Varman Samuel, MD, PhD

My research focuses on the underlying mechanisms leading to ectopic hepatic lipid accumulation (nonalcoholic fatty liver disease, NAFLD) and the impact on liver insulin action and inflammation. Dysregulation of insulin signaling and hepatic glucose production account for two of the most common clinical findings in patients with type 2 diabetes: impaired glucose tolerance and fasting hyperglycemia. Hepatic insulin resistance arises when an increase in hepatic sn 1,2 diacylglycerol activated protein kinase c epsilon which then impairs hepatic insulin receptor kinase activation. This proximal defect in insulin signaling impacts all downstream pathways tied to insulin signaling.

Recently, our lab has been focused on fructose metabolism. We have explored the use of ketohexokinase inhibition using novel antisense oligonucleotides on the development of insulin resistance in rodents fed modest fructose diets that mimic the amounts consumed by humans. Interestingly, this seems to primarily improve white adipose tissue insulin action, suggesting that the primary defect induced by modest amounts of fructose may be at the level of white adipose tissue. The development of hepatic steatosis and hepatic insulin resistance may be secondary to adipose dysfunction. We will explore this hypothesis in rodent and tissue culture models.

In addition, we have used our experience and techniques studying NAFLD to better understanding the pathogenesis of alcohol-associated liver disease (AALD). Together with collaborators, we are applying novel isotopic techniques to quantifying changes in liver mitochondrial flux in acute and chronic models of AALD and assessing the impact of emerging NALFD therapies (i.e. mitochondrial uncouplers and acetyl-CoA carboxylase inhibition). These studies may provide insights into the links between mitochondrial function, lipid accumulation and inflammation