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Effects of exenatide on the energetic metabolism, muscarinic RECEPTORS,FERTILITY and dynamics of bone in obese and diabetic rats

Grant number: 13/13963-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): January 01, 2014
Effective date (End): March 31, 2015
Field of knowledge:Biological Sciences - Physiology - Compared Physiology
Principal Investigator:Paulo Flávio Silveira
Grantee:Rafaela Fadoni Alponti Vendrame
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


Problem under study: Among the most recent pharmacological resources for diabetes mellitus (DM) type 2 there is the exenatide, which was developed from a peptide isolated from the Gila monster (Heloderma suspectum) venom and presenting agonism on glucagon-like peptide-1 hormone receptor and resistance to the hydrolysis by dipeptidyl-peptidase IV. There are evidences that this drug can be effective to reduce food intake and body weight and to ameliorate learning and memory performance. However, its differential actions on the profiles of energetic and osseous metabolism and on fertility are not fully characterized, and no data exist about its influence on muscarinic receptors in animal models of DM or obesity. General objectives: To evaluate changes in energetic and osseous metabolism and fertility, in postsynaptic mechanisms of muscarinic receptors in the hippocampus, in morphometry, and mainly to characterize the effects of exenatide on these alterations in the hypothalamic obesity, dietetic obesity, and DM. Justification/Relevance: To increase the pathophysiological knowledge on models of obesity and DM and on the pharmacology and comparative physiology of compounds originated from animal venoms. Furthermore, this project can contribute to the discovery of new mechanisms involved in the etiology of obesity and to the prevention and treatment of DM, obesity and comorbidities such as infertility, bone damage and neurodegenerative processes. Methods: Neonatal administration of monossodium glutamate and streptozotocin, and offer of high caloric diet to young adults, respectively for induction of hypothalamic obesity, DM and dietetic obesity in male rats. These animals will be comparatively evaluated regarding to affinity, density and subtypes of muscarinic receptors in the hippocampus, and insulin and glucagon secretion ability and viability of isolated Langerhans islets, food and water intake, body temperature, locomotor activity, naso-anal length, body mass and adiposity, as well as hematocrit and glycated hemoglobin in the blood, and osmolality, triglycerides, cholesterol (total, HDL, LDL and VLDL), glucose, testosterone, follicle-stimulating hormone, luteinizing hormone, osteocalcin, cross-linked carboxy-terminal telopeptide of type I collagen, N-terminal propeptide of type 1 procollagen, and total protein in the plasma, and regarding the effects of exenatide on all these parameters, in relation to healthy animals without exenatide treatment.