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The Q121 PC-1 Variant and Obesity Have Additive and Independent Effects in Causing Insulin Resistance

Istituto di Medicina Interna, Endocrinologia e Malattie del Metabolismo, Ospedale Garibaldi, Università di Catania (L.F., R.B., D.S., R.V.), 95123 Catania; Unità Operativa e di Ricerca di Endocrinologia, Istitito Scientifico Ospedale Casa Sollievo Sofferenza (R.D.P., V.T.), 71013 San Giovanni Rotondo (Foggia); and Dipartimento di Medicina Sperimentale e Patologia, Università di Roma "La Sapienza" and Istituto Scientifico Mendel CSS (A.P.), 00100 Roma, Italy

Address all correspondence and requests for reprints to: Lucia Frittitta, M.D., Endocrinologia, Ospedale Garibaldi, Piazza Santa Maria di Gesù, 95123 Catania, Italy. E-mail: segmeint{at}mbox.unict.it

Abstract

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 µmol/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.

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