Digenic inheritance of severe insulin resistance in a human pedigree

Nat Genet. 2002 Aug;31(4):379-84. doi: 10.1038/ng926. Epub 2002 Jul 15.


Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • CHO Cells
  • Cricetinae
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diabetes Mellitus, Type 2 / genetics
  • Female
  • Frameshift Mutation
  • Heterozygote
  • Humans
  • Insulin Resistance / genetics*
  • Male
  • Middle Aged
  • Pedigree
  • Phosphoprotein Phosphatases / genetics*
  • Phosphoprotein Phosphatases / metabolism
  • Protein Phosphatase 1
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • Transcription Factors
  • PPP1R3A protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1