Low paraoxonase activity in type II diabetes mellitus complicated by retinopathy.
Human serum paraoxonase 1 (PON1) is located on high-density lipoprotein and has been implicated in the detoxification of organophosphates, and possibly in the prevention of lipid peroxidation of low-density lipoprotein. PON1 has two genetic polymorphisms, both due to amino acid substitutions: one involving glutamine (Q genotype) and arginine (R genotype) at position 192, and the other involving leucine (L genotype) and methionine (M genotype) at position 55. We investigated the effects of these polymorphisms, and of a polymorphism of the PON2 gene at position 310 (Cys/Ser; C and S genotypes respectively), on serum PON1 activity and concentration, plasma lipids and lipoproteins and glycaemic control in 93 individuals with type II diabetes with no complications and in 101 individuals with type II diabetes with retinopathy. Serum PON1 activity in the group with no complications [median 164.1 nmol.min(-1).ml(-1) (range 8.0-467.8)] was significantly higher than in the group with retinopathy [113.4 nmol. min(-1).ml(-1) (3.0-414.6)] (P<0.001), but the serum PON1 concentration was not different between the groups. The gene frequencies of the PON1-55 and PON1-192 polymorphisms and of the PON2-310 polymorphism were not different between the study populations. The PON1-55 and PON1-192 polymorphisms affected PON1 activity in the way described in a previous study of a control group and subjects with type II diabetes. The PON2-310 polymorphism also significantly affected serum PON1. PON1 activity was significantly higher in individuals with the PON2-310 CC genotype in both groups with type II diabetes, and the PON1 concentration was significantly higher in PON2-310 CC homozygotes with no complications than in the group with retinopathy. Neither the PON1-55 nor the PON1-192 polymorphism was correlated with the serum lipid or lipoprotein concentration in either group. In the group with retinopathy (but not the group with no complications), all three PON polymorphisms were correlated with glycaemic control, which was worse for the PON1-55 genotypes in the order MM>LM>LL (P=0.0032), for the PON1-192 genotypes in the order RR>QR>QQ (P=0.011) and for the PON2-310 genotypes in the order CC>CS>SS (P=0.010). Low serum PON1 activity in retinopathy may be related to an increased tendency for lipid peroxidation. Our findings thus raise the possibility that, in retinopathy, the PON2 gene may influence PON1, and that an inter-relationship between the PON1 and PON2 genes may influence glycaemic control in subjects with type II diabetes complicated by retinopathy.
Mackness
B
B
University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. bmack@central.cmht.nwest.nhs.uk
Durrington
P N
PN
Abuashia
B
B
Boulton
A J
AJ
Mackness
M I
MI
D000368:Aged; D000704:Analysis of Variance; D043303:Aryldialkylphosphatase; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D003930:Diabetic Retinopathy / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D004950:Esterases / Q000097:blood* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
D001786:Blood Glucose; D008055:Lipids; D008074:Lipoproteins; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human