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BRIEF REPORT |
Institut National de la Santé et de la Recherche Médicale, Unité 498 (L.D., E.F., J.-M.P., P.G., B.V.), and Department of Endocrinology and Metabolic Diseases (S.B.-R., M.-L.L.-M., A.B.-P., J.-M.P., J.-M.B., B.V.), Hôpital du Bocage, 21079 Dijon, France
Address all correspondence and requests for reprints to: Dr. Laurence Duvillard, Institut National de la Santé et de la Recherche Médicale, Unité 498, Hôpital du Bocage, BP 77908, 21079 Dijon Cedex, France. E-mail: laurence.duvillard{at}chu-dijon.fr.
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Abstract |
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Design: To check this hypothesis, we performed two apolipoprotein (apo) B100 kinetic studies in seven type 1 diabetic patients, first under sc insulin infusion and then 3 months after the beginning of ip insulin infusion.
Results: Glycemic control was similar under sc insulin infusion and ip insulin infusion, as assessed by glycated hemoglobin A1c and the capillary glycemic curve determined during the kinetic study. Very low-density and intermediate-density lipoprotein apoB100 pool size, production rate, and fractional catabolic rate (FCR) were similar under sc insulin infusion and ip insulin infusion. The low-density lipoprotein apoB100 FCR tended to decrease under ip insulin (0.45 ± 0.06 vs. 0.55 ± 0.11 pool/d), but the difference did not reach statistical significance (95% confidence interval for the difference, –0.33, 0.11). The low-density lipoprotein apoB100 pool size and production rate remained unchanged under ip insulin infusion compared with sc insulin infusion.
Conclusion: In type 1 diabetic patients, the replacement of sc insulin infusion with ip insulin infusion does not induce profound modifications of apoB100-containing lipoprotein production and FCRs.
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Introduction |
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The replacement of continuous sc insulin infusion (CSII) by continuous ip insulin infusion (CIPII) has been associated with modifications of lipoprotein triglyceride (TG) or cholesterol content, although changes are inconstant and sometimes controversial (2, 3, 4). Moreover, one study showed that the transition from sc to ip insulin induced a decrease in lipoprotein lipase (LPL) and cholesteryl ester transfer protein activities (5), and another study reported an increase in hepatic lipase activity (4).
A better knowledge of the impact of each insulin delivery route on lipoprotein metabolism in type 1 diabetic patients is critical to choose between the different therapeutic possibilities in the near future. To this end, we performed a stable isotope apoB100 kinetic study to compare the metabolism of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) in type 1 diabetic patients first treated by CSII and then by CIPII. Importantly, glycemic control was not modified by the change in insulin delivery route in the patients participating in our study, and we removed possible lipoprotein changes secondary to modifications in glycemic level.
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Patients and Methods |
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Seven type 1 diabetic patients (six men and one woman; mean age, 48 ± 6.5 yr) participated in this study. They had no diabetic complications (microalbuminuria, <20 µg/min) and were not taking any medication known to affect lipid metabolism. Two kinetic studies were performed in each subject, the first while patients were receiving CSII, then a second 3 months after the beginning of CIPII by an implantable pump.
CSII was accomplished using a 506 or 507 Minimed pump (Northridge, CA). Insulin infusion was continuous, with additional boluses administered at each mealtime. CIPII was accomplished using a 2007C or 2007A Minimed pump implanted sc in the abdomen, with the catheter inserted into the peritoneal cavity. Insulin infusion was continuous, with additional boluses administered at each mealtime.
The protocol was approved by the Dijon University Hospital ethics committee, and written informed consent was obtained from each subject before the study.
Experimental protocol
The kinetic study was performed in the fed state by the endogenous labeling of apoB with L-[1-13C]leucine (99 atom %; Eurisotop, Saint Aubin, France), as previously performed by our group (6, 7).
The usual basal insulin infusion was not modified during the kinetic study. Four boluses of insulin (4–6 U) were administered at 0800, 1200, 1800, and 2200 h. The same total amount of insulin was administered in the boluses as usual, except that it was fractionated into four, instead of three, boluses.
Kinetic analytical procedure
VLDL, IDL, and LDL were isolated from plasma by gradient ultracentrifugation, using an SW41 rotor in an L90 apparatus (Beckman Instruments, Palo Alto, CA). VLDL apoB was isolated by preparative SDS-PAGE, as described previously (7). IDL and LDL apoB was isolated by selective precipitation with butanol-isopropyl ether as previously described (8).
ApoB-100 was hydrolyzed, and amino acids were lyophilized and converted to N-acetyl-O-propyl esters (6, 7) before being analyzed on a Delta Plus Advantager isotope ratio mass spectrometer (Finnigan Mat, Bremen, Germany) for [13C]leucine enrichment measurement.
Modeling
Data were analyzed with the Simulation Analysis and Modeling II program (SAAM Institute, Inc., Seattle, WA) using the multicompartmental model (published in Ref.7).
The pool sizes of VLDL, IDL, and LDL apoB were calculated by averaging apoB measurements at four different times (0, 4, 8, and 12 h after the beginning of tracer infusion) and correcting them compared with plasma measurements. The same correction factor was applied to VLDL, IDL, and LDL apoB.
Biochemical analysis
Plasma glucose concentrations were measured by an enzymatic method (glucose oxidase) on a Vitros 950 analyzer (Ortho Clinical Diagnostics, Rochester, NY). Glycated hemoglobin A1c (HbA1c) was measured with ion exchange HPLC (Bio-Rad Laboratories, Richmond, CA). Total and HDL cholesterol, TG, and apoB concentrations were measured on a Dimension analyzer with dedicated reagents (Dade Behring, Newark, NE). ApoB was measured by immunoturbidimetry. The within-run coefficient of variation for that method was less than 5% at 2 mg/dl. Fructosamine was measured on the Dimension analyzer with ABX Diagnostics reagents (Montpellier, France).
Statistical analysis
Data are reported as the mean ± SD. Statistical calculations were performed using the StatView software package (SAS Institute, Inc., Cary, NC). Quantitative data for patients under CSII and CIPII were compared by the nonparametric Wilcoxon matched pair test. A two-tailed value of 0.05 was considered statistically significant. The 95% confidence intervals for the difference in means were reported before P values in parentheses.
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Results |
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Glycemic control was good in type 1 diabetic patients treated by CSII and was not modified after 3 months of CIPII, as assessed from HbA1c and fructosamine determinations (Table 1
). The daily insulin doses, including basal flux and boluses, were comparable between CSII and CIPII (Table 1). Figure 1 shows capillary glycemia in type 1 diabetic patients during the kinetic study and indicates that glycemic control was fair throughout the study for both CSII and CIPII. The mean glycemia values during the day of the kinetic were 150 ± 36 and 163 ± 40 mg/dl, respectively (95% confidence interval of CIPII-CSII, –37, 63; not significant).
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Plasma TG and total, LDL, and HDL cholesterol levels were normal during CSII and were not modified after 3 months of CIPII (Table 1
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ApoB100 kinetic parameters
Individual apoB100 kinetic data are presented in Table 2. VLDL and IDL apoB pool sizes, production rates, and fractional catabolic rates (FCRs) were similar in our type 1 diabetic patients treated by CSII and CIPII. LDL apoB FCR was lower by 18%, on the average, during CIPII compared with CSII. A decrease was observed in six to seven patients, but the difference did not reach statistical significance using a nonparametric test. Neither LDL apoB pool size nor LDL apoB100 production rate was significantly modified during CIPII compared with CSII.
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Discussion |
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Our study was performed in the fed state. This state influences apoB100 kinetic parameters compared with the fasted state (9). However, the fed state is the most frequent for humans over a 24-h period, which explains why we have chosen to study the metabolism of apoB in the fed state. The daily food intake was divided into small portions taken every 2 h starting 6 h before tracer perfusion to achieve steady-state VLDL, IDL, and LDL apoB concentrations (6).
The replacement of CSII with CIPII could have induced a change in the portal to peripheral gradient of insulin, modifying the effect of insulin on the different steps of hepatic TG metabolism and VLDL assembly, with modifications of VLDL apoB synthesis rate (10, 11, 12, 13, 14). Actually, we did not observe any difference between these two ways of insulin administration. Our results are similar to those previously reported in pancreas-transplanted patients with insulin delivery in either the portal vein or the peripheral system (15) and with those observed when comparing the effects of acute portal vs. peripheral insulin on the VLDL apoB production rate in healthy males (16). On the whole, kinetic data suggest either that portal insulinization did not change between CSII and CIPII or that the change was too moderate to induce modifications in the apoB VLDL production rate. Alternatively, the inducing effect of more free fatty acids delivered from adipose tissue on the TG and VLDL production rate could be counteracted by an increase in the suppressive effect of insulin on the hepatic VLDL production rate when CSII is replaced with CIPII (10, 11, 12). However, this hypothesis seems unlikely, because glycemic control was comparable during CSII and CIPII, indicating that hepatic glucogenesis was similarly controlled in both cases, and that portal insulinization did not change significantly.
Bagdade et al. (5) reported a decrease in LPL activity when CSII was replaced with CIPII. However, changes occurred in a normal range. Moreover, other studies were not able to show any significant modification of LPL activity in type 1 diabetic subjects receiving sc insulin therapy compared with controls (3, 17). Thus, the lack of modification in VLDL FCR when CSII was replaced with CIPII in our study may not be surprising. We did not measure LPL activity in our study and cannot totally exclude a lack of variation between the two routes of insulin administration, but we can hypothesize that variations in LPL activity in the normal range are not necessarily accompanied by changes in VLDL FCR, especially in normotriglyceridemic subjects (18).
LDL FCR decreased in six to seven patients between CSII and CIPII. This difference did not reach statistical significance due to the small number of patients participating in our study. The reasons for such a decrease are not clear. LDL composition did not change between the two regimens of insulin administration (data not shown). Therefore, a change in LDL affinity to their receptor between CSII and CIPII is very unlikely. A decrease in portal insulinization during CIPII compared with CSII would be able to explain a decrease in LDL FCR after a decrease in hepatic LDL receptor expression. However, this hypothesis is very unlikely, because glycemia was satisfactory during CIPII, indicating that hepatic glucogenesis is well controlled. Subcutaneous insulin infusion usually induces peripheral hyperinsulinism. Because insulin up-regulates LDL receptor expression, peripheral hyperinsulinism may stimulate the expression of LDL receptors on extrahepatic tissues during CSII, and this could explain the higher LDL FCR we observed during CSII compared with CIPII (19). However, this hypothesis needs to be proved by additional experimentation.
A limitation of this study is the possible lack of power due to the limited number of recruited subjects. Only a few type 1 diabetic patients are treated by implantable pump, which explains why studies of ip insulin infusion usually include only a few patients.
In summary, we could not show any modification of VLDL and IDL apoB production rates or FCRs 3 months after the replacement of CSII with CIPII in type 1 diabetic patients, indicating that the change in the gradient between the portal vein and the peripheral circulation that occurs concomitantly has no profound effect on VLDL and IDL metabolism. For LDL apoB, we observed a trend toward a decrease in the FCR, but the reasons for this decrease remain unclear.
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Acknowledgments |
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Footnotes |
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First Published Online August 9, 2005
Abbreviations: apoB, Apolipoprotein B; CIPII, continuous ip insulin infusion; CSII, continuous sc insulin infusion; FCR, fractional catabolic rate; HbA1c, hemoglobin A1c; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; TG, triglyceride; VLDL, very low-density lipoprotein.
Received May 5, 2005.
Accepted July 29, 2005.
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) and CIPII (
). Vertical arrows indicate the times of boluses of insulin (4–6 U).