title: Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes.
abstract: OBJECTIVE
  Genetic defects in human pericentrin (PCNT), encoding the centrosomal protein pericentrin, cause a form of osteodysplastic primordial dwarfism that is sometimes reported to be associated with diabetes. We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system.
  
  
  METHODS
  A cross-sectional metabolic assessment of 21 patients with PCNT mutations was undertaken. Pericentrin expression in human tissues was profiled using quantitative real-time PCR. The effect of pericentrin knockdown on insulin action and adipogenesis in 3T3-L1 adipocytes was determined using Oil red O staining, gene-expression analysis, immunoblotting, and glucose uptake assays. Pericentrin expression and localization also was determined in skeletal muscle.
  
  
  RESULTS
  Of 21 patients with genetic defects in PCNT, 18 had insulin resistance, which was severe in the majority of subjects. Ten subjects had confirmed diabetes (mean age of onset 15 years [range 5-28]), and 13 had metabolic dyslipidemia. All patients without insulin resistance were younger than 4 years old. Knockdown of pericentrin in adipocytes had no effect on proximal insulin signaling but produced a twofold impairment in insulin-stimulated glucose uptake, approximately commensurate with an associated defect in cell proliferation and adipogenesis. Pericentrin was highly expressed in human skeletal muscle, where it showed a perinuclear distribution.
  
  
  CONCLUSIONS
  Severe insulin resistance and premature diabetes are common features of PCNT deficiency but are not congenital. Partial failure of adipocyte differentiation may contribute to this, but pericentrin deficiency does not impair proximal insulin action in adipocytes.
authors.affiliation: Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Huang-Doran
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Francis M
authors.initials: FM
authors.lastname: Finucane
authors.forename: Nuno
authors.initials: N
authors.lastname: Rocha
authors.forename: Keith M
authors.initials: KM
authors.lastname: Porter
authors.forename: Y C Loraine
authors.initials: YC
authors.lastname: Tung
authors.forename: Ferenc
authors.initials: F
authors.lastname: Szekeres
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.forename: John J
authors.initials: JJ
authors.lastname: Nolan
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Michael
authors.initials: M
authors.lastname: Bober
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D000941:Antigens / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001823:Body Composition / Q000235:genetics; D002648:Child; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000941:Antigens; C086178:pericentrin