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Diabetes Care 26:1390-1394, 2003
© 2003 by the American Diabetes Association, Inc.

Epidemiology/Health Services/Psychosocial Research
Original Article

Transfer of Insulin Lispro Across the Human Placenta

In vitro perfusion studies

Rada Boskovic, MD1, Denice S. Feig, MD2, Lidia Derewlany, PHD1, Brenda Knie, RT1, Galina Portnoi, MD1 and Gideon Koren, MD1

1 Division of Clinical Pharmacology and Toxicology, the Hospital for Sick Children, Toronto, Ontario, Canada
2 Department of Endocrinology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
OBJECTIVE—Insulin lispro (Humalog), a human insulin analog, has a more rapid onset, earlier peak, and shorter duration of glucose lowering activity than regular human insulin. However, it is not known whether insulin lispro crosses the human placenta and reaches the fetus. Therefore, the objective of the present study was to examine whether insulin lispro crosses the placenta using the technique of perfusing a human placental lobule in vitro.

RESEARCH DESIGN AND METHODS—Term human placentae from uncomplicated pregnancies were obtained immediately after delivery. Insulin lispro, at concentrations ranging from 100 to 1000 µU/ml, was introduced into the maternal reservoir. The maternal side of the placenta was perfused with constant concentration of lispro insulin; the fetal circulation was closed. Samples were drawn from both the maternal and fetal circulations at regular intervals. The appearance of insulin lispro in the fetal circulation was analyzed by a specific radioimmunoassay.

RESULTS—No placental transfer of lispro could be detected during perfusion with 100 and 200 µU/ml. In contrast, there was a small concentration-dependent transfer to the fetus at concentrations of 580 µU/ml and higher, detectable after at least an hour of constant concentration of insulin lispro during perfusion. The rate of placental transfer was 0.019 µU · min-1 · g tissue-1 at maternal levels of 580 µU/ml and 0.045 µU · min-1 · g-1 tissue at maternal levels of 1000 µU/ml. Measuring lispro levels in 11 pregnant women revealed that a dose of 50 units may achieve serum concentrations >200 µU/ml with apparent linear correlation between dose and levels.

CONCLUSIONS—Insulin lispro is not likely to cross the placenta at a single standard dose. This study suggests that insulin lispro is unlikely to reach or harm the unborn baby.

Abbreviations: hCG, human chorionic gonadotrophin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Insulin lispro is an insulin analog in which two amino acids, lysine and proline, on the B-chain are reversed. This results in a weaker tendency for self-association after subcutaneous injection, allowing for more rapid absorption of the insulin, faster onset, and shorter duration of action when compared with regular human insulin (1,2). Studies of insulin lispro have confirmed that postprandial glucose levels are lower using insulin lispro compared with regular human insulin, independent of HbA1c level (2). This may be important in pregnancy where high postprandial glucose levels can lead to fetal macrosomia (3). Adjustment of insulin therapy in gestational diabetes to normalize postprandial glucose levels leads to normalized birth weight and lower rates of cesarean sections (4). There is also evidence that the use of insulin lispro is associated with a reduction in the frequency of hypoglycemia compared with regular human insulin (5). In a meta-analysis of eight large clinical trials comparing insulin lispro to regular human insulin, the frequency of severe hypoglycemic episodes was lower in patients taking insulin lispro (6). There is an increased risk of severe hypoglycemic episodes in pregnancy (7), hence strategies to reduce this risk now include the use of insulin lispro. In a randomized double-blind trial of insulin lispro versus human regular insulin using a continuous subcutaneous insulin infusion, patients using insulin lispro had significantly lower HbA1c levels (8).

Whereas early in vitro studies suggested that insulin does not cross the human placenta (9), a subsequent placental perfusion study demonstrated that a small amount of human insulin, representing 1–5% of the insulin concentration in the maternal artery, was transferred from the maternal to the fetal circulation (10). The concentrations of insulin used in that experiment (59, 104, 448, and 1,198 µU/ml) would, based on an assumption of linear pharmacokinetics, correspond to peak serum insulin levels achieved after subcutaneous injection doses of ~14, 24, 104, and 278 units of insulin, respectively (1). In addition, there is some evidence that beef-pork–insulin antibody complexes can cross the placenta leading to neonatal macrosomia (11). Currently, there is limited information on the placental transfer of insulin lispro. The potential consequences of placental transfer include the risk of neonatal hyperinsulinemia and hypoglycemia. Animal studies suggest that hypoglycemia may cause teratogenesis (12). There has been a recent report of congenital anomalies in the offspring of two women taking insulin lispro throughout pregnancy, despite optimal glycemic control (13). However, no causal relation with insulin lispro was established. In studies with insulin lispro in pregnant rats and rabbits, no evidence of impaired fertility or harm to the fetuses was observed with doses as high as four times the average dose in humans (14). The objective of the present study was to examine whether insulin lispro crosses the placenta using the technique of perfusing a human placental lobule in vitro.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
Study design
The eight human placentae were obtained after vaginal or cesarean section delivery from uncomplicated term pregnancies and transported to the laboratory in heparinized ice-cold PBS. Independent maternal and fetal circulations were established to a peripheral placental lobule within 30 min of the delivery of the infant, as previously described by our laboratory (15).

After residual blood was cleared out of the vessels and intervillous space, a 1-h "closed" (recirculated) circuit control period preceded the experimental period. During the control period, glucose and oxygen consumption and lactate and human chorionic gonadotrophin (hCG) production were measured to determine the baseline of these values for each experiment. All values measured were compared with those of the initial control period to ensure the maintained integrity of the placental preparation throughout the course of the perfusion experiment.

The physical integrity of the placental preparation was assessed by monitoring the stability of the fetal perfusion pressure and volume loss from the fetal reservoir; increases or decreases in pressure (>10 mmHg) and volume loss (>3 ml/h) were criteria for rejection of the preparation. After the 1-h control period, the perfusates in both the maternal and fetal circulations were replaced with fresh media, and insulin lispro at a concentration of 100 µU/ml was introduced into the maternal reservoir in four experiments. In four additional perfusion experiments, the concentrations of insulin lispro in the maternal circulation were 200, 580, and 1,000 µU/ml. The maternal circuit was "open" (nonrecirculated) to deliver a constant concentration of drug to the lobule, while the fetal circuit was "closed" (recirculated).

Samples were obtained from the fetal reservoir and the maternal artery and vein every 20 min for the first 2 h and subsequently every 30 min for the last 2 h to measure insulin lispro, antipyrine, lactate, glucose, and hCG concentrations. Antipyrine is a freely diffusible flow-dependent transfer marker to which drug transfer is commonly compared. Oxygen, glucose consumption, and lactate production were measured during the perfusion to confirm that the tissue maintained its ability for energy metabolism. After 4 h of perfusion with insulin lispo, the perfusates in both maternal and fetal reservoirs were replaced again with fresh media and circulations "closed" for a final 1-h control period. All values measured were compared with those of the initial control period to ensure that the integrity of the preparation was maintained during perfusion.

Sample analysis
Perfusate samples were kept at -20°C until analysis. The concentrations of insulin lispro were measured using the insulin lispro competitive-binding radioimmunoassay with overnight equilibrium incubation at room temperature (Linco Research, St. Charles, MO). This assay is highly specific for insulin lispro (100%) and has negligible cross-reactivity with native human insulin or proinsulin (<0.5%). Whereas the limit of quantitation is quoted at 2.5 µU/ml for a 100-µl sample using the manufacturers’ kit, in blank samples of fetal buffer we measured levels of 5.89 µU/ml. Hence, we used this concentration to subtract from all apparent levels measured during the experiment in the fetal circulation. pH and pO2 of the perfusate samples were measured by using a blood gas analyzer (Radiometer ABL 330; Radiometer, Copenhagen). The perfusate concentrations of lactate, glucose, and hCG, as well as tissue hCG content, were measured as described previously in our laboratory (15). Antipyrine concentrations were determined spectrophotometrically.

Statistical analysis
The mean fetal concentration-time relation was plotted graphically. Least square regression analysis was used to study the relation between measured fetal drug concentration and time. The rate of appearance on the fetal circulation was calculated by the mean of the slope of insulin lispro appearance (in microunits) versus time (in minutes) and expressed as microunits per minute per grams of tissue. Comparisons among values were made using the Student’s t test.

In vivo studies
In 11 women 31–40 years of age, we measured serum insulin lispro levels 60 min after subcutaneous injection of a single lispro dose of 3–52 units. Of 11 women, 9 were pregnant, 2 had gestational diabetes, 5 had type 1 diabetes, and 3 had type 2 diabetes. One of nine women was in the first trimester, and the others were in the second or third trimester of pregnancy.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
The mean mass of the perfused cotyledons was 11.8 ± 3.4 g. Placental glucose and oxygen consumption and oxygen delivery and transfer as indicators of metabolic viability of the placental tissue did not change significantly throughout the perfusion experiment (Table 1). The fetal inflow pressures were not different between the control and experimental periods. The overall rate of lactate production during the control period was 0.39 ± 0.21 µmol/ml, significantly higher than the rate of lactate production during the experimental period (0.18 ± 0.04 µmol/ml, P = 0.015). This is most likely due to the washout of lactate that accumulated in the tissue during the period of hypoxia after delivery.


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  		Table 1— Parameters of viability during in vitro perfusion of the human placental cotyledon

 
During the 4-h experimental period with a constant concentration of 100 and 200 µU/ml of insulin lispro on the maternal side of the placenta, insulin lispro was undetectable in the fetal side of the placenta. At higher concentrations of insulin lispro in the maternal circulation (580 and 1,000 µU/ml), insulin lispro accumulated linearly in the closed fetal circulation (Fig. 1). The accumulation of insulin lispro on the fetal side started after 80 min for the 580-µU/ml concentration and 60 min for the 1,000-µU/ml concentration. The mean calculated rate of insulin lispro transfer was 0.045 µU · min-1 · g tissue-1 at circulating maternal level of 1,000 µU/ml and 0.019 µU · min-1 · g tissue-1 at 580 µU/ml (Table 2).



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  		Figure 1— Time course of insulin lispro appearance in the fetal circulation during 4 h of perfusion with maternal circuit opened and fetal closed. MR, maternal reservoir concentrations. {square}, MR 580 µU/ml; {blacktriangleup} MR 1,000 µU/ml.

 

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  		Table 2— Maternal to fetal transport of insulin lispro

 
In vivo studies
In 11 women treated with insulin lispro, serum levels of insulin lispro ranged from 2 to 576 µU/ml with an apparent linear correlation (Fig. 2). One woman receiving 52 units achieved a level of 576 µU/ml.



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  		Figure 2— Dose versus serum levels of lispro. Each data point in the chart represents a single measurement.

 

   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
The placental perfusion model enables the noninvasive collection of information regarding human placental transfer of molecules (15). Because transfer is measured in intact tissue, the model approximates the in vivo situation more closely than subcellular or cell culture systems. Importantly, it obviates the enormous ethical hurdles of studying human placental transfer in vivo. At the end of normal pregnancy, postprandial insulin levels are elevated and plasma insulin concentration may reach 100–200 µU/ml (16).

In the current study, we chose an insulin lispro concentration of 100 µU/ml as our baseline level to mimic the peak levels typically measured after administration of ~13 units of insulin lispro to healthy volunteers (2). Assuming linear pharmacokinetics, the higher concentrations used in our experiment (200, 580, and 1,000 µU/ml) would correspond to peak serum insulin levels achieved after subcutaneously administered doses of ~26, 75, and 130 units of insulin lispro, respectively (1). There is an increased need for insulin throughout pregnancy. Women with type 1 diabetes require on average 1.2 units/kg insulin per day; however, the range is broad (16). Women with type 2 diabetes often require larger doses. In one study, women with type 2 diabetes required on average 1.6 units/kg a day or ~150 units of insulin per day. Women who are very obese may even start with 2 units/kg a day, requiring larger doses as the pregnancy progresses (17). Because a typical multiple daily insulin regimen may include ~40–60% of the total insulin dose used as a short- or rapid-acting insulin analog, a patient with type 1 diabetes in pregnancy may require up to 10–18 units of insulin lispro per meal and a patient with type 2 diabetes in pregnancy potentially requiring up to 20–30 units of insulin lispro per meal. For those women who are very obese and/or very insulin resistant, requirements can go up to 40–60 units of insulin lispro per meal. Among 11 women monitored by us, serum lispro levels were <200 µU/ml in all those receiving <50 units, whereas higher doses had concentrations associated with placental transfer of the hormone.

The two lower concentrations of insulin lispro used in our experiments (100 and 200 µU/ml) correspond to peak plasma insulin levels achieved after subcutaneous administration of ~13 and 26 units of insulin lispro and suggest that these results are clinically relevant (17). The higher two concentrations (580 and 1,000 µU/ml) would correspond to subcutaneous doses of insulin lispro of ~75 and 130 units, respectively, which are less likely to be utilized clinically.

Our study demonstrated a small placental transfer of insulin lispro at higher concentrations, after at least 60 min of constant concentration in the maternal reservoir. This experimental condition of maintaining high levels in the maternal circulation for several hours does not occur in the clinical setting due to the short elimination half-life of insulin lispro. Hence, even the transfer of insulin lispro shown by us in excessive maternal levels with constant concentration on maternal side is not likely to occur in vivo.

Lack of transfer of insulin lispro across the placenta was suggested in a study of insulin lispro in women with gestational diabetes (18). In that study, four women received an intravenous infusion of insulin lispro at a dose of 0.2 units · kg-1 · h-1 during labor, and no insulin lispro was detected in the umbilical cord blood of their infants. In our study, maternal insulin lispro concentrations of >=580 µU/ml led to a small transfer of insulin lispro across the placenta. To put the results of our study in context, one should compare the placental transfer of insulin lispro to that of human insulin. In a single study by Challier et al. (10), human insulin was shown to appear in the fetal circulation after its introduction in the maternal reservoir. The measured levels by Challier et al., using the same perfusion model that we used, appear to be higher than those measured by us for insulin lispro. In their study, Challier et al. did not address the possibility that the low levels of fetal insulin were due to contamination by the residual blood in the perfused cotyledon. To address this question, we have now measured human insulin levels at the beginning of our perfusion experiment (before insulin lispro was introduced) and thereafter. Insulin levels, measured by a sensitive radioimmunoassay, were below the detection limits. This lends further credibility to the results by Challier et al. showing that human insulin does cross the placenta. Hence, it appears that small amounts of insulin cross the placenta when both human insulin and insulin lispro are present at clinically high concentrations.

Although the use of third-trimester placentae might be considered a potential limitation to our study, there is evidence to suggest that the qualitative aspects of transfer do not differ between placentae taken at earlier versus later phases of gestation (19).

The placentae of diabetic mothers may exhibit chronic disturbance in intervillous circulation, dilatation of capillaries, and relatively immature villous structure. The impact of these changes on the placental transfer of regular insulin or insulin lispro is unknown.

In summary, when used clinically, insulin lispro is not likely to cross the human placenta. There is a small dose-dependent transfer of insulin lispro across the term human placenta at concentrations >=580 µU/ml. These concentrations likely correspond to peak insulin levels achieved with high doses of insulin lispro at ~75 units or higher. Only in very rare situations would diabetic women receive doses that would lead to sustained plasma levels sufficiently high (580 µU/ml) for fetal exposure.

The marginal magnitude of the transfer of insulin lispro in terms of amounts, appears to be less than that shown by others to occur with similar concentrations of human insulin, and hence suggests that insulin lispro does not pose a risk for the fetus.


   Acknowledgments
 
This study was supported by grants from the Canadian Institute of Health Research (CIHR), by Eli Lilly Canada, and by the Research Leadership for Pharmacotherapy During Pregnancy and Lactation. G.K. is a senior scientist of CIHR. R.B. is supported by a Fellowship from the Canadian Society for Clinical Pharmacology.

We thank Loren Grossman, MD, for his valuable comments.


   Footnotes
 
Address correspondence and reprint requests to Gideon Koren, MD, FACMT, FRCPC, Division of Clinical Pharmacology/Toxicology, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. E-mail: gkoren{at}sickkids.ca.

Received for publication 7 October 2002 and accepted in revised form 10 February 2003.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.


   References
TOP
 ABSTRACT
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. Howey DC, Bowsher RR, Brunelle RL Woodworth JR: Lys(B28), Pro(B29)-Human insulin: a rapidly absorbed analog of human insulin. Diabetes 43:396–4021, 1994[Abstract]
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