The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes.
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.
Prudente
Sabrina
S
CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy.
Scarpelli
Daniela
D
Chandalia
Manisha
M
Zhang
Yuan-Yuan
YY
Morini
Eleonora
E
Del Guerra
Silvia
S
Perticone
Francesco
F
Li
Rong
R
Powers
Christine
C
Andreozzi
Francesco
F
Marchetti
Piero
P
Dallapiccola
Bruno
B
Abate
Nicola
N
Doria
Alessandro
A
Sesti
Giorgio
G
Trischitta
Vincenzo
V
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*
D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D017346:Protein Serine-Threonine Kinases; D005947:Glucose