The genes responsible for insulin resistance are poorly defined. Plasma cell differentiation antigen (PC-l) 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 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 KK subjects. Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 ± 16.1 rs. 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.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism