S. Ura et al., MOLECULAR SCANNING OF THE INSULIN-RECEPTOR SUBSTRATE-1 (IRS-1) GENE IN JAPANESE PATIENTS WITH NIDDM - IDENTIFICATION OF 5 NOVEL POLYMORPHISMS, Diabetologia, 39(5), 1996, pp. 600-608
Citations number
36
Categorie Soggetti
Endocrynology & Metabolism","Medicine, General & Internal
Since the insulin receptor substrate-1 (IRS-1) is the major substrate
of the insulin receptor tyrosine kinase and has been shown to activate
phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, t
he IRS-1 gene is a potential candidate for development of non-insulin-
dependent diabetes mellitus (NIDDM). In this study, we have identified
IRS-1 gene polymorphisms, evaluated their frequencies in Japanese sub
jects, and analysed the contribution of these polymorphisms to the dev
elopment of NIDDM. The entire coding region of the IRS-1 gene of 94 su
bjects (47 NIDDM and 47 control subjects) was screened by polymerase c
hain reaction-single stranded conformation polymorphism (PCR-SSCP) ana
lysis. Seven SSCP polymorphisms were identified. These corresponded to
two previously identified polymorphisms [Gly(971)-->Arg (GGG-->AGG) a
nd Ala(804) (GCA-->GCG)] as well as five novel polymorphisms [Pro(190)
-->Arg (CCC-->CGC), Met(209)-->Thr (ATG-->ACG), Ser(809)-->Phe (TCT-->
TTT), Leu(142) (CTT-->CTC), and Gly(625) (GGC-->GGT)]. Although the pr
evalence of each of these polymorphisms was not statistically differen
t between NIDDM and control subjects, the prevalence of the four IRS-1
polymorphisms with an amino acid substitution together was significan
tly higher in NIDDM than in control subjects (23.4 vs 8.5%, p < 0.05),
and two substitutions (Met(209)-->Thr and Ser(809)-->Phe) were found
only in NIDDM patients. Equilibrium glucose infusion rates during a eu
glycaemic clamp in NIDDM and control subjects with the IRS-1 polymorph
isms decreased by 29.5 and 22.0%, respectively on the average when com
pared to these in comparable groups without polymorphisms, although th
ey were not statistically significant. Thus, IRS-1 polymorphisms may c
ontribute in part to the insulin resistance and development of NIDDM i
n Japanese subjects; however, they do not account for the major part o
f the decrease in insulin-stimulated glucose uptake which is observed
in subjects with clinically apparent NIDDM.