A cluster of three single nucleotide polymorphisms in the 3'-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is associated with increased PC-1 protein content and insulin resistance-related abnormalities.
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.
Frittitta
L
L
Institute of Internal Medicine, Endocrine and Metabolic Diseases, University of Catania, Ospedale Garibaldi, Catania.
Ercolino
T
T
Bozzali
M
M
Argiolas
A
A
Graci
S
S
Santagati
M G
MG
Spampinato
D
D
Di Paola
R
R
Cisternino
C
C
Tassi
V
V
Vigneri
R
R
Pizzuti
A
A
Trischitta
V
V
D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D016466:CHO Cells; D015331:Cohort Studies; D006224:Cricetinae; D003609:Dactinomycin / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005091:Exons; D005260:Female; D006580:Genetic Carrier Screening; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007558:Italy; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011755:Pyrophosphatases; D012333:RNA, Messenger / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D012307:Risk Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D044465:White People / Q000235:genetics
D020413:3' Untranslated Regions; D001786:Blood Glucose; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D003609:Dactinomycin; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases