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/m²], who were subdivided into 220 nonobese (BMI ≤ 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 μ mol/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.