Comparação do perfil metabólico e funcionalidade de ilhotas pancreáticas, sob efeito da exenatida, em modelos experimentais de obesidade e diabetes melito no rato

Abstract

Exenatide, a synthetic exendin-4 peptide isolated from the venom of Heloderma suspectum lizard is among the most recent pharmacological resources for the treatment of type 2 diabetes mellitus (DM2), with agonist effect on the receptor of glucagon-like type 1 peptide hormone (GLP-1), and resistance to the hydrolysis by dipeptidyl-peptidase IV (DPPIV). This drug has also been suggested as effective in reducing food intake and body weight. However, its differential action on the metabolic and morphometric profiles in animals models of DM induced by streptozotocin (STZ) and obesity induced by monosodium glutamate (MSG) or high calorie diet (DIO) is not fully understood. The present study compared these models in relation to the gain of body weight (MC), as well as naso-anal length (CNA), Lee index, food and fluid intake, oral glucose tolerance (OGTT), insulin tolerance (ITT), mass of periepididymal and retroperitoneal fat pads, preprandial glucose, triglycerides (TG), cholesterol (total, HDL, LDL and VLDL), glycated hemoglobin (HbA1c), plasma protein, plasma osmolality, glucagon and insulin secreted by isolated islets, and about the effects of exenatide on all these parameters (STZ-E, MSG-E, DIO-E). DIO presented higher MC and CNA gain, Lee index, mass of retroperitoneal fat pad, preprandial glucose, TG, total cholesterol, VLDL and HbA1c, as well as lower food intake, glucose disappearance rate for ITT (Kitt) than healthy control (C-S). MSG presented higher Lee index, mass of retroperitoneal and periepididymal fat pads, preprandial glucose, TG, LDL and VLDL, as well as lower food and fluid intake, Kitt and plasma protein than C-S. STZ presented lower MC gain, mass of periepididyma and retroperitoneal fat pad, secreted insulin, tolerance to glucose and insensitivity to insulin, as well as higher HDL, preprandial glucose and HbA1c than C-S. The treatment with exenatide, for 20 consecutive days at human therapeutic dose, had beneficial effects on important metabolic and morphometric parameters in all groups, mainly in DIO-E, where it decreased MC gain, food intake, mass and retroperitoneal fat pad, preprandial glucose, HbA1c, TG, VLDL, total cholesterol and promoted insulin sensitivity. In MSG-E the preprandial glucose and secreted insulin were increased, and the insulin sensitivity was ameliorated. In STZ-E was increased and preprandial blood glucose and HbA1c were ameliorated without changing in the secretion of insulin and glucagon. Data contribute to the knowledge of the comparative pharmacology and physiology of compounds from animal venoms and to elucidate new mechanisms involved in the etiology and development of obesity, as well as to the prevention and treatment of obesity and DM.