title: The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes.
abstract: BACKGROUND
  The prevalence of type 2 diabetes (T2D), particularly among young adults, has been rising steadily during the past 2 decades. T2D, especially in its early-onset subtype, is under genetic control. TRIB3 inhibits insulin-stimulated Akt phosphorylation and subsequent insulin action. A TRIB3 gain-of-function polymorphism, Q84R (rs2295490), impairs insulin signaling.
  
  
  OBJECTIVE
  The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped or not according to age at diagnosis (early-onset, <45 yr, or >or= 45 yr); 2) insulin secretion and sensitivity in nondiabetic individuals; or 3) in vitro insulin secretion from isolated human islets.
  
  
  METHODS
  Four different case-control samples comprising a total of 5,469 whites were examined. Insulinogenic and insulin sensitivity indexes and their interplay (disposition index) were assessed in 645 nondiabetic individuals at oral glucose tolerance test, glucose (16.7 mmol/liter)-induced in vitro insulin secretion was assessed in islets isolated from 54 nondiabetic donors.
  
  
  RESULTS
  In the whole sample, the R84 variant was nominally associated with T2D (odds ratio 1.17, 95% confidence interval 1.00-1.36, P = 0.04). When stratifying according to age of diabetes onset, R84 carriers had an increased risk of early-onset T2D (odds ratio 1.32, 95% confidence interval 1.10-1.58, P = 0.002). Among 645 nondiabetic subjects, R84 carriers had higher glucose levels (P = 0.005) and lower insulinogenic (P = 0.03) and disposition index (P = 0.02) during the oral glucose tolerance test. R84 islets were more likely to display relatively low glucose-stimulated insulin release (P = 0.04).
  
  
  CONCLUSIONS
  The TRIB3 R84 variant is associated with early-onset T2D in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association.
authors.affiliation: CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Prudente
authors.forename: Daniela
authors.initials: D
authors.lastname: Scarpelli
authors.forename: Manisha
authors.initials: M
authors.lastname: Chandalia
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Eleonora
authors.initials: E
authors.lastname: Morini
authors.forename: Silvia
authors.initials: S
authors.lastname: Del Guerra
authors.forename: Francesco
authors.initials: F
authors.lastname: Perticone
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Christine
authors.initials: C
authors.lastname: Powers
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Nicola
authors.initials: N
authors.lastname: Abate
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases; D005947:Glucose