Showing papers by "K. G. M. M. Alberti published in 1987"

Basal and 24-h C-peptide and insulin secretion rate in normal man.

Abstract: An understanding of the metabolic abnormalities rising from inappropriate insulin delivery in diabetic patients demands a knowledge of 24-h and basal insulin secretion rates in normal man. We have used biosynthetic human C-peptide to determine its kinetic parameters in 10 normal subjects and applied these to measurements of plasma concentrations in the same subjects to determine pancreatic secretion rate. Metabolic clearance rate measured by stepped primed infusion of biosynthetic human C-peptide at rates of 10, 19 and 26 nmol/h was 4.7 +/- 0.7 (+/- SD) ml X kg-1 X min-1, and was independent of infusion rate. Fractional clearance (T1/2, 26 +/- 3 min) and distribution volume (0.178 +/- 0.039 l/kg) were calculated from the decline in concentration after cessation of the highest rate infusion. Basal insulin secretion calculated from the C-peptide metabolic clearance rate and plasma concentrations for the period 02.00 to 07.00 hours was 1.3 +/- 0.4 U/h. Over 24 h total insulin secretion on a standard high carbohydrate diet was 63 +/- 15 U, calculated from the area under the C-peptide concentration curve. Basal insulin secretion, therefore, accounted for 50 +/- 8% of total insulin secretion. Although only 5.6 +/- 1.1% of C-peptide was detected in 24-h urine collections, urinary C-peptide excretion was significantly related to 24-h C-peptide secretion (r = 0.74, p less than 0.02).

Carnitine acyltransferases and acyl-CoA hydrolases in human and rat liver

Abstract: The activities of carnitine acyltransferases and acyl-CoA hydrolases were determined in human and rat liver to establish the validity of extrapolating from studies on rats to human metabolism. In human liver, carnitine acetyltransferase activity was 10-14 times higher and carnitine octanoyltransferase 1.7-2.4 times higher than in rat liver, while carnitine palmitoyltransferase activity was similar in human and rat. Acetyl-CoA hydrolase and octanoyl-CoA hydrolase activities were lower in human (42-57%) than in rat liver, but palmitoyl-CoA hydrolase activity was similar in both species. The activity of citrate synthase was lower (44%) in human than in rat liver. The low citrate synthase activity and the high carnitine acetyltransferase in human liver suggest that in man acetylcarnitine might be more important as a vehicle for export of acetyl units from mitochondria than citrate. The high activity of carnitine acetyltransferase in human liver is consistent with the observation that acetylcarnitine is the predominant acylcarnitine excreted in diabetic ketosis in man. It is concluded that the rat may not be a valid model for carnitine metabolism in man, and that in human liver carnitine may have an important role in transfer of acetyl groups out of mitochondria and possibly also to extra-hepatic tissues.

Insulin insensitivity and skeletal muscle enzyme activities in response to overinsulinization in the rat.

Abstract: Periods of overinsulinization with low blood glucose levels are a recognized feature of intensive insulin injection therapy. The relationship of these features to insulin insensitivity is controversial, and the mechanisms underlying any such changes are unclear. Normal rats have therefore been overinsulinized for 6 weeks before measurement of in vivo insulin sensitivity by the glucose clamp technique. Skeletal muscle glycogen synthase and pyruvate dehydrogenase activities were measured at the end of the clamp. Sensitivity to insulin as measured by the glucose clamp technique at euglycemic levels was decreased in the insulin overtreated animals (glucose requirements, 108 ± 2 μmol/min/kg v 170 ± 10 μmol/min/kg, P < 0.001). Total skeletal muscle glycogen synthase activity was increased in the experimental group (2.83 ± 0.12 v 1.96 ± 0.14 U/g wet weight, P < 0.001), and as a result the active fraction was higher at the end of the clamp (0.79 ± 0.04 v 0.66 ± 0.04 U/g wet weight, P < 0.05). Skeletal muscle glycogen content was consistent with the glycogen synthase activity. Pyruvate dehydrogenase in the same tissue showed increased activation prior to the clamp (6.6 ± 0.6 v 4.7 ± 0.6%, P < 0.05), but neither active nor total activity was abnormal at the end of the clamp. Thus overinsulinization decreases insulin sensitivity, but this change cannot be accounted for by changes in the activities of these two key enzymes of glucose disposal.

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

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 pL 0·4 (SD) mmol l-1). Glucose requirement to maintain a glucose clamp was significantly reduced (116 pL 3 μmol min-1 kg-1 (SE) vs. 173 pL 5 μmol min-1 kg-1, P < 0·001), compared with weight-matched normal control rats. In the fasting state (blood glucose 3·5 pL 0·2 mmol l-1 vs. 3·9 pL 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 pL 0·12 μmol min-1 kg-1 vs. 3·50 pL 0·07 μmol 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 and 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 pL 0·13 μmol min-1 kg-1 vs. 3·08 pL 0·10 μmol min-1 kg-1, P < 0·05). Triglyceride metabolic clearance rate remained abnormally low in the insulin overtreated animals (4·06 pL 0·10 ml min-1 kg-1 vs. 5·91 pL 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 pL 1·5 vs. controls 28·5 pL 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-trigylceride clearance.