Insulin resistance is characterized principally by impaired insulin-mediated glucose uptake which provokes a compensatory increase in pancreatic B-cell secretory activity. For a time this may produce well-controlled plasma glucose levels but as the insulin resistance worsens the augmented insulin production becomes inadequate to keep plasma glucose at euglycemia leading to the development of non-insulin dependent diabetes mellitus (NIDDM), accompanied by hyperinsulinemia and hyperglycemia. A number of metabolic defects are associated with NIDDM including obesity, hypercoagulability, cardiovascular disease risk factors such as hypertension and dyslipidemia and these constitute the insulin resistance syndrome. The identity of the biochemical factor that might link all these defects is not yet known. We have hypothsisized that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine PAF) may be such a link. In this study, we measured plasma acetylhydrolase (EC.1.1.48), which degrades PAF to the inactive metabolise lyso-PAF, as a surrogate for PAF activity in three groups of hypercholesterolemic subjects: lean controls (n = 9), non-diabetic obese (n = 6) and NIDDM subjects (n = 6). The ages and body mass indices of the subjects were 46 ± 3.1 and 24.2 ± 2.2 for the lean controls, 52 ± 2.5 and 28.7 ± 0.9 for the NIDDM subjects and 60 ± 2 and 27.6 ± 2.1 for the obese, non-diabetic subjects (mean ± S.E.M.). The measurements were made before and after therapy with the cholesterol-lowering drug lovastatin, a 3-hydroxy 3 methylglutaryl (HMG) coenzyme A reductase inhibitor (40 mg/day) for months. Fasting plasma glucose (FPG) levels were 91 ± 11, 96 ± 3 and 146 ± 11 mg/dl, for the lean, obese and NIDDM subjects, respectively, before therapy began. Lovastatin did not affect FPG in any of the three subject groups. Before treatment, the fasting plasma insulin (FPI) levels were 6.1 ± 0.92, 10.83 ± 2.03 and 14.68 ± 3.64 mU/l for the lean, non-diabetic obese and NIDDM subjects, respectively. After lovastatin therapy only the obese group exhibited a significant change in FPI (15.35 ± 2.47 mU/l) (P < 0.05). Total cholesterol levels were similar in all three groups both before and after lovastatin therapy but within each group lovastatin therapy significantly reduced the total cholesterol by 32, 29 and 34% in the lean, obese and NIDDM subject groups respectively (P < 0.0001). Lovastatin therapy reduced LDL-cholesterol levels by 40, 32 and 46% in the lean, obese and NIDDM subjects, respectively, but produced no significant effect on HDL or triglyceride levels. Before therapy, the plasma acetylyhydrolase activities were 104 ± 7, 164 ± 7 and 179 ± 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Lovastatin therapy reduced plasma acetylhydrolase levels to 70 ± 7, 87 ± 6 and 86 ± 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Plasma acetylhydrolase activity was predominantly (> 80%) associated with LDL cholesterol both before and after lovastatin treatment. Also, plasma acetylhydrolase activity significantly correlated with fasting plasma insulin levels before lovastatin therapy but not after. Taken together, this study clearly implicates PAF metabolism in three defects associated with the insulin resistance syndrome; hypercholesterolemia, obesity and NIDDM. Additionally, we conclude that chronic hyperinsulinemia may play a significant role in the production of plasma acetylhydrolase.
- PAF acetylhydrolase
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