The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance.
PC-1 is a membrane glycoprotein that impairs insulin receptor function. Its K121Q polymorphism is a genetic determinant of insulin resistance. We investigated whether the PC-1 gene modulates insulin sensitivity independently of weight status (i.e. both in nonobese and obese individuals). Nondiabetic subjects [164 males, 267 females; age, 37 +/- 0.6 yr, mean +/- SEM; body mass index (BMI), 32.7 +/- 0.5 kg/m(2)], who were subdivided into 220 nonobese (BMI < or = 29.9) and 211 obese, were studied. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P < 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. Insulin sensitivity, measured by euglycemic clamp in a representative subgroup of 131 of 431 randomly selected subjects, progressively decreased (P < 0.001) from nonobese K121K [n = 61; glucose disposal (M) = 34.9 +/- 1.1 micromol/kg/min] to nonobese Q (n = 21; M = 29.9 +/- 2.0), obese K121K (n = 31, M = 18.5 +/- 1.2), and obese Q (n = 18, M = 15.5 +/- 1.2) carriers. The K121Q polymorphism was correlated with insulin sensitivity independently (P < 0.05) of BMI, gender, age, and waist circumference. In conclusion, the Q121 PC-1 variant and obesity have independent and additive effects in causing insulin resistance.
Frittitta
L
L
Istituto di Medicina Interna, Endocrinologia e Malattie del Metabolismo, Ospedale Garibaldi, Università di Catania, 95123 Catania, Italy. segmeint@mbox.unict.it
Baratta
R
R
Spampinato
D
D
Di Paola
R
R
Pizzuti
A
A
Vigneri
R
R
Trischitta
V
V
D000293:Adolescent; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D005215:Fasting / Q000502:physiology; D005260:Female; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D008875:Middle Aged; D009765:Obesity / Q000503:physiopathology*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D012044:Regression Analysis
D001786:Blood Glucose; D007328:Insulin; D008562:Membrane Glycoproteins; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases