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

Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6418-E6426. doi: 10.1073/pnas.1614467113. Epub 2016 Oct 5.


We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation. In the absence of KBTBD2, p85α accumulated to 30-fold greater levels than in wild-type adipocytes, and excessive p110-free p85α blocked the binding of p85α-p110 heterodimers to IRS1, interrupting the insulin signal. Both transplantation of wild-type adipose tissue and homozygous germ line inactivation of the p85α-encoding gene Pik3r1 rescued diabetes and hepatic steatosis phenotypes of Kbtbd2-/- mice. Kbtbd2 was down-regulated in diet-induced obese insulin-resistant mice in a leptin-dependent manner. KBTBD2 is an essential regulator of the insulin-signaling pathway, modulating insulin sensitivity by limiting p85α abundance.

Keywords: Kbtbd2; diabetes; insulin resistance; p85α; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue / metabolism
  • Adipose Tissue / transplantation
  • Animals
  • Blood Glucose
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Cullin Proteins / metabolism
  • Diabetes Mellitus / etiology*
  • Diabetes Mellitus / metabolism*
  • Diet / adverse effects*
  • Disease Models, Animal
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression Regulation
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • Insulin / blood
  • Insulin Resistance* / genetics
  • Lipodystrophy / etiology
  • Lipodystrophy / metabolism
  • Lipodystrophy / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Obesity / etiology
  • Obesity / pathology
  • Phenotype
  • Protein Binding
  • Protein Transport
  • Signal Transduction
  • Ubiquitination


  • Blood Glucose
  • Cul3 protein, mouse
  • Cullin Proteins
  • Insulin
  • Class Ia Phosphatidylinositol 3-Kinase