Pathophysiology of Type 2 Diabetes in Youth

$379,818R01FY2009HDNIH

Yale University, New Haven CT

Investigators

Linked publications & trials

Paper 38410080 Paper 37870826 Paper 37847560 Paper 37227148 Paper 36260807 Paper 35766976 Paper 35235641 Paper 34725443 Paper 34672413 Paper 34000022 Paper 33291552 Paper 32363679 Paper 32125283 Paper 31972003 Paper 31399433 Paper 30938760 Paper 30663201 Paper 30236381 Paper 30225917 Paper 30003666 Paper 29665034 Paper 28640216 Paper 28611053 Paper 28482070 Paper 28279074 Paper 28192105 Paper 27054297 Paper 26718495 Paper 26457389 Paper 26043229 Paper 25919927 Paper 25645909 Paper 25633663 Paper 25168408 Paper 24062325 Paper 24062323 Paper 23913480 Paper 23815500 Paper 23626003 Paper 23582593 Paper 23275357 Paper 23209190 Paper 23179960 Paper 23047931 Paper 22998341 Paper 22933439 Paper 22928563 Paper 22629460 Paper 22523838 Paper 22464745 Paper 22336575 Paper 22315322 Paper 22110092 Paper 22105854 Paper 22093855 Paper 21981958 Paper 21730284 Paper 21525449 Paper 21515842 Paper 21300674 Paper 20843946 Paper 20829185 Paper 20805387 Paper 20803499 Paper 20668154 Paper 20573788 Paper 20467418 Paper 20204321 Paper 20168312 Paper 19717004 Paper 19490496 Paper 19434725 Paper 19153496 Paper 19106382 Paper 18987268 Paper 18761646 Paper 18306404 Paper 18303080 Paper 17977954 Paper 17717283 Paper 17595270 Paper 17593968 Paper 17481469 Paper 17475938 Paper 17118995 Paper 16926246 Paper 16912127 Paper 16639388 Paper 16456682 Paper 16231019 Paper 16150383 Paper 15919795 Paper 15797955 Paper 15793193 Paper 15673061 Paper 15522932 Paper 15175438 Paper 15001593 Paper 14511928 Paper 12727947

Abstract

DESCRIPTION (provided by applicant): This proposal requests renewed funding to continue our investigations of the pathophysiology of type 2 diabetes (T2DM) in youth. During the previous cycle, we studied the role of insulin resistance and beta-cell secretion in youth with impaired glucose tolerance (IGT). These studies revealed: 1) A high prevalence in IGT and the metabolic syndrome in obese youth (NEJM 2002 and 2004);2) Adolescents with IGT have profound peripheral insulin resistance associated with increased intramyocellular (IMCL) and visceral fat, beta-cell dysfunction, and low adiponectin levels (Lancet, 2003). 3) In only two years, 30% of the obese youth transitioned from IGT to T2DM. This new proposal represents the natural progression of our research into the health effects of childhood obesity by addressing mechanisms related to the development of IGT. The specific aims are: 1) To determine whether treatment of obese adolescents with IGT with Rosiglitazone will restore normal glucose tolerance by improving insulin sensitivity and affecting lipid deposition. 2) To determine whether inadequate beta-cell compensation to insulin resistance is present in obese subjects with normal glucose tolerance. To unmask early beta-cell dysfunction, we will assess insulin secretion in response to different stimuli (hyperglycemia, GLP-1, and arginine) and use mathematical modeling of c-peptide to determine insulin secretion in a selected sample of obese subjects with a high vs. a low Disposition Index. 3) To characterize the metabolic phenotype of obese subjects presenting with Non-Alcoholic Fatty Liver Disease (high ALT) and compare them to weight-matched controls. We will also determine in a longitudinal study if NAFLD predates IGT in obese adolescents. To accomplish these aims, we will use glucose clamps, stable isotopes kinetics, and MRI and 1H-NMR imaging. The study proposed here will not only provide further insights in the pathophysiology of T2DM in obese youth but will serve as a template for a large intervention study for the prevention of T2DM in this group.

View original record on NIH RePORTER →