Efeito imunomodulador de hipoglicemiantes orais em cultura de linfócitos de pacientes com diabetes tipo 2 / Immunomodulatory effects of oral antidiabetic drugs in lymphocyte cultures from patients with type 2 diabetes

INTRODUCTION AND OBJECTIVE: It has been suggested that type 2 diabetes is an inflammatory response manifestation. The main drugs used to treat type 2 diabetes are sulphonylureas and biguanides. The aim of this study was to demonstrate the modulatory effects of oral hypoglycemic drugs (chlorpropamide and metformin) on lymphocyte proliferation in vitro and ex vivo. METHODS: Peripheral blood mononuclear cells were isolated from human blood by gradient centrifugation. T-lymphocytes were stimulated by phytohemagglutinin (PHA) and oral hypoglycemic drugs. RESULTS: In both in vitro and ex vivo experiments, there was a reduction in cell proliferation after treatment with oral hypoglycemic drugs. When both drugs were used in combination, a high level of cytotoxicity was observed, which made analysis of immunomodulatory effects unfeasible. DISCUSSION AND CONCLUSION: We demonstrated that diabetes itself may reduce cell proliferation significantly when stimulated by PHA, which may indicate that diabetic patients have difficulties in promoting an efficient inflammatory response. Moreover, the use of oral hypoglycemic drugs may aggravate this situation.

INTRODUÇÃO E OBJETIVOS: Tem sido sugerido que o diabetes mellitus tipo 2 (DM2) é uma manifestação da resposta inflamatória. As principais drogas utilizadas no tratamento do DM2 são as sulfonilureias e as biguanidas. O objetivo deste trabalho é demonstrar os efeitos moduladores na proliferação de linfócitos causada pelos hipoglicemiantes orais (clorpropamida e metformina), in vitro e ex vivo. MÉTODOS: Células mononucleares de sangue periférico foram isoladas de seres humanos por gradiente de centrifugação. Os linfócitos T foram estimulados com fito-hemaglutinina (PHA) e hipoglicemiantes. RESULTADOS: Nos experimentos in vitro e ex vivo, mostramos a redução da proliferação celular quando do tratamento com drogas hipoglicemiantes orais. Quando as drogas foram utilizadas em combinação, foi observado alto grau de citotoxicidade, tornando inviável a análise do efeito imunomodulador. DISCUSSÃO E CONCLUSÃO: Mostramos que o diabetes, por si, pode reduzir significativamente a proliferação celular quando estimulada por PHA, o que pode indicar que o paciente diabético tem dificuldade em promover a eficiente resposta inflamatória e que o uso de hipoglicemiantes pode piorar esta situação.

effect of a 6 month treatment course of male healthy rats by chlorpropamide and glibenclamide on vascular tone of aorta

Diabetes mellitus is the most common endocrine disorder with an ever-increasing prevalence. Cardiovascular complications are the major cause of death in diabetic patients. Type II diabetes mellitus is usually treated by sulfonylureas. There are controversial reports regarding cardiovascular side effects of these drugs. Conflicting evidences exist about side effects of the first and second-generation sulfonylureas. In this study, the vascular effects of chlorpropamide and glibenclamide [first and second generations of sulfonylureas respectively] were investigated in healthy male rats. Male rats were treated by the above-mentioned drugs for six months and the response of aortic rings to acetylcholine, isosorbide dinitrate and phenylephrine were studied and compared to normal control group. Data were analyzed by means of ANOVA test. There was no significant difference between the response of aortic rings of treated and control group to acetylcholine, isosorbide dinitrate and phenylepherine. Sulfonylureas through closing ATP dependent potassium channels, which exist in beta-cells of pancreas and other organs such as heart and vascular smooth muscles may affect the vascular tone. Based on the results of this study long term oral consumption of chlorpropamide and glibenclamide in normal rats did not affect aortic contractile property. Further studies are needed to clarify the vascular effects of sulfonylureas

Effect of ATP-dependent K+ channel openers and blockers on serum concentration of aldosterone in rats

There are many reports for involvement of ATP-sensitive potassium channels in pancreatic, cardiac and vascular smooth muscle cells. This study examined the effect of single doses of K+ channel openers; diazoxide, minoxidil and K+ channel blockers; chlorpropamide, glibenclamide on serum concentration of aldosterone in male rats. Blood samples were obtained 60 minutes after drug treatment and serum aldosterone level was determined by RIA. The basal serum aldosterone was 659.32 +/- 71.48 pg/ml and after diazoxide or minoxidil administration increased to 1188.53 +/- 99.45 pg/ml and 1392.69 +/- 177.83 pg/ml, respectively. Chlorpropamide or glibenclamide treatment did not produce any change in basal serum aldosterone concentration, but in early streptozotocin-induced diabetic rats decreased serum aldosterone level significantly [P<0.001]. Pretreatment with glibenclamide blocked aldosterone response to diazoxide but did not affect aldosterone response to exogenous ACTH to the same extent. Effect of diazoxide in insulin-treated rats was approximately similar to that of normal rats. Comparison of blood glucose concentration determined in normal, insulin treated and diabetic rats after different drug administration showed that there is no correlation between blood glucose level and the responses observed in serum hormone concentration. The results indicate that regulatory processes involved in the secretion of aldosterone are responsive to drugs affecting glibenclamide-sensitive K+ channels

Experiencia clínica con un inhibidor de la alfa glucosidasa (acarbosa) en el tratamiento de la diabetes no insulinodependiente: estudio multicéntrico / Multicentric study on the effect of an alpha glucosidase inhibitor in the treatment of non insulin dependent diabetes

Diabetic patients received acarbose, 150 mg/day durign four weeks and this dose was increased to 300 mg/day durign 3 months. Afterwards, patients were followed for a period of 12 weeks without acarbose. Fasting and post-prandial blood glucose and glycosilated hemoglobin were measured sequentially durign the study. Results: Eighty five patients were recruited for the study but 64 complied with the treatment protocol. The age of these patients was 56 ñ 8.8 years old, their diabetes duration was 7.8 ñ 8.8 years and their body mass index was 27.6 ñ 3.6 kg/m². During acarbose treatment, glycosilated hemoglobin decreased from 8.36 ñ 1.33 to 7.71 + 1.7 percent (p < 0.001), fasting blood glucose decreased from 173 ñ 48 to 159 ñ 59 mg/dl (p < 0.03) and post-prandial blood glucose decreased from 254 ñ 80 to 241 ñ mg/dl (NS). After discontinuing acarbose glycosilated hemoglobin and blood glucose levels returned to basal levels. Body weight and blood pressure did not change during the treatment period. Fifty nine patients bad gastrointestinal symptoms (meteorism, flatulence and abdominal distention) that were mild in 59 percent and moderate in 39 percent. Episodes of hypoglycemia were not observed. Conclusions: Acarbose, associated to sylphonylureas is an effective drug to reduce blood glucose and glycosilated hemoglobin levels in patients with non insulin dependent diabetes