Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice

Abstract

Significance We report an essential regulator of insulin sensitivity. Mutations affecting this protein, KBTBD2, cause severe insulin-resistant diabetes, lipodystrophy, hepatic steatosis, and growth retardation. KBTBD2 is the substrate recognition subunit of a ubiquitin ligase, and its essential molecular target is p85α, the regulatory subunit of phosphoinositol-3-kinase. KBTBD2 is highly conserved among vertebrates and expressed in liver, brain, muscle, and adipocytes. In the absence of KBTBD2, p85α levels rise 30-fold in adipocytes, interrupting the insulin signal, which is fully restored by p85α knockout. Transfer of KBTBD2-sufficient adipose tissue to KBTBD2-deficient animals rescues insulin-resistant hyperglycemia. Within adipocytes, KBTBD2 expression is markedly down-regulated in response to a high-fat diet. This appears to be an important cause of the insulin resistance caused by obesity.