The G972R variant of the insulin receptor substrate-1 (IRS-1) gene, body fat distribution and insulin-resistance.
OBJECTIVE
Insulin resistance is recognised as the core factor in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, hypertension and atherosclerosis. Several studies indicate the possible role of mutations of the insulin receptor substrate-1 (IRS-1) gene in the pathogenesis of insulin-resistance and suggest a possible interaction between the IRS-1 gene and obesity, either by an effect on the development of obesity or by causing or aggravating the obesity-associated insulin resistance. Therefore, the prevalence of the G972R mutation of the IRS-1 gene was compared in 157 non-diabetic obese subjects (BMI > 30 m/kg2) and in 157 lean subjects (BMI < 28 m/kg2). By investigating the relation between this IRS-1 mutation, measures of obesity and metabolic parameters, we explored the possible influence of this mutation on body fat distribution and insulin resistance.


METHODS
The G972R mutation was detected by PCR amplification and BstN-1 restriction enzyme digestion. Data were analysed by univariate and multivariate analysis.


RESULTS
The G972R allele was significantly more frequent in obese subjects than in lean subjects (p < 0.002); however, no difference was found between centrally and peripherally obese subjects. Obese G972R carriers had significantly higher BMI (p < 0.001), fasting insulin (p < 0.001), triglycerides (p < 0.03) and HOMAIR (p < 0.001) than obese non-carriers. No differences were observed between G972R carriers and non-carriers among control subjects. Multivariate analysis confirmed that the IRS-1 G972R mutation was significantly and independently associated with reduced insulin sensitivity (p < 0.009) in the obese group.


CONCLUSIONS
The G972R mutation of the IRS-1 gene associates with obesity, but not with fat distribution, in this Italian cohort, and within the obese subjects this IRS-1 variant strongly associates with metabolic parameters suggesting greater insulin-resistance. These findings indicate a possible interaction between the IRS-1 variant and obesity in worsening insulin sensitivity.
Baroni
M G
MG
Department of Clinical Science, Division of Endocrinology, University of Rome La Sapienza, Rome, Italy.
Arca
M
M
Sentinelli
F
F
Buzzetti
R
R
Capici
F
F
Lovari
S
S
Vitale
M
M
Romeo
S
S
Di Mario
U
U
D000273:Adipose Tissue / Q000033:anatomy & histology*; D019943:Amino Acid Substitution; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007558:Italy; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012016:Reference Values; D014280:Triglycerides / Q000097:blood; D044465:White People / Q000235:genetics
D001786:Blood Glucose; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008055:Lipids; D010750:Phosphoproteins; D014280:Triglycerides; C047564:CCANNNNNNTGG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific