The effect of continuous subcutaneous insulin infusion (CSII) on very-low-density lipoprotein triglyceride (VLDL-TG) metabolism was studied in seven normolipidemic type I diabetic patients. VLDL-TG transport was determined using 3 H-glycerol as an endogenous precursor of VLDL-TG, and the resultant turnover curves were evaluated by multicompartmental analysis. Kinetic studies were performed in the diabetic patients during conventional insulin therapy and again after 3 wk of euglycemia achieved with CSII, and the results were compared with those obtained in 5 age-, weight-, and sex-matched normolipidemic nondiabetic subjects.After 3 wk of CSII, the mean (± SEM) 24-h plasma glucose levels in the diabetic patients decreased from 238 ± 1 5 mg/dl on conventional therapy to 99 ± 11 mg/dl (P < 0.05) on CSII therapy. The total glycosylated hemoglobin levels decreased from 10.2 ± 0.5 to 6.5 ± 0.4%. There was a significant decrease in fasting plasma cholesterol (172 ± 13 mg/dl to 136 ± 4 mg/dl), LDL cholesterol (104 ± 9 mg/dl to 82 ± 4 mg/dl), plasma triglyceride (114 ± 24 mg/dl to 71 ± 9 mg/dl), and VLDL-TG (68 ± 18 mg/dl to 37 ± 5 mg/dl) levels. There was no change in the HDL cholesterol concentration.Results of the kinetic studies in the conventionally treated diabetic patients revealed normal VLDL-TG transport rates and fractional catabolic rates (FCR). CSII caused a marked and significant fall in mean VLDL-TG transport rates (12.2 ± 3.5 to 4.1 ± 0.8 mg/h/kg IW, P < 0.05) to levels below those observed in the nondiabetic subjects (10.2 ± 2.1 mg/h/kg IW, P < 0.05).There was no change in the mean FCR with CSII. These data thus suggest that the mechanism responsible for the observed change in plasma triglyceride levels in normolipidemic type I diabetic patients that occurs with 3 wk of CSII treatment is due to suppression of hepatic VLDL-TG synthesis rather than the result of increased lipoprotein clearance. DIABETES 32:75-81, January 1983. H ypertriglyceridemia is a common clinical problem in patients with poorly controlled type I diabetes mellitus, 1 " 3 and this appears to be largely related to the degree of diabetic control. 4 " 6 Most often, plasma triglyceride levels return to normal with improved diabetic control; failure of plasma lipids to normalize with diabetic treatment suggests an underlying primary form of hyperlipidemia. 7 We have recently shown that 2-3 wk of euglycemia achieved by continuous subcutaneous insulin infusion (CSII) results in a significant decrease in plasma concentrations of cholesterol, triglyceride (TG), very-lowdensity lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterol in type I diabetic patients, 8 and that these changes persist for at least 6 mo if the CSII treatment is continued. 9 The present study was designed to evaluate the mechanism^) responsible for the observed decrease in plasma triglyceride concentrations resulting from CSII therapy. Kinetic studies of VLDL-TG metabolism were carried out in seven normolipidemic type I diabetic patients while they were hyperglycem...

Plasma lipid and lipoprotein-cholesterol levels were measured in 10 insulin-dependent (Type I) diabetics taking their usual dose of conventionally administered insulin during 6 months of a continuous subcutaneous insulin infusion delivered with a small, portable, battery-powered pump. With this insulin delivery system we were able to provide near normal glucoregulation 24 hours a day for the entire study. This improved glucoregulation resulted in significant reductions in total plasma cholesterol and triglyceride, and very low density and low density lipoprotein-cholesterol levels within 2 to 4 weeks of treatment. These changes persisted for the entire 6 months of observation. High density lipoprotein-cholesterol levels rose significantly after 2 months of treatment and continued to increase during the 6-month study. These changes in plasma lipid and lipoprotein-cholesterol levels in response to treatment with continuous subcutaneous insulin infusion would favorably alter the predicted risk for the development of premature atherosclerosis in these patients.

We studied the relation between the control of blood glucose and the width of skeletal-muscle capillary basement membrane in 23 insulin-dependent (Type I) diabetic patients. After initial measurement of levels of glycosylated hemoglobin and width of skeletal-muscle capillary basement membrane, the patients were divided into two groups: an experimental group of 13 patients who were treated with continuous subcutaneous insulin infusion, and a control group of 10 patients who continued to receive conventional treatment--usually two injections of insulin daily. After two years, the experimental group had a significant decrease in glycosylated hemoglobin levels as compared with base-line values (mean +/- S.E.M., 7.6 +/- 0.4 vs 10.2 +/- 0.7 per cent; P less than 0.001), reflecting improved control of blood glucose, and a significant reduction in the width of skeletal-muscle capillary basement membrane (1293 +/- 68 vs. 1717 +/- 182 A; P less than 0.05). The control group of patients had no significant change in their levels of glycosylated hemoglobin or in the width of their skeletal-muscle capillary basement membranes. If changes in the capillaries in skeletal muscle parallel those in the capillaries in retinal or renal tissue, then meticulous control of blood glucose may be beneficial over time in preventing the microvascular complications of diabetes.

A d d ress correspondence and reprint requests to James F. McLeod, MD, Clinical Pharm a c o l o g y, Novartis Pharmaceuticals Corporation, Route 10 East, East Hanover, NJ 07936. E-mail: james.mcleod@pharm a. n o v a rt i s. c o m .

We studied short-term changes in plasma lipid levels in type I diabetics treated with either a conventional insulin regimen or continuous subcutaneous insulin infusion. Mean plasma glucose dropped from 260 +/- 18 to 134 +/- 8 mg/dl when conventional treatment was used and from 194 +/- 18 to 108 +/- 8 mg/dl with CSII. Both forms of therapy were associated with a significant fall in plasma triglyceride levels. However, only CSII treatment produced significant changes in total plasma cholesterol and LDL cholesterol levels. Total cholesterol fell from 195 +/- 17 mg/dl to 161 +/- 11 mg/dl and LDL cholesterol fell from 129 +/- 13 mg/dl to 102 +/- 9 mg/dl. We conclude that improved diabetic control by any method is effective in lowering plasma triglyceride levels, but it requires almost perfect metabolic control to affect plasma cholesterol and LDL cholesterol levels. The changes in plasma lipid and lipoprotein achieved with CSII may favorably alter the prediction for the development of premature atherosclerosis in our patients.

To determine the hormonal status of somatostatin in man, plasma levels of approximately 1600-dalton somatostatin-like immunoreactivity (SLI) were measured before and after a mixed meal. Plasma was subjected to gel filtration and the fractions coeluting with somatostatin were concentrated ninefold before radioimmunoassay. In this system the recovery of synthetic somatostatin added to plasma averaged 71 +/- 4.6% (mean +/- SE, N = 5). Synthetic somatostatin infused into normal volunteers gave a dose-related increase in the measured SLI value. Fasting SLI in 13 normal volunteers was 8.0 +/- 0.7 pg/ml (mean +/- SE) and rose to 18.6 +/- 1.5 pg/ml and 20.3 +/- 2.0 pg/ml at 60 and 120 min, respectively, after the meal (P less than 0.001). In seven type I diabetics, the fasting level was 11.5 +/- 1.6 pg/ml and the 60- and 120-min postprandial levels were 21.4 +/- 2.5 and 22.3 +/- 2.9 pg/ml, respectively. The meal-induced rise in approximately 1600 M.W. SLI approximated that produced by infusing somatostatin at 2 microgram/h, a rate that significantly suppressed glucagon levels. These results are therefore consistent with a hormonal role for somatostatin in man.

The present study was designed to examine pancreatic and gastric D-cell function during the intestinal phase of a liver meal. The intraduodenal instillation of a 20% liver meal (5 ml/min) elicited a significant rise in the plasma levels of somatostatinlike immunoreactivity (SLI) in the pancreatic vein and inferior vena cava, together with the rise in glucagon and insulin levels. The rise in pancreatic vein SLI was not reduced after truncal vagotomy or during atropine infusion. In the stomach, the intestinal liver meal elicited a significant rise in antral but not fundic vein SLI levels. The rise in antral vein SLI was augmented after truncal vagotomy and abolished during atropine infusion, as was the rise in inferior vena caval SLI. In contrast to the protein meal, intravenous infusion of an amino acid mixture elicited a rise in pancreatic vein SLI but not antral or fundic vein SLI. It is concluded that during the intestinal phase of a protein meal, pancreatic and antral but not fundic SLI release is stimulated. The effects of truncal vagotomy and atropine infusion on these responses suggest a close interaction between the vagus and muscarinic cholinergic mechanisms and the D cells of the stomach and pancreas.

Near-normal glucoregulation was maintained in five patients with juvenile-onset diabetes mellitus for 4--5 wk with a preprogrammed, continuous, subcutaneous insulin infusion using a portable battery-powered infusion pump. This form of therapy significantly lowered immunoreactive glucagon (IRG) levels below those observed while on conventional insulin treatment at several times during the 24-h profile. The maximum IRG levels were also reduced in all five subjects. Thus, a flexible system of insulin delivery, as is provided by certain open-loop pump systems, can overcome inappropriate glucagon secretion that occurs with conventional insulin therapy.