The paraoxonase PON1 promoter polymorphism C(-107)T is associated with increased serum glucose concentrations in non-diabetic patients.

AIMS/HYPOTHESIS: Oxidative stress could contribute to diabetes and its complications by predisposing to insulin resistance. Lipid peroxidation products are thought to be one mechanism involved in reduced insulin sensitivity. The serum enzyme, paraoxonase-1, protects lipoprotein lipids from oxidation. We examined the hypothesis that paraoxonase-1 could be associated with abnormal serum glucose concentrations in non-diabetic patients. METHODS: Serum paraoxonase-1 activities and concentrations, as well as paraoxonase-1 gene polymorphisms, were analysed as a function of fasting glucose concentrations in non-diabetic patients and in Type II (non-insulin-dependent) diabetic patients. RESULTS: Serum paraoxonase-1 activities and concentrations were lower (p <0.05) in non-diabetic patients with abnormal fasting glucose concentrations. It was due to a higher frequency of low expressor paraoxonase-1 promoter genotypes in patients with abnormal glucose control. Promoter polymorphisms were independent determinants of abnormal fasting glucose concentrations. Low expressor genotypes were associated with higher glucose concentrations in non-diabetic patients (p = 0.046) and a trend to higher concentrations in Type II diabetic patients. The coding region paraoxonase-1 polymorphisms L55 M and Q192R was not associated with differences in fasting glucose. CONCLUSION/INTERPRETATION. The promoter polymorphism C(-107)T is a marker for abnormal fasting glucose concentrations in non-diabetic patients. It could indicate an active role for paraoxonase-1, possibly pre-disposing to insulin resistance, or linkage of paraoxonase-1 polymorphisms with other gene products implicated in glucose metabolism.

The apolipoprotein epsilon2 allele and the severity of coronary artery disease in Type 2 diabetic patients.

AIMS: To examine the hypothesis that apolipoprotein E2 is associated with more severe coronary disease in Type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In this retrospective cohort study, 491 patients with angiographically assessed coronary disease were recruited from those attending a university hospital cardiology department. Participants completed detailed questionnaires, from which the presence or absence of diabetes was determined. Fasting blood samples were obtained for apolipoprotein E genotype and measurement of blood lipid parameters. RESULTS: The prevalence of triple vessel disease was significantly lower in non-diabetic, epsilon2 allele carriers (39.3% vs. 16.2%; odds ratio (OR) 0.30 (0.12-0.71), P < 0.03) compared with E3/3 carriers. In Type 2 diabetic patients, epsilon2 allele carriers had an excess of triple vessel disease compared with E3/3 genotypes (43.3 vs. 68.8%; OR 2.8 (1.07-7.30), P < 0.05). The differences were independent of other variables. The apo E4 subgroup showed no significant differences in the frequency of triple vessel disease. CONCLUSIONS: Diabetic epsilon2 allele carriers had more severe coronary artery disease than diabetic patients with other apo E isoforms. In non-diabetic patients the epsilon2 allele appeared to protect against severe coronary disease. We hypothesize that interaction between the diabetic milieu and the epsilon2 allele accelerates plaque progression. It suggests that diabetic patients who are carriers of the epsilon2 allele, even in the heterozygous form, should be the focus of particular therapeutic attention. Diabet. Med. 18, 445-450 (2001)

Acute hyperinsulinemia and very-low-density and low-density lipoprotein subfractions in obese subjects.

BACKGROUND: The influence of hyperinsulinemia on concentrations of lipoprotein subfractions in obese, nondiabetic persons has not been clarified. OBJECTIVE: We analyzed VLDL and LDL subfractions before and after a euglycemic, hyperinsulinemic clamp. DESIGN: Lipoprotein subfractions were isolated from plasma samples obtained in the basal state and after a 4-h clamp from obese patients, obese patients with type 2 diabetes, and nonobese control subjects. RESULTS: Hyperinsulinemia tended to reduce concentrations (&xmacr;: 20%) of large, triacylglycerol-rich VLDL(1) in obese patients but had a minor effect on VLDL(2) and VLDL(3). Placing obese patients into insulin-sensitive and insulin-resistant subgroups revealed distinct effects of the degree of insulin sensitivity on VLDL. VLDL(1) concentrations decreased by a mean of 38% (P < 0.05) in insulin-sensitive patients after the clamp, similar to but less marked than the decrease observed in control subjects (&xmacr;: 62%; P < 0.01). VLDL(1) concentrations did not change significantly after the clamp in insulin-resistant patients (and patients with type 2 diabetes), whereas VLDL(3) concentrations decreased in both groups, in contrast with the changes seen in the insulin-sensitive patients and control subjects. Acute hyperinsulinemia modified the LDL subfraction profile toward a greater prevalence of small, dense LDLs in insulin-resistant patients and patients with type 2 diabetes. CONCLUSIONS: Insulin resistance appears to be the primary determinant of the modifications to VLDL subfraction concentrations. Our results suggest a continuum of impaired insulin action on VLDL, ranging from that in healthy persons to that in patients with type 2 diabetes, in which obese patients occupy a transition state. Insulin resistance may also play a role in detrimental modifications to the LDL profile by allowing the development of hypertriglyceridemia.