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. OBJECTIVE: Non-insulin dependent diabetes mellitus (NIDDM) is a common metabolic disorder that affects approximately ten million Americans and occurs with increased frequency in Mexican-Americans. The treatment of this disorder and related complications presents a large financial burden on the health care system. Despite numerous investigations into the pathogenesis of NIDDM, the primary metabolic and molecular abnormalities responsible for the glucose intolerance remain unclear. NIDDM patients with overt fasting hyperglycemia are characterized by the myriad of defects involving both insulin secretion and insulin action. The insulin resistance has been shown to affect all insulin target tissues, including muscle, adipose tissue, and liver, and to involve all pathways of glucose metabolism that have been examined. Disturbances in insulin receptor tyrosine kinase, glucose transport, glycogen synthesis, total glycolysis, anaerobic glycolysis, glucose oxidation, hepatic glucose production, and gluconeogenesis have been described. However, at this late stage in the natural history of NIDDM it is difficult to establish which defects are primary, and therefore inherited, and which defects are acquired secondarily to the decompensated metabolic state (i.e., hyperglycemia, insulinopenia, elevated plasma free fatty acid/amino acid levels and oxidation rate). To address this issue we will employ a comprehensive metabolic/molecular approach to study the normal glucose tolerant offspring of two Mexican-American parents with NIDDM. We have shown that the offspring have a marked impairment in insulin action and presumably are carrying the insulin resistant gene(s) that predispose to development of NIDDM later in life. DNA will be isolated from whole blood and WBC's in order to study DNA polymorphisms and marker genes for insulin resistance and to develop inheritance maps for NIDDM. RESEARCH PLAN AND METHODS: Our studies will employ state-of-the-art methodology developed in our laboratory to quantitate in vivo at the whole body and muscle level the following: glucose transport, glucose phosphorylation, total glycolysis, anaerobic glycosysis, glucose oxidation, and glycogen synthesis. These in vivo measurements will be correlated with in vitro quantitation of the activity of the key muscle enzymes (hexokinase II, glycogen synthase, pyruvate dehydrogenase, phosphofructokinase) involved in the regulation of flux through the major pathways of glucose disposal. The hexokinase II, glycogen synthase, and GLUT 4 transporter genes will be sequenced from the DNA which is harvested from peripheral leukocytes. Using immunoblot and RNase protection assays, respectively, the amount of hexokinase II/glycogen synthase/GLUT 4 protein and mRNA will be determined in biopsies obtained from the vastus lateralis muscle. By combining quantitative measures of transcription, translation, and enzymatic activity with in vivo fluxes in a normal glucose tolerant, insulin resistant population at high risk to develop NIDDM, we hope to be able to define the early metabolic and molecular defect(s) responsible for the pathogenesis of type II diabetes in Mexican-Americans. CLINICAL
From the qualitative standpoint, the metabolic defects that characterize NIDDM in Mexican-Americans are similar to those in Caucasians, we believe that our results will have generalized importance and will help to define the genetic basis of type II diabetes in other populations. Mexican-Americans comprise 5% (12 million) of the U.S. population and definition of the cause of NIDDM in this ethnic group alone would have major scientific, therapeutic and healthcare delivery significance.
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