or 40 mg of acarbose/100 g diet). After 3 months, blood glucose, cholesterol, triglyceride, insulin, leptin and adiponectin were analysed. Insulin signalling was determined in isolated adipocytes as the stimulation of mitogen-activated protein kinase (MAPK) and Akt phosphorylation; the level of hypothalamic NPY was assessed by immunohistochemistry. 3. Acarbose-treated rats had lower levels of blood glucose, cholesterol, triglyceride, insulin and leptin and an increase in adiponectin compared with untreated animals. There were no changes in bodyweight and adiposity. Stimulation of adipocyte MAPK activity by insulin was higher in rats treated with both doses of acarbose, whereas higher stimulation of Akt phospho- rylation was observed with the highest dose of acarbose. Although food intake was not significantly reduced in rats treated with acarbose, the acarbose-treated rats had lower NPY expression in the arcuate nucleus. 4. We conclude that the improvement in overall insulin sensitivity in WDF rats after prolonged acarbose treatment is paralleled by increases in circulating adiponectin and adipocyte insulin responsiveness. Acarbose neither decreases food intake nor reverts obesity, but decreases leptin levels and the expression of the orexigenic NPY in the hypothalamus. Key words: acarbose, adiponectin, insulin signalling, leptin, neuropeptide Y, obesity. INTRODUCTION Acarbose is a complex oligosaccharide of microbial origin that binds competitively to the a-glucosidases at the brush border of the small intestine, thus delaying the breakdown of sucrose, starch and com- plex carbohydrates and the absorption of glucose and fructose. It has proven efficacious in reducing post-prandial increases in glucose and insulin. 1–3 Several clinical trials have shown the efficacy of acarbose in improving glycaemic control in obese hypertensive subjects with normal glucose tolerance 4 and in individuals with either impaired glucose tolerance 5,6 or overt diabetes. 7–13 However, with regard to the effect of acarbose on overall insulin sensitivity, controversial data have been reported. Thus, an improvement of insulin sensitivity has been observed in obese 4 and glucose-intolerant 5 subjects, as well as in elderly 10 and obese 14 type 2 diabetics, whereas no changes have been reported in most studies with diabetic patients. 7–9,12 Changes in insulin action at the tissue level in response to prolonged administration of acarbose have been studied in obese mice and rats. Administration of acarbose over a period of 4 months to mice made obese by gold-thioglucose treatment did not result in any improvement of isolated soleus muscle insulin sensitivity, despite an effect on bodyweight and glycaemic control. 15 In obese Zucker rats, treatment with acarbose for a period of 12 weeks results in marked improvement of glucose tolerance, overall insulin sensitivity and insulin action on glucose transporter (GLUT)-4 translocation to the plasma membrane in soleus and cardiac muscle. 16 In obese diabetic Wistar (WDF) rats, we have reported previously that chronic treatment with acarbose improves glycaemic and lipidic control and ameliorates overall insulin sensitivity. 17 In addition to its effects on glycaemic control and insulin sensi- tivity, acarbose treatment has been reported to decrease bodyweight in obese rats 16,17 and mice, 15 as well as circulating leptin in both lean and obese Zucker rats. 16 Leptin is mainly produced by the adipose tissue and we have recently reported that hyperleptinaemia impairs insulin signalling in rat isolated adipocytes. 18 Because the insulin resistance of adipose tissue appears to play a key role in the development Correspondence: Professor José M Carrascosa, Centro de Biologia Molecular ‘Severo Ochoa’, Facultad de Ciencias, Campus de Cantoblanco, Universidad Autónoma, 28049 Madrid, Spain. Email: jmcarrascosa@cbm.uam.es Received 6 June 2007; revision 2 August 2007; accepted 8 August 2007. © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd