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/m2) 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 x kg(-1) x 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 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.

Resistin is overexpressed in human adipose tissue of obese individuals and is likely to modulate insulin sensitivity. Resistin is, therefore, a candidate gene for insulin resistance. We searched for polymorphisms in the resistin gene by single strand conformation polymorphism and direct sequencing. An ATG triplet repeat in the 3'-untranslated region was identified and considered for association with insulin resistance. Three alleles were identified (allele 1: 8 repeats, allele frequency, 0.3%; allele 2: 7 repeats; allele frequency, 94.5%; allele 3: 6 repeats; allele frequency, 5.2%). Two hundred and three unrelated white Caucasian nondiabetic subjects from Sicily and 456 from the Gargano area (center east coast of Italy) were analyzed. Among Sicilians, subjects carrying allele 3 had a lower fasting insulin and insulin resistance index (homeostasis model assessment of insulin resistance; P < 0.001 for both) and glucose (P = 0.025) and insulin (P = 0.002) levels during the oral glucose tolerance test. In subjects from Gargano, those carrying allele 3 had lower fasting plasma glucose levels and serum triglycerides (P = 0.01 for both). When the 2 populations were analyzed together, subjects carrying allele 3 had lower fasting insulin levels (P < 0.005), homeostasis model assessment of insulin resistance (P < 0.005), and serum triglycerides (P = 0.01). In conclusion, our data suggest that subjects carrying allele 3 of the resistin gene are characterized by relatively high insulin sensitivity.

Glycoprotein PC-1 inhibits insulin signaling and, when overexpressed, plays a role in human insulin resistance. Mechanisms of PC-1 overexpression are unknown. We have identified a haplotype in the 3-untranslated region of the PC-1 gene that may modulate PC-1 expression and confer an increased risk for insulin resistance. Individuals from Sicily, Italy, carrying the "P" haplotype (i.e., a cluster of three single nucleotide polymorphisms: G2897A, G2906C, and C2948T) were at higher risk (P < 0.01) for insulin resistance and had higher (P < 0.05) levels of plasma glucose and insulin during an oral glucose tolerance test and higher levels of cholesterol, HDL cholesterol, and systolic blood pressure. They also had higher (P < 0.05-0.01) PC-1 protein content in both skeletal muscle and cultured skin fibroblasts. In CHO cells transfected with either P or wild-type cDNA, specific PC-1 mRNA half-life was increased for those transfected with P (t/2 ‫؍‬ 3.73 ؎ 1.0 vs. 1.57 ؎ 0.2 h; P < 0.01). In a population of different ethnicity (Gargano, East Coast Italy), patients with type 2 diabetes (the most likely clinical outcome of insulin resistance) had a higher P haplotype frequency than healthy control subjects (7.8 vs. 1.5%, P < 0.01), thus replicating the association between the P allele and the insulin resistance-related abnormalities observed among Sicilians. In conclusion, we have identified a possible molecular mechanism for PC-1 overexpression that confers an increased risk for insulin resistance-related abnormalities.

Insulin resistance characterizes type 1 diabetes in patients with albuminuria. A PC-1 glycoprotein amino acid variant, K121Q, is associated with insulin resistance. We examined the impact of the PC-1 K121Q variant on the rate of decline of the glomerular filtration rate (GFR) by creatinine clearance derived from the Cockroft-Gault formula in 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years (range 2.5-15). Patients carrying the Q allele (n = 22; 20 with KQ and 2 with QQ genotypes) had a faster GFR decline than those patients with the KK genotype (n = 55) (median 7.2 vs. 3.7 m l · min -1 · year -1 ; range 0.16 to 16.6 vs. -3.8 to 16.0 m l · min -1 · year -1 ; P < 0.001). Significantly more patients carrying the Q allele belonged to the highest tertile of GFR decline (odds r a t i o = 5.7, 95% CI 4.1-7.2, P = 0.02). Levels of blood pressure, HbA 1 c , and albuminuria were comparable in the two genotype groups. Albuminuria (P = 0.001), mean blood pressure (P = 0.046), and PC-1 genotype (P = 0.036) independently correlated with GFR decline. Because all patients were receiving antihypertensive treatment, the faster GFR decline in the patients carrying the Q allele could be the result of reduced sensitivity to the renoprotective effect of antihypertensive t h e r a p y. PC-1 genotyping identifies type 1 diabetic patients with a faster progression of diabetic nephr o p a t h y. D i a b e t e s 4 9 :5 2 1-524, 2000 T he rate of progression of diabetic nephropathy (DN) varies greatly among individuals. Differences in environmental factors may explain part of this variability, but genetic factors, which are mostly unknown, also play an important role (1-6).Insulin resistance characterizes type 1 diabetes in patients with albuminuria and their nondiabetic first-degree relatives (7,8) and underlies many of the alterations of DN, including high blood pressure, lipid abnormalities, increased left ventricular mass, and a family history of hypertension and cardiovascular disease (9). These observations suggest that insulin resistance is likely to precede and play a role in the vascular damage of DN. As for DN, insulin resistance also recognizes genetic determinants (10). It is possible, therefore, that DN and/or its progression and insulin resistance share a common genetic background.The molecular mechanisms of insulin resistance are not completely understood (10,11). Recently, the role of specific inhibitors of insulin signaling has been described in human insulin resistance (10,11). These inhibitors include membrane glycoprotein PC-1 (12-16). We have recently reported an amino acid polymorphic variant of PC-1 glycoprotein, K121Q, which is strongly associated with insulin resistance (17). Because of the relationship between insulin resistance and DN, we have examined the impact of the PC-1 Q121 amino acid variant on the rate of DN progression.From January 1995 to April 1997, 77 type 1 diabetic patients with albuminuria attended the diabetes units of five participating centers (as descr...

OBJECTIVE -To study the relationships between the PC-1 K121Q variant and diabetic nephropathy (DN) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -A total of 125 patients with type 2 diabetesand abnormal albumin excretion rate (AER) (range 20 -5,416 g/min) were followed up for 4 years with repeated measurements of glomerular filtration rate (GFR). Genomic DNA was extracted from all patients, and the PC-1 K121Q polymorphism was determined by the PCR AvaII restriction enzyme. A subset of 64 patients underwent a percutaneous kidney biopsy at baseline, and glomerular structure was analyzed by electron microscopic morphometric analysis. At baseline, age (56 Ϯ 8 vs. 59 Ϯ 7 years), BMI (28.3 Ϯ 4.3 vs. 28.6 Ϯ 3.7 kg/m 2 ), known duration of type 2 diabetes (11.1 Ϯ 7 vs. 11.9 Ϯ 8 years), and HbA 1c (8.6 Ϯ 1.8 vs. 8.4 Ϯ 1.7%) were similar in K121K (KK, n ϭ 87, 73 men/14 women) and XQ (35 K121Q ϩ 3 Q121Q, n ϭ 38, 27 men/11 women) patients. Baseline GFR was 96 Ϯ 28 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 and was related (P ϭ 0.01-0.001) to age, known diabetes duration, and systolic blood pressure.RESULTS -XQ patients had lower GFR (P Ͻ 0.05) than KK patients (88 Ϯ 30 vs. 100 Ϯ 26 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 ); this difference persisted also after factoring in age and known diabetes duration. The rate of progression of DN was similar in KK and XQ patients: %⌬GFR was 4.1/year (median, range: 22.9 -30.6) vs. 4.2/year (9.8 -26.7). Morphometric parameters of diabetic glomerulopathy were similar in the two genotype groups.CONCLUSIONS -Among patients with type 2 diabetes with abnormal AER, those carrying the Q PC-1 genotype have more severe DN but not a faster GFR decline than KK patients, thus suggesting faster DN development since diabetes diagnosis in XQ patients. Insulin resistance has been suggested to play a role in DN in both type 1 diabetic (6) and type 2 diabetic (7) patients. Insulin resistance also has a genetic background (8); therefore, it is possible that insulin resistance and DN share some common genetic determinants. In line with this hypothesis, it has recently been reported that a plasma membrane glycoprotein PC-1 amino acid variant (Q121), which associates with insulin resistance in several populations (9,10), also associates with DN progression in some (11), although not all (12), European populations of type 1 diabetic patients with albuminuria. The Q121 PC-1 variant has also been reported to be associated with higher risk of early-onset end-stage renal failure in type 1 diabetic patients from the U.S. (13). Whether the Q121 PC-1 variant is associated with features of DN also in type 2 diabetic patients is unknown.The present study was aimed at investigating the relationship between the PC-1 gene and both severity and progression of kidney disease in a cohort of type 2 diabetic patients with abnormal albumin excretion rate (AER). In addition, in a subset of patients, the impact of the PC-1 gene on glomerular structure was investigated. RESEARCH DESIGN AND METHODS PatientsThis study was designed to explore the asso...