A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance

The genes responsible for insulin resistance are poorly defined, Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance, We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m(2)) nondiabetic (by oral glucose tolerance test [OGTT]) Caucasians from Sicily, Compared with 80 KK subjects, Q allele carriers (n = 41, 39 KQ and 2 QQ) showed higher glucose and insulin levels during OGTT (P < 0.001 by two-way analysis of variance) and insulin resistance by euglycemic clamp (M value = 5.25 +/- 1.38 [n = 24] vs, 6.30 +/- 1.39 mg kg(-1) min(-1) [n = 49], P = 0,005), Q carriers had higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1,28-7,0], P < 0,001), Insulin receptor autophosphorylation was reduced (P < 0.01) in cultured skin fibroblasts from KQ versus RR subjects, Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 +/- 16.1 vs, 17.5 +/- 15 ng/mg protein, P = 0,3), These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease.