The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance

被引:48
作者
Frittitta, L
Baratta, R
Spampinato, D
Di Paola, R
Pizzuti, A
Vigneri, R
Trischitta, V
机构
[1] Univ Catania, Osped Garibaldi, Ist Med Interna Endocrinol & Malattie Metab, I-95123 Catania, Italy
[2] Osped Casa Sollievo, Unita Operat & Ricerca Endocrinol, Ist Sci, I-71013 San Giovanni Rotondo, Foggio, Italy
[3] Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, I-00100 Rome, Italy
[4] Ist Sci Mendel CSS, I-00100 Rome, Italy
关键词
D O I
10.1210/jc.86.12.5888
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (ie. 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/m(2)], who were subdivided into 220 nonobese (BMI less than or equal to 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 mu 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.
引用
收藏
页码:5888 / 5891
页数:4
相关论文
共 21 条
[1]   Putting the genes for type II diabetes on the map [J].
Almind, K ;
Doria, A ;
Kahn, R .
NATURE MEDICINE, 2001, 7 (03) :277-279
[2]   Genetic polymorphisms and disease [J].
Altshuler, D ;
Kruglyak, L ;
Lander, E .
NEW ENGLAND JOURNAL OF MEDICINE, 1998, 338 (22) :1626-1626
[3]   METABOLIC AND GENETIC-CHARACTERIZATION OF PREDIABETIC STATES - SEQUENCE OF EVENTS LEADING TO NON-INSULIN-DEPENDENT DIABETES-MELLITUS [J].
BECKNIELSEN, H ;
GROOP, LC .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 94 (05) :1714-1721
[4]   INSULIN-RESISTANCE - INTERACTIONS BETWEEN OBESITY AND A COMMON VARIANT OF INSULIN-RECEPTOR SUBSTRATE-1 [J].
CLAUSEN, JO ;
HANSEN, T ;
BJORBAEK, C ;
ECHWALD, SM ;
URHAMMER, SA ;
RASMUSSEN, S ;
ANDERSEN, CB ;
HANSEN, L ;
ALMIND, K ;
WINTHER, K ;
HARALDSDOTTIR, J ;
BORCHJOHNSEN, K ;
PEDERSEN, O .
LANCET, 1995, 346 (8972) :397-402
[5]   The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121) [J].
Costanzo, BV ;
Trischitta, V ;
Di Paola, R ;
Spampinato, D ;
Pizzuti, A ;
Vigneri, R ;
Frittitta, L .
DIABETES, 2001, 50 (04) :831-836
[6]   A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans [J].
Duggirala, R ;
Blangero, J ;
Almasy, L ;
Arya, R ;
Dyer, TD ;
Williams, KL ;
Leach, RJ ;
O'Connell, P ;
Stern, MP .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (05) :1149-1164
[7]   PC-1 content in skeletal muscle of non-obese, non-diabetic subjects: Relationship to insulin receptor tyrosine kinase and whole body insulin sensitivity [J].
Frittitta, L ;
Youngren, J ;
Vigneri, R ;
Maddux, BA ;
Trischitta, V ;
Goldfine, ID .
DIABETOLOGIA, 1996, 39 (10) :1190-1195
[8]   Elevated PC-1 content in cultured skin fibroblasts correlates with decreased in vivo and in vitro insulin action in nondiabetic subjects - Evidence that PC-1 may be an intrinsic factor in impaired insulin receptor signaling [J].
Frittitta, L ;
Spampinato, D ;
Solini, A ;
Nosadini, R ;
Goldfine, ID ;
Vigneri, R ;
Trischitta, V .
DIABETES, 1998, 47 (07) :1095-1100
[9]   Increased adipose tissue PC-1 protein content, but not tumour necrosis factor-alpha gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine-kinase activity [J].
Frittitta, L ;
Youngren, JF ;
Sbraccia, P ;
DAdamo, M ;
Buongiorno, A ;
Vigneri, R ;
Goldfine, ID ;
Trischitta, V .
DIABETOLOGIA, 1997, 40 (03) :282-289
[10]   Association between the human glycoprotein PC-1 gene and elevated glucose and insulin levels in a paired-sibling analysis [J].
Gu, HF ;
Almgren, P ;
Lindholm, E ;
Frittitta, L ;
Pizzuti, A ;
Trischitta, V ;
Groop, LC .
DIABETES, 2000, 49 (09) :1601-1603