This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the United States, the prevalence of diabetes mellitus has increased dramatically over the past 30 years. The vast majority of cases are insulin-resistant or type 2 diabetes mellitus (T2DM). This rapid increase in the prevalence of T2DM parallels the dramatic increase in obesity (and its attendant effects on insulin sensitivity). Cardiovascular disease is the leading cause of death in patients with T2DM, with atherosclerosis accounting for approximately 80% of the cases. The reason for suseceptibility of T2DM patients to cardiovascular disease in general and atherosclerosis in particular, is multifactorial. The cluster of insulin resistance, hyperglycemia, dyslipidemia, hypercoagubility, obesity and hypertension known as the 'metabolic sydrome' is largely responsible for the increase in coronary atherosclerosis. However, even when evidence of epicarial involvement of coronary atherosclerosis is not present, significant abnormalities in myocardial endothelial-dependent vasodilator capacity can manifest. Moreover, there is increaseing evidence for true diabetic cardiomyopathy - The presence of left ventricular systolic and diastolic dysfunction that occurs in the absence of concomitant coronary artery disease. Indeed, the presence of diabetes mellitus significantly increases the risk for congestive heart failure in both older men and women. Consequently, the clinical picture of cardiovascular disease in the T2DM patient is complex. That being said, there is a burgeoning body of evidence to suggest that abnormalities in both whole-body and myocardial substrate metabolism are contributing to the cardiovascular abnormalities observed in T2DM patients. The primary objective is to extend our studies of the alterations in myocardial substrate metabolism and function in patients with type 1 diabetes mellitus (T1DM), to the study of myocardial substrate metabolism and function in relation to whole-body substrate metabolism in patients with T2DM. There is a wealth of evidence obtained in experimental models of T2DM and our own data in patients wih T1DM that suggests a central role for increased fatty acid availability (in the form of NEFA and TG) for the increase in myocardial fatty acid metabolism and the decrease in glucose metabolism and subsequent decline in left ventricular diastolic function in patients with T2DM. To test our hypothesis that reaching both a targeted level of glycemic contorl and lowering plasma NEFA and TG levels will be associated with a greater decline in the dependence of the myocardium on fatty acid metabolism and a greater improvement in myocardial diastolic function than treatment strategies designed solely to reach target level of glycemic control, our specific aims are: 1A: To assess the impact of lowering plasma NEFA in patients with T2DM, we will determine the effect of adding the PPARy (peroxisome proliferator activated receptor-gamma) agonist ROSI to a regimen of metformin (MET) +/- other non-thiazolidinedione oral agents (MET) on whole body substrate metabolism and on myocardial substrate metabolism and function. 1B: To assess the impact of lowering plasma TG in patients with T2DM, we will determine the effect of adding an extended-release niacin agent, NI to a regimen of MET +/- other non-thiazolidinedione oral agents (MET) on whole-body substrate metabolism and on myocardial substrate metabolism and function. We will perform a series of experiments that utilize PET (positron emission tomography) quantification of myocardial substrate metabolism, echocradiographic measurements of left ventricular systolic and diastolic function and stable isotopic measurement of whole-body fatty acid and glucose kinetics in T2DM patients. The measurements will be obtained in three groups; those on MET alone, those on MET and ROSI, and those on MET and NI. When combined with the results from Project 2, alterations in whole-body and myocardial substrate metabolism in response to specific interventions observed in humans with T2DM will be linked to changes in gene expression in the rodent models undergoing the same interventions. This data may potentially provide support for a paradigm shift in the treatment of T2DM through the incorporation of therapies designed to decrease NEFA delivery to the heart. Successful completion of this project should provide key insights into the link between the effects of T2DM on peripheral substrate metabolism, myocardial substrate metabolism and left ventricular (LV) function. Demonstration that reduced fatty acid delivery results in less myocardial dependence on fatty acid metabolism and improved LV function will provide strong evidence for the need for aggressive lowering of plamsa NEFA and TG. Furthermore, information may be obtained about the relative merits of lowering NEFA as opposed to TG. Data from this project may help stimulate the development of novel therapeutics designed to decrease plasma fatty acid availability in patients with T2DM. Moreover, it may provide the basis for larger studies to evaluate the clinical efficacy of therapies designed to lower plasma fatty acid availability either alone or in combination with therapies targeted primarily to glycemic control in patients with T2DM.
Showing the most recent 10 out of 497 publications
