Figure 9. Scheme illustrating the mechanism of ‘selective insulin resistance' in type 2 diabetes with obesity.

In type 2 diabetes with obesity, while the hepatocyte Irs1 expression levels remain unaffected by the hyperinsulinemia, the expression of Irs2 is downregulated in both the PP and PV zones. Thus, in the PP zone, where Irs1 is less abundantly expressed and Irs2 expression is downregulated, insulin signaling is impaired despite the hyperinsulinemia, leading to the impaired suppression of gluconeogenesis and hyperglycaemia; in contrast, in the PV zone, where Irs1 is abundantly expressed, insulin signaling is rather stimulated in the presence of hyperinsulinemia despite the downregulation of Irs2, resulting in the increased lipogenesis and development of steatosis.