MITOCHONDRIA AND METABOLIC SYNDROME IN A SOUTHERN CALIFORNIA CHINESE COHORT

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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. Since our laboratory's initial linkage of Type 2 diabetes to a mtDNA rearrangement in a three generation maternal pedigree 13 years ago, there has been increasing support for our hypothesis that mitochondrial dysfunction plays an important role in the etiology of Type 2 Diabetes Mellitus (DM) and the overlapping Metabolic Syndrome (MS). With this study we are planning to substantially expand upon the existing knowledge in the field by an extensive investigation of defects in mitochondrial oxidative phosphorylation (OXPHOS) caused potentially by deleterious sequence variants in the mitochondrial DNA (mtDNA). These diabetogenic mtDNA variants are proposed to range from recent, relatively severe, mutations resulting in substantial OXPHOS defects with familial DM & MS to ancient, relatively mild, polymorphisms that result in partial OXPHOS defects and an increase in the risk to develop DM & MS. To test this hypothesis, we propose to analyze the mtDNAs of an existing collection of samples from Taiwan Chinese families, which exhibit maternal transmission of DM & MS as well as approximately 500 Taiwan Chinese DM/MS non familial cases and controls to identify causal pathogenic mtDNA mutations. The study is designed to look for associations between the common Asian mtDNA lineages (haplogroups) and predisposition to MS and DM. The Taiwanese cohort of samples will not be included under this IRB application but will fall under a separate, exempt status application which has been submitted to the Investigational Review Board. (application submitted 11/01/05). Once diabetes associated mtDNA mutations and polymorphisms have been identified in the Taiwanese cohort, the robustness of the association between the Asian mtDNA variants and DM & MS needs to be confirmed. For this and also to control for environmental effects, we will then recruit a total of 500 DM & MS patients and unaffected controls from the Southern California Chinese population and screen them for the familial mtDNA mutations and for associations between Asian-specific haplogroups and DM & MS. This cohort of patients will be consented under the current application. All of the enrolled DM/ MS patients will be ascertained by Dr Ping Wang of the UCI Medical Center . Normal controls will be recruited using listservs, the uci website as well as other recruitment materials (i.e. flyers). All study participants will need to be characterized by sex, age, weight, height, weight/height ratio, body mass index (BMI), age of onset of symptoms (in patients) and hypertension. A blood samples for fasting blood glucose (AC), post-loading blood glucose (PC), blood triglyceride levels (TG), total blood cholesterol (TCHO), low density lipoprotein (LDL), high density lipoprotein (HDL), blood creatinine (Cre), hemoglobin A1C (HbA1C, glycated hemoglobin) needs to be submitted. In addition a blood sample for generation of DNA is required and will be used for all mtDNA analyses. No invasive procedures other than blood draw are included in this proposal. A subset of up to 15 patients of the Southern California DM & MS patients, found to have contributory mtDNA variants, will then be offered to participate in more extensive physiological investigations. If interested these patients will be enrolled into our Master Protocol : Mitochondrial Inborn Errors of Metabolism and ANT Defects in Mitochondrial Diseases; A Master Protocol (IRB # 2002-2608). This group of patients is then extensively characterized clinically, physiologically, and biochemically to clarify the nature of the mitochondrial defect(s) associated with DM & MS. Once the mitochondrial defect(s) of these patients has been defined, the data will be used to develop two non-invasive screening tools to detect mitochondrial defects in DM & MS patients: Micro-Organic Breath Test (MOBT) to evaluate the patient's metabolic status and Trans-Dermal Near Infrared Spectroscopy (TDNIRS) to assess muscle mitochondrial OXPHOS function.