Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes. The Finnish Diabetes Prevention Study.
OBJECTIVE
Type 2 diabetes is a complex disorder with strong heritability. The aim of our study was to investigate whether common polymorphisms in the genes regulating the early insulin signalling pathway (insulin; A-23T, insulin-like growth factor 1 receptor [IGF-1R]; GAG1013GAA, plasma cell membrane glycoprotein 1 [PC-1]; K121Q, insulin receptor substrate [IRS-1]; G972R, insulin receptor substrate 2 [IRS-2]; G1057D and phosphatidylinositol 3-kinase p85 alpha [PI3K]; M326I) affect the weight change and development of Type 2 diabetes in the Finnish Diabetes Prevention Study.


METHODS
We screened for the polymorphisms in 490 overweight subjects with impaired glucose tolerance whose DNA was available from the Finnish Diabetes Prevention Study. These subjects were randomly allocated into a control group and an intervention group characterised by intensive, individualised diet and exercise.


RESULTS
In carriers of the GAA1013GAA genotype of IGF-1R, the R972 allele of IRS-1 and the D1057D genotype of IRS-2, lifestyle intervention did not lead to significant differences in weight loss between the intervention and control groups, implying a role of these risk genotypes in the regulation of body weight. We observed a statistically significant difference in the conversion rate from IGT to diabetes between the genotypes of the IGF-1R gene (GAG1013GAG: 18.6%, GAG1013GAA: 10.4%, GAA1013GAA: 19.5%, p=0.033). Common polymorphisms in the insulin, PC-1 and PI3K genes did not regulate weight change or conversion to diabetes.


CONCLUSIONS
The common polymorphisms of the IGF-1R, IRS-1 and IRS-2 genes may modify the weight change response to a lifestyle intervention but not the conversion from IGT to Type 2 diabetes, whereas IGF-1R may also regulate the risk of developing Type 2 diabetes.
Laukkanen
O
O
Department of Medicine, University of Kuopio, Finland.
Pihlajamäki
J
J
Lindström
J
J
Eriksson
J
J
Valle
T T
TT
Hämäläinen
H
H
Ilanne-Parikka
P
P
Keinänen-Kiukaanniemi
S
S
Tuomilehto
J
J
Uusitupa
M
M
Laakso
M
M
D015992:Body Mass Index; D001835:Body Weight / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D005387:Finland / Q000453:epidemiology; D005787:Gene Frequency; D018149:Glucose Intolerance / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008019:Life Style; D018598:Minisatellite Repeats; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D015398:Signal Transduction / Q000235:genetics*
D007328:Insulin