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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD042172-03
Application #
6921448
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Grave, Gilman D
Project Start
2003-07-07
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$126,792
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
041581026
City
New York
State
NY
Country
United States
Zip Code
10467
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Lin, Chia-Lei; Williams, Lyda; Seki, Yoshinori et al. (2014) Effects of genetics and in utero diet on murine pancreatic development. J Endocrinol 222:217-27
Williams, Lyda; Seki, Yoshinori; Vuguin, Patricia M et al. (2014) Animal models of in utero exposure to a high fat diet: a review. Biochim Biophys Acta 1842:507-519
Vuguin, Patricia M; Hartil, Kirsten; Kruse, Michael et al. (2013) Shared effects of genetic and intrauterine and perinatal environment on the development of metabolic syndrome. PLoS One 8:e63021
Ouhilal, Sophia; Vuguin, Patricia; Cui, Lingguang et al. (2012) Hypoglycemia, hyperglucagonemia, and fetoplacental defects in glucagon receptor knockout mice: a role for glucagon action in pregnancy maintenance. Am J Physiol Endocrinol Metab 302:E522-31
Seki, Yoshinori; Williams, Lyda; Vuguin, Patricia M et al. (2012) Minireview: Epigenetic programming of diabetes and obesity: animal models. Endocrinology 153:1031-8
Vuguin, P M; Charron, M J (2011) Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models. Diabetes Obes Metab 13 Suppl 1:144-50
Vuguin, Patricia Myriam (2010) Interventional studies for polycystic ovarian syndrome in children and adolescents. Ped Health 4:59-73
Raab, Elisabeth L; Vuguin, Patricia M; Stoffers, Doris A et al. (2009) Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats. Am J Physiol Regul Integr Comp Physiol 297:R1785-94

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