Very low density lipoprotein metabolism after insulin over-treatment and during a euglycaemic clamp

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Abstract
The disturbance of very low density lipoprotein (VLDL) metabolism that occurs as a result of intensive insulin treatment and during a euglycaemic clamp have been investigated in a rat model. Normal rats were maintained with fed blood glucose levels below 5 mmol l-1 for 8 weeks by subcutaneous insulin injections (normal fed levels 5.8 .+-. 0.4 (SD) mmol l-1). Glucose requirement to maintain a glucose clamp was significantly reduced (116 .+-. 3 .mu.mol min-1 kg-1 (SE) vs. 173 .+-. 5 .mu.mol min-1 kg-1, P < 0.001), compared with weight-matched normal control rats. In the fasting state (blood glucose 3.5 .+-. 0.2 mmol l-1 vs. 3.9 .+-. 0.1 mmol l-1, NS) plasma non-esterified fatty acid levels were reduced. Fasting VLDL-triglyceride turnover, measured by bolus injection of 14C-VLDL, was also lower (3.17 .+-. 0.12 .mu.mol min-1 kg-1 vs. 3.50 .+-. 0.07 .mu.mol min-1 kg-1, P < 0.05). Despite decreased turnover, insulin over-treated rats had normal plasma triglyceride concentrations indicating a removal defect. At the end of a 3-h euglycaemic clamp, plasma triglyceride concentrations of VLDL-triglyceride turnover were decreased in both normal control and insulin over-treated animals, and turnover remained significantly lower in the insulin over-treated rats (2.59 .+-. 0.13 .mu.mol min-1 kg-1 vs. 3.08 .+-. 0.10 .mu.mol min-1 kg-1, P < 0.05). Triglyceride metabolic clearance rate remained abnormally low in the insulin overtreated animals (4.06 .+-. 0.10 ml min-1 kg-1 vs. 5.91 .+-. 0.17 ml min-1 kg-1, P < 0.001). This was associated with a significant decrease in skeletal muscle lipoprotein lipase activity in both the fasting state and at the end of the clamp. Adipose tissue lipoprotein lipase activity was not different between the two groups under these conditions, and did not change with the clamp. In ad libitum fed rats adipose tissue lipoprotein lipase activities were much higher than during the clamps, particularly in the insulin overtreated animals (47.4 .+-. 1.5 vs. controls 28.5 .+-. 1.7 U g-1 wet wt, P < 0.001). The findings indicate that long term over-insulinization is associated with insulin insensitivity, decreased quadriceps muscle lipoprotein lipase activity, and decreased plasma VLDL-triglyceride clearance.

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