Unraveling the Regulation of Hepatic Metabolism by Insulin

Abstract

During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechanisms in insulin regulation of liver glucose and lipid metabolism. We posit that a failure of insulin to inappropriately regulate liver metabolism during T2DM is not exclusively from an inherent defect in canonical liver insulin signaling but is instead due to a combination of hyperinsulinemia, altered substrate supply, and the input of several extrahepatic signals.

Keywords: de novo lipogenesis; hepatic glucose production; insulin signaling; liver metabolism.

Figure 1. Insulin-dependent signaling mechanisms in liver in the regulation of hepatic lipid and glucose metabolism

In response to a meal, insulin concentrations rise and signal in liver to regulate hepatic lipid and glucose metabolism. Upon engagement of its receptor (insulin receptor) resulting in autophosphorylation, insulin receptor substrates (IRS) are recruited and phosphorylated. IRS proteins then recruit and activate PI3K, which phosphorylates PIP₂ to generate PIP₃. PDK1 is then activated by PIP₃, which phosphorylates Akt at Thr308. Additionally, Akt is activated by phosphorylation by mTORC2 at Ser473. Once fully activated, Akt signals via phosphorylation to control multiple metabolic processes in liver including glycogen synthesis, gluconeogenesis, glycolysis, and lipid synthesis. Active Akt induces glycogen synthesis by both multiple mechanisms including GSK3-dependent and independent pathways. Akt inhibits gluconeogeneic gene expression by phosphorylating and inhibiting FoxO1, which is a transcription factor involved in the activation of G6pc and Pck1. In addition, inhibition of FoxO1 in part leads to the induction of glucokinase gene expression. Lastly, Akt activates the mTORC1 and protein synthesis pathways by phosphorylating and inhibiting the TSC proteins. By activating mTORC1 and inhibiting FoxO1, Akt promotes the activation of SREBP1c and the lipogenic gene program increasing lipid synthesis.