Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Insulin Resistance In Adolescents With Diabetes: A New Frontier For Cardiovascula

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Diabetes mellitus (DM) is increasingly prevalent among youth, forecasting early complications. Type 1 (T1D) and Type 2 diabetes (T2D) cause premature cardiovascular disease (CVD), shortening lifespan despite advances in glycemic control and CV risk factor modification. Insulin resistance (IR) appears predominant in the pathophysiology of CVD in T2D, but the cause of increased CVD in T1D remains unclear. IR may contribute to CVD in T1D as in T2D, as we and others reported the presence of IR in T1D. Much less is known about IR in T1D vs.T2D, but for both, a better understanding of the mechanistic role of IR is critical to understanding causes and directing treatments of CVD complications. Our long-term goal is to understand early CVD pathogenesis in DM and thereby target interventions to decrease DM-associated morbidity and mortality. Our novel preliminary data suggest that even reasonably well-controlled, non-obese, T1D youth are IR, correlating with CV abnormalities and exercise defects, but with a unique clinical phenotype that appears to differ from T2D. The immediate goals of this proposal are to determine the unique CV abnormalities in T1D compared to T2D youth, their relationship to IR, and the distinctions in the IR phenotype of T1D vs. T2D youth. A clear understanding of these facets will help point the way to underlying mechanisms, and direct future specific interventions aimed at improving the abnormalities identified. Hypothesis 1: IR negatively impacts cardiac and vascular function in T1D and T2D youth. Aim 1: To determine whether cardiac and vascular function differ in T1D vs. T2D youth compared to controls, using stress echocardiography and vascular measures, and whether the differences are related to IR. Hypothesis 2: The IR of T1D is primarily skeletal muscle in origin, in contrast to T2D, which includes a combination of muscle, liver and adipose IR. Aim 2: To determine if IR in T1D youth is primarily skeletal muscle in origin, and thus differs from T2D. Aim 2a: To define and compare the degree and site of IR in youth with T1D compared to T2D, by exploring the relative contribution(s) of hepatic, peripheral, and adipose IR by hyperinsulinemic clamp. Aim 2b: To determine whether abnormalities in hepatic, visceral and muscle fuel stores, substrate utilization and/or lipid metabolism by MRI/MRS, all potential contributors to IR, occur in T1D youth vs.T2D and controls. Hypothesis 3: Improved glycemic control will improve the IR, cardiac, and vascular dysfunction of T1D. Aim 3: To determine the effects of intensive glucose control on IR and CV dysfunction in T1D youth. Examining the effects of intensive glucose control will help determine hyperglycemias importance in cardiac and vascular dysfunction and identify aspects of IR not ameliorated by glycemic control. This data will enhance our understanding of early CV dysfunction and may support early intensification of glycemic control and/or focused treatment of IR in T1D youth, potentially changing the entire approach to T1D management in all youth.
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