This is a competing renewal to evaluate factors contributing to insulin resistance and beta-cell compensation in overweight Hispanic children during puberty. The overall objective is to examine mechanisms underlying changes in insulin action, insulin secretion and beta-cell function in the progression of type 2 diabetes (T2D) and cardiovascular risk during this critical period. We have established a cohort of 222 overweight Hispanic children and shown that 28% have pre-diabetes (associated with reduced beta cell function), and 30% have the metabolic syndrome (related to greater insulin resistance). The continuation has four aims: 1) To determine the contribution of visceral fat, intramyocellular lipid (IMCL), liver fat and adipokines to insulin resistance. It is hypothesized that visceral fat, IMCL and liver fat will all independently contribute to greater insulin resistance, and these effects will be mediated by adipokines. 2) To examine the impact of puberty on insulin resistance, insulin secretion and beta-cell compensation. It is hypothesized that there will be progressive worsening of insulin resistance across all stages of puberty and compensatory insulin secretion will be blunted in advanced maturation. 3) To determine changes in insulin resistance, insulin secretion and beta-cell compensation in the progression to T2D. It is hypothesized that T2D will develop when there is failure in beta-cell compensation. 4) To assess the impact of the metabolic syndrome on progression of T2D and cardiovascular disease via the measurement of intima media thickness (IMT) of the carotid artery. It is hypothesized that IMT will be greater in adolescents with the metabolic syndrome and will worsen in parallel with the progression of insulin resistance and development of T2D. This study will establish whether the factors contributing to insulin resistance, beta-cell compensation, cardiovascular risk and T2D are similar in Hispanic adolescents compared to adults. The findings will be valuable for the design of treatment and prevention interventions in this high-risk population. ? ?
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