Co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes.
OBJECTIVE
Paralleling the rise of pediatric obesity, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) is increasing among youth. In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents.


METHODS
We studied 714 obese subjects (290 boys and 424 girls; mean age 13.6 ± 3.1 years; mean z score BMI 2.2 ± 0.4) and evaluated the insulin secretion by using the oral minimal model and, in a subgroup of 37 subjects, the hyperglycemic clamp. Also, 203 subjects were followed up for a mean of 2.1 years.


RESULTS
We observed that the increase of risk alleles was associated with a progressive worsening of insulin secretion (P < 0.001) mainly due to an impairment of the dynamic phase of insulin secretion (P = 0.004); the higher the number of the risk alleles, the higher the chance of progression from normal glucose tolerance (NGT) to IGT/T2D (P = 0.022). Also, for those who were IGT at baseline, a higher risk score was associated with a lower odds to revert to NGT (P = 0.026).


CONCLUSIONS
Obese children and adolescents developing IGT/T2D have a higher genetic predisposition than those who do not show these diseases, and this predisposition is mainly related to gene variants modulating the early phase of insulin secretion. Although these data are very interesting, they need to be replicated in other cohorts.
Corresponding author: Nicola Santoro, nicola.santoro@yale.edu.
Cosimo
C
Giannini
Chiara
C
Dalla Man
Leif
L
Groop
Claudio
C
Cobelli
Hongyu
H
Zhao
Melissa M
MM
Shaw
Elvira
E
Duran
Bridget
B
Pierpont
Allen E
AE
Bale
Sonia
S
Caprio
Nicola
N
Santoro
D000293:Adolescent; D000483:Alleles; D002648:Child; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D009765:Obesity / Q000235:genetics*; D011236:Prediabetic State / Q000235:genetics*
D007328:Insulin