Project Abstract/Summary Nonalcoholic steatohepatitis (NASH) is known to occur often in type 2 diabetes mellitus (T2DM). Hepatologists know this firsthand from their clinical experience as well as from many cross-sectional studies, where T2DM is common among patients with cirrhosis or HCC. However, this knowledge has not trickled down to primary care physicians (PCPs) or translated into a systematic screening of patients with T2DM. Most PCPs simply remain largely unaware about the health risks associated with NASH and have limited information about the epidemic of NASH in the primary care setting, therefore, not finding a reason why to screen or treat. New studies have led to a consensus among hepatologists that patients with moderate fibrosis (≥F2) are on a disease path that leads to cirrhosis or HCC, more cardiovascular disease and increased mortality. Unfortunately, most NASH patients today are not diagnosed until it is too late. With evidence that a generic drug such as pioglitazone (PIO) leads to resolution of NASH in ~60% of patients, this is a missed opportunity to save lives and resources. However, most hepatologists are uncomfortable with prescribing PIO due to undesirable side effects (weight gain, lower extremity edema, bone loss, bladder cancer?). However, since even low doses of PIO (15 mg/day) increases adiponectin ~2-fold and improves adipose tissue insulin resistance, it is likely that a similar effect may be achieved on hepatic “lipotoxicity” and liver histology with doses that have minimal side effects. However, this hypothesis has never been tested before in a dose-response study in pts with NASH. We propose to develop a novel strategy for patients with T2DM and NASH shifting the focus from a late diagnosis and referral to hepatology, to an early diagnosis and intervention in the PCP clinics. First, to establish the magnitude of the problem of moderate-to-advanced fibrosis (≥F2) within the PCP setting (Aim 1) we will screen for NAFLD/liver fibrosis by CAP/VCTE (Fibroscan). Those with NASH-fibrosis will be offered treatment with low-dose PIO (15 mg/day) or placebo (Aim 2; an intermediate-dose of 30 mg/day will be also used to compare safety and efficacy, but interest is on the 15 mg/day dose). We will avoid the high 45 mg/day doses used by our group for proof-of-concept studies but associated with long-term safety concerns and limited clinical acceptance. In Aim 3, all patients with T2DM and NAFLD (not participating in Aim 2) will be followed for ~4 years to establish the impact of NAFLD on diabetic complications (compared to diabetics without NAFLD). Recent cross-sectional studies suggest that NAFLD carries a greater risk of micro- and macrovascular diabetic complications. However, this has never been prospectively studied. In summary, the above highly complementary studies will offer the first compelling evidence of the epidemic of NASH-fibrosis within PCP clinics; test that NASH-fibrosis can be identified early-on in T2DM a...