The past two decades have seen an explosive increase in the number adolescents, diagnosed with type diabetes mellitus (T2DM) worldwide. The initial manifestations of the new epidemic of T2DM at midpuberty are insulin resistance and obesity. Most children who develop T2DM do so during puberty. Puberty is a susceptible period characterized by a transient reduction in insulin sensitivity, compensated by an adjusted increase in pancreatic insulin secretion. Therefore, the investigators hypothesize that puberty induced insulin resistance exacerbates the deleterious effect of excessive fat consumption on both insulin action and insulin secretion which may be irreversible. To elucidate the mechanisms by which excess fat intake during puberty leads to T2DM the investigators will use a chronically catheterized rat model, which allows for a longitudinal assessment of factors that modulate insulin action and secretion during puberty. The investigators will also determine the response of these factors to alterations in the composition of the diet. These in vivo tests will be coupled with the in vitro analysis to determine alterations on the cellular mechanism of insulin action (insulin receptor signaling: glucose transport activity, levels of IRbeta, IRS-1, IRS-2, GLUT4 and p85a regulatory subunit of the PI3Kinase, AKT and adipokines, together with the levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1). Because the capacity of the b-cell is closely associated with insulin action, the investigators will characterize the ability of the pancreatic b-cell to secrete insulin in vivo during fat excess. The investigators will determine if the defect in b-cell function is functional or structural. Understanding the biological events that take part in the development of insulin resistance and/or defective insulin secretion with increased fat intake during puberty may lead to the development of new strategies to prevent T2DM in the young population.
NIH ExPorter
NIH ExPorter