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Project summary

Non-alcoholic fatty liver disease (NAFLD) is now the most common form of liver disease in the Western world, affecting one in three people in the general population, 90% of obese patients with type 2 diabetes, and 5.5 of 6 million Australians with liver disease – accounting for much of the $51 billion annual cost to our healthcare system. Liver fat is increasingly considered a primary driver of type 2 diabetes, although exact mechanisms remain unclear, and is an independent risk factor for atherosclerosis. Furthermore – and most clinically challenging – it is unknown which patients with liver fat will progress to metabolic complications.

We recently discovered a new plasma biomarker (dimethylguanidino valeric acid [DMGV]) of liver fat that independently predicted diabetes up to 12.8 years before diagnosis in three distinct human cohorts of different ethnicity (O’Sullivan et al., J Clin Invest, 2017). We have subsequently shown that DMGV is elevated in a human cohort of hepatic insulin resistance, and that the gene producing DMGV is upregulated in fatty liver disease. Intriguingly, in dietary models of NAFLD, we found sucrose (fructose + glucose) caused the most dramatic dysregulation of this pathway, consistent with recent reports showing fructose to have dramatic effects on hepatic insulin resistance in humans and mice.

Together, these data suggest this pathway is most activated in lipogenesis leading to hepatic insulin resistance. We have put together a comprehensive plan to test our proposed hypothesis, including dietary models and genetically modified murine models in addition to liver biopsy and plasma samples from carefully characterised human cohorts.

Publication

DMGV is a Marker of Liver Fat and Predicts Future Diabetes. John F O’Sullivan, Jordan E Morningstar, Baohui Zheng, Sarah Jeanfavre, Justin Scot, Qiong Yang, Celine Fernandez, Ramachandran S. Vasan, Michelle T. Long, Olle Melander, Thomas J. Wang, Caroline Fox, Randall T. Peterson, Clary Clish, Kathleen Corey, Robert E. Gerszten. J Clin Invest. 2017. PMID: 29083323.