Mechanism of Insulin Secretion and Action In Different Animal Models: Neonatal, Malnourished, Hyperlipidemic, and Insulin Resistant

• Grant number: 98/12139-1
• Support Opportunities: Research Projects - Thematic Grants
• Duration: June 01, 1999 - June 30, 2003
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Antonio Carlos Boschiero
• Grantee: Antonio Carlos Boschiero
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Diabetes mellitus (DM) is defined as a sindrome of persistent hyperglycemia resulting from the lack of insulin production generally associated to increased resistance to the hormone. DM is classified in at least four categories: 1) insulin dependent diabetes mellitus (IDDM) or type 1 diabetes; 2) non insulin dependent diabetes mellitus (NIDDM) or type 2 diabetes; 3) diabetes mellitus associated to other illness, or secondary diabetes mellitus, and 4) gestational diabetes mellitus. The DM type 1, usually manifested during childhood and adolescence, has autoimmune origin. Some variation of this modality has been proposed recently. Among these, the latent autoimmune diabetes (LADA), that represents an expressive percentage of the adult diabetic patients with the onset of the illness around age 20. Almost 90% of diabetic patients belong to the type 2. This is an endocrine disorder characterized by multiple defects in insulin action and insulin secretion. I. Insulin action in target celis involves the tyrosine phosphorylation of the insulin receptor (IR) and other proteins named insulin receptor substrates (IRSs). These substrates couple the IR to different intracellular proteins like PI-3-kinase,Grb2/S0S, SHP2, NCK, CRK, etc. We have recently demonstrated that IR, IRS-1 and IRS-2 are present in isolated islets of Langerhans. These proteins had tyrosine phosphorylation increased by high concentrations of glucose (1 1 or 22 mM) and by insulin (10-7M) indicating a regulatory role (feed back) of insulin on its own secretion. It was also demonstrated that IRS-2 knockout mouse (but not IRS-I)displayed features similar to that observed for type 2 diabetes; i.e. increased insulin resistance followed by reduction of insulin secretion. Interestingly, control of transcription of pro-insulin gene by insulin involves a cascade of reactions including IRS-2, PI-3-kinase, and p70 s6K showing that IRSS, especially the IRS-2, participate in the mechanism of insulin synthesis and secretion. In a first project we aim at studying the possible alterations in the cascade of events responsible for the insulin signal in the insulin secreting cells in: neonatal rats (where the insulin secretion mechanism is not yet fully developed), in malnourished rats (where the insulin secretion is reduced), and in different animal models of insulin resistance (that could provoke diabetes)... (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

COLLARES-BUZATO‚ C.B.; LEITE‚ A.R.; BOSCHERO‚ A.C.. Modulation of gap and adherens junctional proteins in cultured neonatal pancreatic islets. PANCREAS, v. 23, n. 2, p. 177, 2001. (98/12139-1)