NONALCOHOLIC FATTY LIVER DISEASE IN TYPE 2 DIABETES MELLITUS

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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. OBJECTIVE: The objectives are to establish the magnitude of the epidemic of NAFLD in T2DM (protocol #1 or "Screening Study") and to compare the current standard of care (dietary intervention alone) vs. the insulin-sensitizer pioglitazone (protocol #2 or "Treatment of NAFLD Study"). We want to establish if pioglitazone is a disease-modifying agent for patients with T2DM and NAFLD/NASH. RESEARCH PLAN: Type 2 diabetes mellitus (T2DM) is a major public health problem, but less well recognized is that obesity and T2DM are fueling another "silent epidemic": nonalcoholic fatty liver disease (NAFLD). NAFLD is a chronic liver condition associated with insulin resistance, impaired glucose intolerance or frank type 2 diabetes (T2DM) and hepatic fat accumulation, ranging from simple steatosis to severe steatohepatitis with necroinflammation (NASH) and eventually fibrosis. The diagnosis of NAFLD and NASH is difficult as it gives few symptoms, the most common being vague right upper quadrant discomfort, and while liver enzymes may be elevated (ALTAST) in NAFLD, the real problem is that they are normal in ~2/3 of patients. Therefore, a large number of patients are undiagnosed and undergoing chronic liver damage. METHODS: There are two steps in this proposal. The first is to establish the magnitude of the epidemic of NAFLD in T2DM (protocol #1 or "Screening Study"). To this end, we plan to screen 250 unselected patients with T2DM for NAFLD from the San Antonio area non-invasively by magnetic resonance spectroscopy (MRS) which is the gold-standard technique. The second aim as outlined in protocol #2 ("Treatment of NAFLD Study") will be to estimate the incidence of NASH (hepatic fat accumulation plus necroinflammation and/or fibrosis by liver biopsy - the only way to establish this diagnosis as it cannot be done by imaging) and compare two treatments: the current standard of care (the empiric approach based on dietary intervention alone) vs. the insulin-sensitizer pioglitazone. This will allow us to establish if pioglitazone is a disease-modifying agent during long-term treatment, capable of changing the natural history of NAFLD/NASH in patients with T2DM. CLINICAL RELEVANCE: There are no large studies to date as the one proposed here to bridge the gap in our knowledge about the real magnitude of the epidemic of fatty liver disease in T2DM. The greater availability of MRS has allowed a fast and highly reproducible way to measure liver fat. In our experience with MRS over the past five years, we have established that ~80% of patients with T2DM have NAFLD and Hispanics had a greater hepatic fat content when matched for major pertinent variables (unpublished). Recent studies have confirmed that Hispanics are at much greater risk of NAFLD than Caucasians or African-Americans, making this proposal particularly relevant for the San Antonio community in order to develop new prevention and early intervention strategies.