Figure 1. Overview of insulin action.

Left Panel: In the fed state, dietary carbohydrate (CHO) increases plasma glucose and promotes insulin secretion from the pancreatic β-cells. Insulin has numerous actions to promote storage of dietary calories, but only several are illustrated here. In the skeletal muscle, insulin increases glucose transport, permitting glucose entry and glycogen synthesis. In the liver, insulin promotes glycogen synthesis and de novo lipogenesis while also inhibiting gluconeogenesis. In the adipose tissue, insulin suppresses lipolysis and promotes lipogenesis. Middle Panel: In the fasted state, insulin secretion is decreased. The drop in insulin (as well as the action of other hormones which are not depicted), serve to increase hepatic gluconeogenesis and promote glycogenolysis. Hepatic lipid production diminishes while adipose lipolysis increases. Right Panel: In type 2 diabetes, ectopic lipid accumulation impairs insulin signaling (as depicted by the red “x”). With accumulation of intramyocellular lipid (IMCL), insulin mediated skeletal muscle glucose uptake is impaired. As a result, glucose is diverted to the liver. In the liver, increased liver lipid also impairs the ability of insulin to regulate gluconeogenesis and activate glycogen synthesis. In contrast, lipogenesis remains unaffected, and together with the increase delivery of dietary glucose, leads to increased lipogenesis and worsening NAFLD. Impaired insulin action in the adipose tissue allows for increased lipolysis which will promote re-esterification of lipids in other tissues (e.g. liver) and further exacerbates insulin resistance. Coupled with a decline in pancreatic β-cells (depicted by the smaller lines emanating from the pancreas), hyperglycemia develops.