Novel insulin-sensitizing NASH/diabetes drugs.

Obesity is associated with an increased risk of a number of chronic and progressive diseases and obesityrelated metabolic diseases constitute a significant public health burdenThe increased likelihood of developing insulin resistance and diabetes is probably the most commonly recognized risk of being obeseIn additionobesity is also associated with accumulation of lipid in the liver parenchymahepatic steatosis or nonalcoholic fatty liver diseaseNAFLDThe termNAFLDencompasses both hepatic steatosisthe accumulation of neutral lipid within the cytosol of hepatocytesand the more severe nonalcoholic steatohepatitisNASHhepatic inflammation and fibrosis associated with steatotic lesionsA significant proportion of NAFLD and NASH patients will progress to cirrhosis and liver failure and are at increased risk for developing hepatocellular carcinomaNASH is currently a disease without an approved treatment and constitutes a significant unmet medical needImportantlyinflammationinsulin resistanceand diabetes are tightly linked to development of NASH and thus drugs that target these contributing pathways are lead candidates for treating the diseaseThis application is designed to test the efficacy of new insulin sensitizing agents that act via a novel mechanism to improve insulin action while reducing side effectsWe will study a novel prototype compoundMSDCand its backupMSDCfor efficacy at treating insulin resistance and NASHIn Phase Iwe will determine whether these compounds improve insulin sensitivity and test the hypothesis that phospholipase DPLDsignaling is their molecular targetIn Phase IIwe will examine the hepatic effects of MSDCand MSDCin a mouse model of NASH and validate PLDgenetically in this modelFindings obtained in these studies will define mechanisms and provide proof ofconcept evidence supporting future clinical trials to test the efficacy of these drugs in patients with diabetes and other obesity related cardiometabolic diseases that have the potential to benefit millions of Americans Obesity is associated with increased risk of developing metabolic diseases including typediabetes and fatty liver diseaseThis project is designed to test the effects of new compounds as therapeutics for treating these metabolic diseases in miceIf successfulthese studies could pave the way to clinical trials to determine whether these drugs are effective in people as well